Normoglycemic Diabetic Ketoacidosis in Pregnancy

Home , Ketoacidosis

Journal of Perinatology (2008) 28, 310–312 r 2008 Nature Publishing Group All rights reserved. 0743-8346/08 $30 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Normoglycemic diabetic ketoacidosis in pregnancy

M Chico1, SN Levine1 and DF Lewis2 1Section of Endocrinology and Metabolism, Department of Internal Medicine, Louisiana State University Health Sciences Center, Shreveport, LA, USA and 2Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

fetus. Fetal mortality rates as high as 30 to 90% have been reported, The clinical presentation of diabetic ketoacidosis in pregnancy is usually the although more recently, it has decreased to as low as 9% due same as in nonpregnant women, although the blood glucose may not be as to better prenatal care and diabetic management.2,3,8 high as in the nongravid state. We report a case of a pregnant woman who The clinical presentation of DKA in pregnancy is usually developed diabetic ketoacidosis with a normal blood glucose and review the the same as in nonpregnant women. In most patients, there is pertinent medical literature. A 29-year-old woman with type I diabetes hyperglycemia and ketonemia with a high anion gap metabolic developed diabetic ketoacidosis during induction of labor. She had a glucose acidosis. However, the blood glucose may not be as high as in level of 87 mg per 100 ml with ketonuria, a metabolic acidosis, and an the nongravid state. Both the fetus and placenta utilize large À1 anion gap of 20 mmol l . Normoglycemic diabetic ketoacidosis during quantities of glucose resulting in lower maternal fasting glucose pregnancy is truly unusual but can occur with relatively low, or even levels.2,3,4,7 Several cases of ‘normoglycemic’ DKA have been normal, blood sugars and necessitates prompt recognition and treatment. reported in the literature, but the lowest fasting glucose level In this case, the combination of an initial episode of hypoglycemia and reported has been 128 mg per 100 ml, a value that by current subsequent blood glucose levels below 95 mg per 100 ml led to a prolonged deﬁnitions is elevated.6,9,10 delay in the initiation of a planned insulin infusion for insulin coverage We report the case of a 29-year-old G2P0101 woman with class during the induction of labor. A signiﬁcant ketoacidosis consequently C type I diabetes for 24 years who truly had normoglycemic DKA. developed, despite the absence of even a single elevated blood glucose At the time the diagnosis was established her highest blood measurement. This case illustrated the importance of not withholding glucose was 93 mg per 100 ml. insulin in a patient with type I diabetes for more than a few hours even if the blood glucose is normal. Journal of Perinatology (2008) 28, 310–312; doi:10.1038/sj.jp.7211921 Case presentation Keywords: diabetic ketoacidosis; pregnancy; diabetes mellitus, type I; A 29-year-old G2P0101 woman with type I diabetes for 24 years was blood glucose admitted to the hospital at 24 weeks gestation with poor diabetic control, nausea, vomiting and preterm labor. At the time of admission her hemoglobin A1c was 6.6%. Her preterm labor was Introduction arrested with magnesium sulfate. At 29 weeks gestation she had Normal pregnancy is characterized by a state of decreased insulin preterm premature rupture of membranes. She was treated with sensitivity, as well as accelerated lipolysis and ketogenesis.1–4 The 7 days of antibiotics. Her diabetic condition improved and she was concentration of serum ketones has been estimated to be two to under good control with 30 units of neutral protamine Hagedorn four times greater than in the nonpregnant state.1,5 In addition, insulin and 19 units of regular insulin in the morning, 16 units pregnant women have a respiratory alkalosis, lowering the serum of regular insulin at supper and 16 units of neutral protamine bicarbonate concentration, thus reducing the capacity to buffer Hagedorn insulin at bedtime. During the hospitalization there was hydrogen ions. Despite these changes, the incidence of diabetic no evidence of any infection and she did not receive steroids for ketoacidosis (DKA) in pregnant diabetic women is only 1 to 3%.6,7 fetal lung maturation. At 34 weeks gestation a pitocin induction Ketoacidosis is associated with increased risks to the mother and and an intravenous infusion of 0.9% NaCl was begun at 0800 hours with a blood glucose of 67 mg per 100 ml. The plan was Correspondence: Dr SN Levine, Section of Endocrinology and Metabolism, Department of to start intravenous infusions of insulin and glucose when the Internal Medicine, Louisiana State University Health Sciences Center, 1501 Kings Highway, blood glucose exceeded 100 mg per 100 ml. Over the next 24 h her Shreveport, LA 71103, USA. E-mail: [email protected] blood glucose ranged from 45 to 93 mg per 100 ml without insulin Received 8 November 2007; revised 16 November 2007; accepted 26 November 2007 (Table 1). At this time she was still in labor without nausea or Normoglycemic DKA in pregnancy M Chico et al 311

