Diabetic ketoacidosis in pregnancy Mary Anne Carroll, MD; Edward R. Yeomans, MD Objective: The development of diabetic ketoacidosis in pregnancy is a medical emergency, requiring treatment in an intensive care setting. Both the mother and the fetus are at risk for significant morbidity and mortality. Physiologic changes unique to pregnancy provide a background for the development of diabetic ketoacidosis. An understanding of these physiologic changes assists in the management of the two patients being treated. Treatment of the patient with diabetic ketoacidosis includes insulin therapy and careful fluid management; recommendations for management are presented. F ortunately for obstetricians and intensivists, the vast majority of women who become pregnant are both young and healthy. Of the relatively small percentage of pregnant women with pregestational medical complications, an even smaller group will experience what we would call a medical emergency, that is, a condition that poses an immediate threat to the life of mother, fetus, or both. Diabetic ketoacidosis (DKA) is such an entity. Once diagnosed, the first order written by the admitting physician should be “Admit to ICU.” In our review of this important subject, we will attempt to present useful information to two groups of readers: a) physiologic changes unique to pregnancy for the medical intensivist, because these changes affect management; and b) a “cookbook” algorithm of medical management for the obstetrician who may have to provide emergency care before consulting an intensivist. Again, fortunately for us, the incidence of DKA in pregnancy has declined substantively over the years, and so has the perinatal mortality (Table 1) (1–5). However, the From the Department of Obstetrics, Gynecology and Reproductive Science, University of Texas Health Science Center-Houston, Houston, TX. The authors have no financial or ethical conflict of interest regarding the contents of this submission. Copyright © 2005 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000183164.69315.13 Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) Patients: Pregnant women, either with preexisting diabetes or with diabetes diagnosed during pregnancy. Conclusions: Prompt recognition of the clinical manifestations of diabetic ketoacidosis, followed by appropriate, timely treatment will optimize outcome for the pregnant woman and her fetus. (Crit Care Med 2005; 33[Suppl.]:S347–S353) KEY WORDS: diabetic ketoacidosis; pregnancy; anion gap; osmotic diuresis; ketone bodies; acidosis; dehydration; nitroprusside test; insulin importance of providing prompt, effective medical care is unaltered or perhaps even increased, due to the unrealistic expectation for a perfect outcome for all pregnancies. creases with advancing gestation. Insulin dose adjustments may not keep pace with increasing requirements, a fact that may explain the higher incidence of DKA in the second and third trimesters of pregnancy (9). Adaptation to Pregnancy A detailed account of physiologic changes induced by pregnancy is presented elsewhere in this supplement. Here we review only a few pertinent facts. The acid-base state of pregnancy is a compensated respiratory alkalosis. Normal pH is 7.43, PCO2 is 30 mm Hg, and bicarbonate is 19 –20 mEq/L. The drop in bicarbonate occurs to compensate for the primary respiratory alkalosis. This reduction in buffering capacity renders the pregnant woman more susceptible to metabolic acidosis, particularly DKA. Normal pregnancy is a diabetogenic state, marked by relative insulin resistance, enhanced lipolysis, elevated free fatty acids, and ketogenesis (6). Ketone bodies can be demonstrated in the serum and urine of normal pregnant women throughout the antepartum period (7). Several hormones produced in pregnancy, including human placental lactogen, progesterone, and cortisol, impair the action of maternal insulin and contribute to this diabetogenic state. Insulinase, of placental origin, further depletes maternal insulin (8). For these reasons, insulin production by the pancreas is augmented during normal pregnancy. If the woman is a known diabetic, the requirement for exogenous insulin also in- Pathophysiology An overview of the complex pathophysiologic