Table 1 Laboratory data resolved and she had a normal anion gap of 9 mmol lÀ1. Pitocin

À was discontinued because of the failure of labor to progress. Date Time Glucose mg HCO3 Anion gap Miscellaneous (hours) per 100 ml mmol lÀ1 mmol lÀ1 The patient delivered a 3273-g girl by C-section with APGAR score of 5 at 1 min and 9 at 5 min. 1/7/2006 0540 59 1/7/2006 0712 69 1/7/2006 0832 67 Discussion 1/7/2006 0947 45 Diabetic ketoacidosis is a life-threatening, acute metabolic state 1/7/2006 1034 71 that is due to insulin deficiency. Low levels of insulin increase 1/7/2006 1140 64 hepatic glucose production while decreasing glucose uptake and 1/7/2006 1236 55 1/7/2006 1337 53 utilization. DKA is also characterized by increased levels of the 1/7/2006 1437 53 counter-regulatory hormones glucagon, cortisol, catecholamines 1/7/2006 1537 46 and growth hormone. These hormones accelerate the development 1/7/2006 1640 58 of ketoacidosis by increasing gluconeogenesis, glycogenolysis, 1/7/2006 1735 87 ketogenesis and insulin resistance. Insulin deficiency increases 1/7/2006 1834 94 hormone-sensitive lipase, releasing large quantities of free fatty 1/7/2006 1931 84 acids from adipocytes. In the presence of high-glucagon and 1/7/2006 2033 78 low-insulin levels free fatty acids are metabolized in the liver to 1/7/2006 2119 78 acetoacetic acid and b-hydroxybutyric acid. The hydrogen ions 1/7/2006 2211 82 that dissociate from these strong organic acids are buffered by 1/8/2006 0057 83 bicarbonate leading to a high anion gap metabolic acidosis. The 1/8/2006 0205 90 hyperglycemia and hyperosmolality seen in patients with DKA 1/8/2006 0307 92 1/8/2006 0504 82 produce the characteristic osmotic diuresis, which ultimately leads 1/8/2006 0615 87 to intravascular volume depletion. If this is not corrected by the 1/8/2006 0704 85 administration of intravenous fluids and insulin, DKA can rapidly 1/8/2006 0805 93 progress to a state of poor tissue perfusion, diminished cardiac 11 1/8/2006 0930 87 12 20 Serum and urine and renal function, multisystem failure and death. ketones positive While the clinical presentation of DKA in pregnant women is 1/8/2006 1240 128 8 19 ABG: pH 7.20, usually similar to that in nonpregnant women, a number of PCO2 27 mm Hg, changes during pregnancy can influence carbohydrate and fat 2–4,8 PO2 120 mm Hg metabolism. Placental lactogen and increased levels of cortisol 1/8/2006 1410 167 15 10 both contribute to increased insulin resistance, particularly toward 1/8/2006 1430 181 9 15 the later stages of pregnancy. Pregnant women have a respiratory 1/8/2006 1830 115 16 9 alkalosis with decreased serum bicarbonate concentrations and 1/8/2006 2040 92 16 7 1/8/2006 2250 77 14 8 a reduced capacity to buffer organic acids. Furthermore, pregnancy 1/9/2006 0200 137 18 5 is considered to be an accelerated state of starvation in which 1/9/2006 0640 74 20 4 an overnight fast can lead to increased lipolysis and ketone body 1/10/2006 0650 107 22 6 concentrations that are two to four times greater than in the nonpregnant state.1,5 Factors that may predispose pregnant woman to develop DKA include starvation, the stress of labor, cessation of insulin therapy, use of b sympathomimetic agents other symptoms suggesting ketoacidosis. Her laboratory tests for premature labor and emesis with accompanying dehydration. included sodium 144 mmol lÀ1, potassium 4.0 mmol lÀ1, It is well recognized that when DKA complicates pregnancy the bicarbonate 12 mmol lÀ1, chloride 112 mmol lÀ1, anion gap initial serum glucose concentration may not be as high as in men 20 mmol lÀ1, BUN 14 mg per 100 ml, creatinine 0.7 mg per or nonpregnant women. In pregnancy during periods of fasting, 100 ml, urine ketones 50 mg per 100 ml, urine glucose negative, glycogenolysis, lipolysis and ketone production are increased. arterial pH 7.22, PCO2 27 and PO2 120. An insulin infusion of 1 unit Under these conditions DKA can develop more rapidly and at per hour along with D5 0.45% NaCl at 125 cc hÀ1 was initiated to lower serum concentrations of glucose than in nonpregnant treat DKA. Glucose levels were measured hourly and the insulin- women.2–4,7 Rare cases of ‘euglycemic’ DKA in pregnancy have infusion rate varied from 1 to 2 units per hour to keep the glucose been reported, although in almost every case the serum glucose between 80 and 150 mg per 100 ml. After 8 h of treatment DKA has exceeded 130 mg per 100 ml.6,9,10

Journal of Perinatology Normoglycemic DKA in pregnancy M Chico et al 312

Cullen et al.6 reported their experience with 20 patients with insulin and dextrose infusions as soon as the glucose was no DKA complicating pregnancy over a period of 10 years. The mean longer low. glucose concentration was 323 mg per 100 ml (range of 130 to While it is well established that DKA in pregnancy can occur 682 mg per 100 ml). In 36% of these cases the glucose was less with only modestly elevated serum glucose level, our literature than 200 mg per 100 ml, with the lowest recorded value of 130 mg review did not identify any previous reports with truly normal per 100 ml. Montero et al.7 described their experience with 20 cases serum glucose concentrations. of DKA in pregnant women cared for from 1972 to 1987. In patients with viable fetuses the mean glucose concentration was 374 mg per 100 ml. Two had a serum glucose of less than Conclusion 200 mg per 100 ml (156 and 180 mg per 100 ml). We conclude that the degree of hyperglycemia in pregnancy At the time our patient was diagnosed as having DKA, she had complicated by DKA may be blunted due to decreased glucose a serum glucose of 87 mg per 100 ml, bicarbonate concentration production or increased glucose utilization. Normoglycemic DKA À1 À1 of 12 mmol l and an anion gap of 20 mmol l . Over the during pregnancy is truly unusual but can occur with relatively preceding 24 h her highest glucose was 93 mg per 100 ml. In low, or even normal, blood sugars and necessitates prompt our patient the serum glucose concentration was <100 mg per recognition and treatment. This emphasizes the importance of À1 100 ml at the time her anion gap was 20 mmol l . In addition, not withholding insulin for more than a few hours in a patient she was asymptomatic with none of the expected clinical features with type I diabetes, even in the presence of a normal blood of DKA such as vomiting, polyuria, hypotension or changes in glucose. If patients are not receiving subcutaneous insulin they her mental status. It is possible that starvation ketosis contributed should be treated with an intravenous infusion of dextrose to the development of the high anion gap metabolic acidosis in along with intravenous insulin to maintain normal glucose levels. our patient. However, it is unlikely that starvation ketosis alone could lead to such a severe degree of ketoacidosis with a pH of 7.22, À1 À1 bicarbonate of 12 mmol l and an anion gap 20 mmol l . Acknowledgments The initial reason for withholding insulin infusion in our patient We would like to acknowledge and thank Dr David E. Scarborough for his was that her blood glucose was noted to be in the hypoglycemic thoughtful review and suggestions in the preparation of this manuscript. range on the morning of induction. At that time she may have This work was funded by the departmental resources. This paper was presented been subject to some residual effect of the prior evening’s bedtime as a poster at the Annual Meeting of the Endocrine Society, June 2006, Boston, dose of neutral protamine Hagedorn insulin. It was anticipated that MA, USA. within a few hours the blood glucose would rise to 100 mg per 100 ml at which time an intravenous insulin infusion could be initiated. However, the blood glucose persisted in the hypoglycemic References range for over 8 h and never even reached a level of 95 mg per 1 Brumﬁeld CG, Huddleston JF. The management of diabetic ketoacidosis in pregnancy. 