process leading to DKA is provided in Figure 1 (10). DKA results from inadequate insulin action and a failure of glucose utilization at the cellular level. With insulin deficiency, the cell is unable to use glucose as an energy substrate. Insulin counterregulatory hormones are released in response to this metabolic condition; glucagon, catecholamines, cortisol, and growth hormone act on insulin-sensitive tissues to facilitate the production of alternative substrates for cellular metabolism, using carbohydrates, proteins, and lipids. Muscle, adipose tissue, and liver are the insulin-sensitive tissues that respond to both the decrease in insulin as well as the increase in counterregulatory hormones seen in DKA. Decreasing glucose utilization in muscle results in hyperglycemia. Additionally, protein catabolism provides free amino acids for gluconeogenesis. In adipose tissue, the combination of decreased insulin and increased counterregulatory hormones results in the activation of hormone-sensitive lipase. This enzyme acts on triglycerides stored in the adipocyte, releasing free fatty acids in S347 Table 1. Incidence of diabetic ketoacidosis in pregnancy Lufkin et al. (1) Kilvert et al. (2) Montoro et al. (3) Chauhan et al. (4) Cullen et al. (5) Time Interval Incidence, % (No.) Perinatal Mortality Rate, % (No.) 1950–1979 1971–1990 1972–1987 1976–1981 1986–1991 1985–1995 7.9 (18/228) 1.7 (11/635) 3.9 (22/560) 22 3 2 (11/520) 27.8 (5/18) 22 35 (7/20) 35 10 9 (1/11) large quantities, which undergo oxidation in the liver to form ketone bodies. Hepatocytes respond to the insulin deficiency and high levels of glucagon by increasing hepatic glucose production. Hyperglycemia results from the increase in gluconeogenesis and glycogenolysis in the liver and a decrease in glucose utilization in peripheral tissues (10 –12). Ketone bodies (acetoacetate, 3-␤hydroxybutyrate and acetone) are produced in the liver from the oxidation of fatty acids, under the influence of an elevated glucagon/insulin ratio (12). ␤-hydroxybutyrate production is selectively accelerated in DKA, to a ratio of up to 10:1 compared with acetoacetate (7). Acetone is produced by spontaneous decarboxylation of acetoacetate (12) and is present in DKA in much lower concentration than either ␤-hydroxybutyrate or acetoacetate. It is highly fat soluble and is excreted slowly via the lungs. Acetone production is clinically apparent as a fruity odor on the breath. In the laboratory, the conventional test for the presence of ketone bodies is the nitroprusside test. This test only detects acetoacetate in serum and urine. Given that ␤-hydroxybutyrate is present in three to ten times greater concentration and that it is metabolized to acetoacetate, the measurement of serum ketones using the nitroprusside reaction may greatly underestimate the degree of ketonemia present in the patient. Quantitative testing for ␤-hydroxybutyrate is available and should be considered if there is concern for a falsenegative nitroprusside result (7). Ketone bodies are organic acids that completely dissociate at physiologic pH and are neutralized by bicarbonate (7). In high concentrations (as seen in DKA), they contribute a large hydrogen ion pool that consumes the normal buffering capacity of serum and tissue, leading to metabolic acidosis with a high anion gap. The kidney plays an important role in the pathogenesis of DKA. Glucose resorption in the tubules of the kidney is effecS348 tive up to a threshold of ⵑ240 mg/dL, designated Tm (tubular maximum), beyond which glucosuria is evident (13). Glucose is an osmotically active substance. With increasing hyperglycemia, an osmotic diuresis ensues, leading to dehydration, hypovolemia, hyperosmolality, and electrolyte depletion. Further depletion of electrolytes occurs because ketoacid anions are first coupled to sodium and potassium salts, which are then excreted (7). Left untreated, worsening acidosis, electrolyte abnormalities, and hypovolemia can have multiple-system effects, including cardiac dysfunction, altered vascular tone, poor tissue perfusion, and diminished renal function, leading to shock, coma, and death. Clinical Presentation Armed with an understanding of altered pregnancy physiology and pathophysiology of