100 ml. Since the patient was NPO with low and later normal blood Clin Obstet Gynecol 1984; 27: 50–59. glucose levels, the decision to begin the infusion was not made 2 Carroll MA, Yeomans ER. Diabetic ketoacidosis in pregnancy. Crit Care Med 2005; 33: until the next morning. At that point it was realized that the S347–S353. prior dose of neutral protamine Hagedorn insulin had long since 3 Kamalakannan D, Baskar V, Barton DM, Abdu TAM. Diabetic ketoacidosis in worn off and that ketoacidosis likely had developed. pregnancy. Postgrad Med J 2003; 79: 454–457. 4 Ramin KD. Diabetic ketoacidosis in pregnancy. Obstet and Gynecol Clin North Am During the ﬁrst 24 h of the induction of labor, when the patient 1999; 26: 482–488. was not eating and not receiving any intravenous glucose, the 5 Metzger BE, Ravnikar V, Vileisis RA, Freinkel N. ‘Accelerated starvation’ and the skipped absence of caloric intake combined with the muscular activity of breakfast in late normal pregnancy. Lancet 1982; 1(8272): 588–592. uterine contractions likely contributed to the both the low blood 6 Cullen MT, Reece EA, Homko CJ, Sivan E. The changing presentations of diabetic glucose and the generation of ketones. However, ketoacidosis would ketoacidosis during pregnancy. Am J Perinatol 1996; 13: 449–451. be expected to occur even in the absence of these factors given 7 Montoro MN, Myers VP, Mestman JH, Xu Y, Anderson BG, Golde SH. Outcome of pregnancy in diabetic ketoacidosis. Am J Perinatol 1993; 10: 17–20. the long interval without insulin effect. This case highlights the 8 American College of Obstetricians and Gynecologists. ACOG practice bulletin No. 60: importance of not withholding insulin for more than a few hours pregestational diabetes. Obstet Gynecol 2005; 105: 675–685. in a patient with type I diabetes. It further illustrates the hazard of 9 Clark JD, McConnell A, Hartog M. Normoglycaemic ketoacidosis in a woman with relying solely on the glucose level as an index of insulin activity, gestational diabetes. Diabet Med 1991; 8: 388–389. especially in clinical settings such as this one where multiple 10 Franke B, Carr D, Hatem MH. A case of euglycaemic diabetic ketoacidosis in pregnancy. Diabet Med 2001; 18: 858–859. factors act together to keep blood glucose levels low. Clearly, the 11 Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI et al. better approach in this case would have been to resolve the initial Management of hyperglycemic crises in patients with diabetes. Diabetes Care 2001; 24: hypoglycemia with intravenous glucose and to begin combined 131–153.

Journal of Perinatology