DKA from the preceding two sections, the clinician is now prepared to encounter a pregnant woman with DKA. Typical presenting features are shown in Table 2. Patients with diabetic ketoacidosis classically present with a triad of concurrent abnormalities, which constitute an acronym: D ⫽ dehydration; K ⫽ ketosis; A ⫽ acidosis (metabolic). Although marked hyperglycemia is often detected as well, DKA is occasionally diagnosed with only mild elevations in serum glucose (10). This is especially true in pregnant women who develop DKA (5, 6). Careful history taking, physical examination, and laboratory evaluation may reveal many of the diagnostic features listed in Table 2 (6, 11, 12, 14). Various triggers of DKA in pregnancy have been reported in the literature (3, 6). In a 15-yr series of consecutive cases of DKA in pregnancy, Montoro et al. (3) found that cessation of insulin therapy in pregnancy was the precipitating factor for DKA in 40% of cases, infection initiated 20% of cases, and 30% of women had previously undiagnosed diabetes until they presented with diabetic ketoacidosis (15, 16). Later in this review, we will present a case of a pregnant woman whose first manifestation of diabetes was DKA. The diagnosis of DKA is less likely to be considered in nondiabetics (15). In addition to Montoro’s three categories, certain obstetrical interventions like ␤-mimetic tocolytic agents and corticosteroids to enhance fetal lung maturity have been reported to trigger DKA (17, 18). Finally, ketoacidosis has been reported as a complication of the use of a subcutaneous insulin infusion pump; however, this risk appears to be small (19, 20). The impact of DKA on pregnancy can be artificially separated into maternal concerns and fetal concerns. In reality, both patients are affected simultaneously. Maternal Concerns In the same way that DKA represents an acute emergency in the nonpregnant individual, it poses an immediate threat to maternal well-being. Severe dehydration can lead to hypotension, acidosis can cause organ dysfunction, and electrolyte imbalance can cause cardiac arrhythmias. Prompt initiation of treatment can correct all of the metabolic derangements. Fetal Concerns Maternal hyperglycemia results in fetal hyperglycemia and fetal osmotic diuresis. The fetus can also become acidotic from ketoacids that cross the placenta. Acidemia decreases uterine blood flow, reduces tissue perfusion, and leads to decreased oxygenation of the fetoplacental unit. Furthermore, a leftward shift of the maternal oxy-hemoglobin dissociation curve with decreased 2,3-diphosphoglycerate increases hemoglobin affinity for oxygen, decreasing fetal oxygen delivery (9, 21, 22). Ketoacids dissociate into hydrogen ions and organic anions, both of which are transported across the placenta. Thus, with increasing maternal ketonemia, fetal metabolic acidosis may develop. Because the fetus is not directly accessible, inferences regarding fetal status are often made from the external recording of the fetal heart rate. Often, decreased or absent variability, absent accelerations, and late decelerations are observed on external fetal heart rate tracings with deCrit Care Med 2005 Vol. 33, No. 10 (Suppl.) Figure 1. Pathophysiologic process leading to diabetic ketoacidosis. compensated maternal DKA. Doppler ultrasound has also been used to look at blood flow in fetal vessels with DKA (23). Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) Transient fetal blood flow redistribution was demonstrated in the umbilical and middle cerebral arteries, as measured by pulsatility index. Reversal of the abnormal flow was demonstrated after treatment of the maternal DKA. Hagay et al. S349 Table 2. Diagnosis of diabetic ketoacidosis (DKA) Signs and Symptoms Malaise Dehydration Polyuria Polydipsia Nausea Vomiting Abdominal pain Ileus Fruity breath odor a Hypotension Tachycardia Tachypnea Hyperventilation (Kussmaul respiration) Drowsiness Mental status change Lethargy Coma Shock Labs Hyperglycemia (⬎250 mg/dL)a Acidosis (arterial pH ⬍ 7.3) Anion gap (⬎12 mEq/L) Low bicarbonate (⬍15 mEq/L) Elevated base deficit (base deficit ⬎4 mEq/L) Ketonemia (ⱖ1:2 dilution) Treatment In pregnancy, DKA can manifest at lower blood glucose values (may be as low as 180 mg/dL). (24) similarly describe improvements in the fetal heart rate tracing following treatment of maternal DKA. Immediate delivery in response to the presence of nonreassuring fetal monitoring is therefore not indicated, until the maternal metabolic condition is corrected. Intervention for fetal indications should be reserved for fetal compromise persisting after maternal resuscitation. Emergency cesarean delivery in the setting of decompensated DKA could further worsen the maternal condition (21, 23, 24). A single episode of DKA poses considerable risk to the fetus. Several retrospective studies have reported a perinatal mortality rate of 9 –35% (1–5). Early recognition and prompt treatment of DKA might well avoid adverse fetal outcome. A recent case of DKA in pregnancy that was not optimally managed resulted in a fetal death. Case A 23-yr-old woman gravida 3, para 2 at 31 wks gestation presented to the Obstetrical Service with complaint of “feeling weak” and “throwing up” for 3 days duration. The patient complained of extreme thirst, nausea, and abdominal pain. She was not known to be diabetic; she denied the development of gestational diabetes in either of her two previous pregnancies. On exam, she was noted to have dry mucous membranes, heart rate of 128 beats/min, and respiratory rate of 26 breaths/min. Her weight was 104 kg, and blood pressure was mildly elevated (169/ 87), which was attributed to agitation. Her oral temperature was 100.3°C. She was noted to be tolerating oral fluid intake. Ultrasound examination of the fetus confirmed cardiac activity. A finger-stick blood glucose measurement was initially read as “too high to calculate,” followed S350 This case illustrates delayed recognition of the clinical manifestations of DKA. Had a timely diagnosis been made, appropriate fluid and insulin therapy could have been instituted, with correction of the maternal metabolic disturbances, and perhaps the fetal death would have been prevented. by a measured finger-stick value of ⬎600 mg%. Initial laboratory work confirmed hyperglycemia (serum glucose of 836 mg/ dL), an anion gap of 23, bicarbonate of 15 mmol/L, blood urea nitrogen of 8, and creatinine of 1.8 mg/dL; urinalysis was positive for glucose (3⫹) and leukocytes. Urine and serum ketones were negative. Several attempts were made to obtain an arterial blood gas, but all were unsuccessful. The patient was admitted with a diagnosis of pyelonephritis and hyperglycemia. Five hours after admission to labor and delivery triage, intravenous fluid and insulin treatment were started. In the first hour, the patient received 500 mL of normal saline and 5 units of regular insulin intravenously. Blood glucose (by finger-stick) values remained ⬎600 mg% for the next 3 hrs, and the anion gap remained elevated at 20 during this time. Normal saline was maintained at 500 mL/hr over this time interval, along with 5 units of intravenous regular insulin administered hourly. For each of the next 6 hrs, the patient received 10 units of regular insulin. Blood glucose values remained in the range of 375– 440 mg/dL. The patient remained tachycardic (125 beats/min), and urine output was recorded at ⵑ100 mL/ hr. The intravenous fluid was changed to 0.45% saline, at a rate of 100 mL/hr over this time period. Potassium chloride was added to intravenous fluids to correct a serum potassium of 3.1 mmol/L. The fetus was monitored by an external fetal heart rate monitor, with a baseline fetal heart rate ranging from 125 to 140 beats/min. Notably, this was the same as the mother’s pulse. Ten hours after admission, after difficulty in obtaining a continuous fetal heart rate tracing, ultrasound confirmed an intrauterine fetal demise. A careful search for the presence of infection is required for every patient presenting in DKA. Infection has been demonstrated to reduce the rate of glucose utilization by 50% (28). The presence of bands on a differential is more telling of infection, as an elevated white blood cell count may be the result of dehydration, rather than infection. Common sites of infection include the urinary tract, lungs, soft tissue, sinuses, skin, and teeth. Prompt treatment of infection with appropriate antibiotic coverage will assist in glucose control. Other precipitating causes of DKA are referenced earlier (17– 20). We now present our recommendations for treatment of DKA. An algorithmic approach is outlined in Figure 2, focusing on the treatment of the fetus, maternal acidosis and dehydration, and the elucidation and treatment of underlying causes of DKA. This is followed by recommendations for therapy in a “cookbook” form, detailing fluid administration, insulin therapy, and electrolyte replacement (Table 3). For the interested reader, we conclude this section with a rationale for our recommendations for treatment of DKA, including pertinent calculations discussed throughout the text (Table 4). Treatment of the pregnant woman with DKA does not differ from the nonpregnant patient. The goals of DKA management are as follows: 1. Improve circulating volume and tissue perfusion. 2. Decrease serum glucose. 3. Clear the serum and urine of ketoacids (correcting acidosis). 4. Correct electrolyte imbalances. 5. Treat initiating causes of DKA. 6. Monitor therapeutic response in the mother and fetus. These goals will be met with volume replacement, insulin therapy, replacement of electrolytes, and treatment of the underlying causes of DKA (10, 14). Fluid Therapy. Volume replacement should be vigorous and sustained to corCrit Care Med 2005 Vol. 33, No. 10 (Suppl.) • • • • Admit to obstetric intensive care unit (or equivalent). Begin monitoring vital signs, pulse oximetry, strict intake and output, patient weight. Labs: arterial blood gas, serum glucose, serum ketones, serum electrolytes, anion gap, urine analysis, urine culture, urine ketones. Fetal monitoring if viable gestational age. Start a bedside flowsheet. Figure 2. Algorithm for treatment of diabetic ketoacidosis. ABG, arterial blood gas; UA, urine analysis; CXR, chest radiograph; IV, intravenous; NS, normal saline. rect dehydration, replete circulating volume, decrease serum glucose concentration, restore renal function, and, importantly, prevent a recurrence of acidosis. The major cause of fluid loss in DKA is osmotic diuresis. Isotonic fluid (0.9% normal saline) should be used for initial fluid replacement. Isotonic fluid has been demonstrated to replete the extracellular fluid compartment and corCrit Care Med 2005 Vol. 33, No. 10 (Suppl.) rect circulating plasma volume most effectively (11). Insulin Therapy. Insulin is the mainstay of treatment, correcting the hyperglycemia, acidosis, and the overproduction of ketones that occur in DKA. Continuous insulin infusion of regular (short-acting) insulin is the preferred method of delivery. Intramuscular administration of insulin leads to a delay in response to treatment due to the impaired absorption of insulin in the setting of volume depletion and acidosis (11). Intravenous insulin therapy should be maintained until after the first dose of subcutaneous insulin is administered, to prevent a recurrence of ketoacidosis. Several protocols describe the subcutaneous administration of insulin after an episode of DKA (11, 25). S351 Table 3. Recommendations for therapy Electrolyte Replacement Fluid therapy Estimate fluid deficit of ⬃100 mL/kg body weight. Correct 75% of estimated fluid deficit over first 24 hrs. Record intake and output hourly. Initial 24 hrs: Use isotonic saline (0.9% NS) First hour Give 1 L NS Second hour Give 0.5–1 L NS Third hour Give 0.5 L NS Thereafter (24 hrs) Give 0.25 L/hr 0.45% NS until 75% deficit corrected Calculate corrected Na⫹ during fluid administration. Monitor serum Na⫹ and Cl⫺; adjust IV fluids if hypernatremia or hyperchloremia. Continue hydration for 24–48 hrs, until anion gap and acidosis have corrected and volume deficit is replaced. Insulin therapy Give 0.1 units/kg bolus regular insulin IV, then 0.1 units/kg/hr IV continuous infusion by pump. Mix 50 units of regular insulin in 500 mL of NS (10 mL ⫽ 1 unit). Flush IV tubing prior to infusing, as insulin binding to tubing occurs. Monitor serum glucose every 1–2 hrs. If serum glucose is not decreased by 20% within first 2 hrs, double insulin infusion rate. Aim for a decrease in serum glucose of 60–75 mg/dL/hr. With blood glucose at 250 mg/dL, add dextrose to IV fluids, to avoid hypoglycemia (maintain insulin rate). Monitor serum ketones every 2 hrs. Continue insulin therapy until bicarbonate and anion gap normalize. After full resolution of ketosis, maintain insulin drip until after the first subcutaneous dose of insulin is administered. Electrolyte replacement Monitor serum electrolytes every 2–4 hrs Potassium Potassium chloride is most often given for replacement; occasionally potassium phosphate or acetate is used. Anticipate deficit of 5–10 mEq/kg. With replacement, maintain adequate urine output (0.5 mL/kg/hr). Maintain serum K⫹ level at 4–5 mEq/L. Suggested protocol using serum K⫹: ⬎5 mEq/L No treatment 4–5 mEq/L 20 mEq/L replacement 3–4 mEq/L 30–40 mEq/L replacement ⱕ3 mEq/L 40–60 mEq/L replacement Phosphate Replacement not normally required. If serum phosphate ⬍1.0 mg/dL or if cardiac dysfunction or obtundation, replace using potassium phosphate. Bicarbonate Replacement is usually not necessary. Potassium. Potassium replacement is indicated after fluid replacement and insulin have been initiated. The most rapid changes in potassium occur in the first few hours of treatment (26). Insulin mediates the shift in K⫹ ion from the extracellular to intracellular space, along with glucose. With correction of acidosis, K⫹ ions are further shifted into the intracellular fluid. Losses of potassium also occur with continued osmotic diuresis and as ketone bodies are excreted by the kidney as potassium salts. The development of significant hypokalemia can precipitate life-threatening arrhythmias (11); close attention to serum electrolytes and potassium replacement is essential to the effective treatment of DKA. On the average, a potassium deficit of 5–10 mEq/kg body weight occurs (11, 12). Various guidelines are described for potassium replacement (12, 25, 27). Maintenance of serum K ⫹ levels at 4 –5mEq/L will prevent hypokalemia and the associated cardiac arrhythmias. Potassium chloride is most often used for replacement, at a maximum rate of 40 mEq/hr. Potassium phosphate may also be used for replacement, if concomitant hypophosphatemia is present or with the development of hyperchloremic acidosis. Phosphate, Magnesium, and Calcium. Inorganic cations are also deficient in DKA; however, the need for replacement of these electrolytes is debated. Studies do not demonstrate the benefit of replacement of these cations (26). As mentioned, potassium phosphate can be used for potassium replacement, if phosphate levels are ⬍1.0 mg/dL (decrease dose of KCl accordingly). Replacement has also been recommended for patients with left ventricular dysfunction or with obtundation of mental status that has not responded after the initial treatment of DKA (27). Bicarbonate. The use of bicarbonate to correct acidosis has been the subject of study and controversy (22, 26). The metabolism of ketone bodies via the citric acid cycle acts to rapidly regenerate bicarbonate levels. Studies demonstrate that bicarbonate administration has not proven beneficial in the treatment of DKA and its use may be associated with risk, including a paradoxical central nervous system acidosis, hypokalemia, hypertonicity, and the development of cerebral edema (22, 26). Treatment of DKA with bicarbonate delays the correction of ke- NS, normal saline; IV, intravenous. Table 4. Calculations ● Anion gap ⫽ [Na ⫺ (Cl ⫹ HCO3)]: normal value 12 mEq/L ⫾ 2 Anion gap measures the difference between unmeasured anions and unmeasured cations. An increased anion gap reflects the presence of a metabolic acidosis, if renal failure is not present. ● Serum osmolality (mOsm/L) ⫽ [2(Na ⫹ K) ⫹ (glucose/18) ⫹ (BUN/2.8)] Normal value ⫽ 290 ⫾ 5 Serum osmolality is elevated less in DKA (300–330 mOsm/L) than in nonketotic hyperosmolar coma (⬎350 mOsm/L). The difference in serum glucose accounts for almost the entire difference in osmolality. ● Corrected serum sodium (mEq/L) ⫽ measured Na ⫹ {([plasma glucose (mg/dL)] ⫺ 100)/100} ⫻ 1.6 Normal range ⬃ 135–145 mEq/L Hyperglycemia dilutes plasma Na by 1.6 mEq/L for every 100 mg/dL increase in glucose. An elevated value indicates marked dehydration; below the range suggests too rapid administration of fluids. ● Total body water deficit ⫽ {[0.6 ⫻ body weight (kg)] ⫹ [1 ⫺ (140/serum Na)]} BUN, blood urea nitrogen; DKA, diabetic ketoacidosis. S352 Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) tonemia (22). Further studies are needed to assess the benefits and risks of bicarbonate administration when pH is ⬍6.9 or in cases complicated by cardiac dysfunction, sepsis, or shock (10). REFERENCES 1. Lufkin ES, Nelson RL, Hill LM, et al: An analysis of diabetic pregnancies at Mayo Clinic, 1950 –79. Diabet Care 1984; 7:539 –547 2. Kilvert JA, Nicholson HO, Wright AD. Ketoacidosis in diabetic pregnancy Diabet Med 1993; 10:278 –281 3. Montoro MN, Myers VP, Mestman JH, et al: Outcome of pregnancy in diabetic ketoacidosis. Am J Perinatol 1993; 10:17–20 4. Chauhan SP, Perry KG, McLaughlin BN, et al: Diabetic ketoacidosis complicating pregnancy. J Perinatol 1996; 16:173–175 5. Cullen MT, Reece EA, Homko CJ, et al: The changing presentations of diabetic ketoacidosis during pregnancy. Am J Perinatol 1996; 13:449 – 451 6. ACOG Practice Bulletin No. 60. Pregestational Diabetes Mellitus. Obstet Gynecol 2005; 105:675– 685 7. Laffel L: Ketone bodies: A review of physiology, pathophysiology, and application of monitoring to diabetes. Diab Metab Res Rev 1999; 15:412– 426 8. Ogata ES. Carbohydrate homeostasis. In: Neonatology Pathophysiology and Management of the Newborn. Avery GB, Fletcher MA, MacDonald MG (Eds). Philadelphia, Lippincott Williams & Wilkins, 1999 Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) 9. Ramin K: Diabetic ketoacidosis in pregnancy. Obstet Gynec Clin NA 1999; 26:481– 488 10. White NH: Management of diabetic ketoacidosis. Rev Endocr Metab Dis 2003; 4:343–353 11. Kitabchi AE, Umpierrez GE, Murphy MB et al: Management of hyperglycemic crises in patients with diabetes. Diabet Care 2001; 24: 131–153 12. Foster DW, Mc Garry JD: The metabolic derangements and treatment of diabetic ketoacidosis. N Engl J Med 1983; 809:159 –169 13. Rose BD. Proximal tubule. In: Clinical Physiology of Acid-Base and Electrolyte Disorders. Rose BD (Ed). New York, McGraw-Hill, 1989, p 43–54 14. Moore TR: Diabetes in pregnancy. In: Maternal Fetal Medicine Principles and Practice. Fifth Edition. Creasy RK, Resnik R, Iams JD (Eds). Philadelphia, Saunders (Elsevier), 2004, pp 1023–1063 15. Sills IN, Rappaport R: New onset IDDM presenting with diabetic ketoacidosis in a pregnant adolescent. Diabet Care 1994; 17: 904 –905 16. Kamalakannan D, Baskar V, Barton DM, et al: Diabetic ketoacidosis in pregnancy. Postgrad Med 2003; 79:699 –714 17. Bernstein IM, Catalano PM: Ketoacidosis in pregnancy associated with the parenteral administration of terbutaline and betamethasone. A case report. J Reprod Med 1990; 35: 818 – 820 18. Bedalov A, Balasubramanyam B: Glucocorticoid-induced ketoacidosis in gestational diabetes: Sequela of the acute treatment of preterm labor. Diabet Care 1997; 20:922–924 19. Gabbe SG, Holing E, Temple P, et al: Benefits, risks, costs, and patient satisfaction as- 20. 21. 22. 23. 24. 25. 26. 27. 28. sociated with insulin pump therapy for the pregnancy complicated by type I diabetes mellitus. Am J Obstet Gynecol 2000; 182: 1283–1291 Lindenbaum C, Menzin A, Ludmir J: Diabetic ketoacidosis in pregnancy resulting from insulin pump failure. A CASE report. J Reprod Med 1993; 38:306 –308 Chauhan SP, Perry KG: Management of diabetic ketoacidosis in the obstetric patient. Obstet Gynecol Clin N Am 1995; 22: 143–155 Rodgers BD, Rodgers DE: Clinical variables associated with diabetic ketoacidosis during pregnancy. J Repro Med 1991; 36:797– 800 Takahashi Y, Kawabata I, Shinohara A, et al: Transient fetal blood flow redistribution induced by maternal diabetic ketoacidosis diagnosed by Doppler ultrasonography. Prenat Diagn 2000; 20:524 –525 Hagay ZJ, Weissman A, Lurie S, et al: Reversal of fetal distress following intensive treatment of maternal diabetic ketoacidosis. Am J Perinatol 1994; 11:430 – 432 Foley MR: Diabetic ketoacidosis in pregnancy In: Obstetric Intensive Care Manual. Second Edition. Foley MR, Strong TH, Garite TJ (Eds). New York, McGraw-Hill, 2004 Adrogue HJ, Madias NE: Management of lifethreatening acid-base disorders. N Engl J Med 1998; 1:26 –33 Magee MF, Bhatt BA: Management of decompensated diabetes. Crit Care Clin 2001; 17: 75–106 Hagay ZJ: Diabetic ketoacidosis in pregnancy: Etiology, pathophysiology, and management. Clin Obstet Gynecol 1994; 37: 39 – 49 S353