Clinical Expert Series
Diabetic Ketoacidosis in Pregnancy Baha M. Sibai,
MD,
and Oscar A. Viteri,
MD
Pregnancies complicated by diabetic ketoacidosis are associated with increased rates of perinatal morbidity and mortality. A high index of suspicion is required, because diabetic ketoacidosis onset in pregnancy can be insidious, usually at lower glucose levels, and often progresses more rapidly as compared with nonpregnancy. Morbidity and mortality can be reduced with early detection of precipitating factors (ie, infection, intractable vomiting, inadequate insulin management or inappropriate insulin cessation, b-sympathomimetic use, steroid administration for fetal lung maturation), prompt hospitalization, and targeted therapy with intensive monitoring. A multidisciplinary approach including a maternal-fetal medicine physician, medical endocrinology specialists familiar with the physiologic changes in pregnancy, an obstetric anesthesiologist, and skilled nursing is paramount. Management principles include aggressive volume replacement, initiation of intravenous insulin therapy, correction of acidosis, correction of electrolyte abnormalities and management of precipitating factors, as well as monitoring of maternal-fetal response to treatment. When diabetic ketoacidosis occurs after 24 weeks of gestation, fetal status should be continuously monitored given associated fetal hypoxemia and acidosis. The decision for delivery can be challenging and must be based on gestational age as well as maternal-fetal responses to therapy. The natural inclination is to proceed with emergent delivery for nonreassuring fetal status that is frequently present during the acute episode, but it is imperative to correct the maternal metabolic abnormalities first, because both maternal and fetal conditions will likewise improve. Prevention strategies should include education of diabetic pregnant women about the risks of diabetic ketoacidosis, precipitating factors, and the importance of reporting signs and symptoms in a timely fashion. (Obstet Gynecol 2014;123:167–78) DOI: 10.1097/AOG.0000000000000060
D
iabetic ketoacidosis is one of the most serious acute complications of diabetes and is characterized by the triad of uncontrolled hyperglycemia, anion gap metabolic acidosis, and ketosis.1,2 Diabetic ketoacidosis is an infrequent complication of pregestational or gestational diabetes mellitus (GDM) during pregnancy, but in the absence of prompt diagnosis and treatment, it can be life-threatening to the mother From the Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, the University of Texas Health Science Center at Houston, Houston, Texas. Continuing medical education for this article is available at http://links.lww. com/AOG/A457. Corresponding author: Baha M. Sibai, MD, 6410 Fannin Street, Suite 210, Houston, TX 77030; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2013 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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and fetus. The worldwide prevalence of diabetes has risen dramatically over the past two decades, corresponding with increasing trends to higher-calorie diets as well as decreased physical activity leading to obesity. Furthermore, the increased rates of obese women and the continued immigration to the United States among populations with high prevalence of type 2 diabetes mellitus (DM) have all significantly contributed to the increasing incidence of gestational and type 2 DM in pregnancy.3 During the past decade, there has been considerable effort to improve pregnancy outcomes in women with type 1 and type 2 DM as well as GDM with preconception and first-trimester control of maternal hyperglycemia, early detection of type 2 DM and GDM (universal screening), nutritional counseling, frequent glucose monitoring, proper oral hypoglycemic or insulin therapy, and timely hospitalization and delivery.3,4 Nevertheless, diabetic ketoacidosis continues to occur in a small percentage of patients with diabetes in pregnancy.
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The purpose of this report is to review the English literature regarding the incidence, pathophysiology, risk factors, diagnosis, management, outcome, and prevention of diabetic ketoacidosis in pregnancy.
INCIDENCE The true incidence of diabetic ketoacidosis in pregnancy is difficult to ascertain and epidemiologic data are based mainly on case reports, retrospective studies with small numbers, and review articles.5–11 Historically, the reported incidence of diabetes in pregnancy ranges from 6% to 7% with 90% of these cases representing women with GDM.12,13 The two populations with the highest risk of diabetes in pregnancy are obese African Americans and those of Hispanic or Latino descent with an overall prevalence as high as 30%.12,14–16 Diabetic ketoacidosis occurrence during pregnancy is exceedingly rare with a reported incidence between 0.5% and 3% of all diabetic gestations.6,11 Formerly considered a hallmark of type 1 DM, diabetic ketoacidosis is now increasingly being reported in individuals with poorly controlled type 2 DM or GDM.17,18 The incidence of diabetic ketoacidosis in pregnancy is expected to increase because of the increased frequency of type 2 DM and gestational diabetes during pregnancy as a result of the change in demographics of women who are pregnant. Pregnancies in women 35 years or older are much more common than a decade ago. Advanced maternal age is associated with increased rates of obesity and both type 2 DM and GDM. Some of these women will also conceive by assisted reproductive technology, resulting in multifetal pregnancies. Indeed, higher order gestations are associated with increased rates of GDM; however, the magnitude of this risk is unclear.19,20 In addition, multifetal gestations are associated with increased rates of preterm labor or premature rupture of membranes,19 resulting in the need for corticosteroids for fetal lung maturation, which, if complicated by diabetes, may increase the maternal risk of diabetic ketoacidosis.
glucose precursors: lipolysis results in excess amounts of glycerol released to the circulation and muscle breakdown results in the release of amino acids, both of which are readily available as sources of energy. Furthermore, as a result of the state of insulin resistance, there is increased lipolysis, which in turn decreases adipocyte storage of free fatty acids.10 The metabolic derangements during an episode of diabetic ketoacidosis result in a chain of events that selfperpetuate the process in a vicious cycle. The elevated glucose levels in the intravascular space create an osmotic gradient, resulting in marked diuresis that in turn leads to a profound state of dehydration and hypovolemia. This further exacerbates the hyperglycemia and acidosis because it promotes the activation of other counterregulatory stress hormones (ie, growth hormone, cortisol). Furthermore, measured sodium levels can become abnormally low as a result of the osmotic diuresis. Additionally, electrolyte salts containing sodium, potassium, and phosphorus become bound to anions from ketoacids in the bloodstream and are excreted in the urine.9 Protein breakdown (as a consequence of the perceived state of starvation) and decreased potassium cellular uptake resulting from the lack of insulin result in normal or elevated serum potassium levels in the presence of diminished total body potassium. During diabetic ketoacidosis, increased b-oxidation of fatty acids resulting from insulin deficiency and concomitant elevations of counterregulatory hormones increase production of acetyl CoA, which in turn is converted by the liver to ketone bodies (3b-hydroxybutyrate and acetoacetate).21 Acetoacetate can undergo decarboxylation and conversion to acetone (which presents as a fruity odor in the patient’s breath). Increasing amounts of ketone bodies in the bloodstream along with lactic acid (which also serves as a gluconeogenesis precursor) are the principal contributors to the metabolic acidosis seen in patients with diabetic ketoacidosis (Fig. 1).22
PATHOPHYSIOLOGY
METABOLIC CONSIDERATIONS UNIQUE TO PREGNANCY
The metabolic profile of diabetic ketoacidosis is the result of an exaggerated counterregulatory response to a perceived lack of glucose supply at the cellular level. In the absence of adequate insulin availability, cells enter a state of starvation, which in turn activates alternative energy-producing pathways. Levels of glucagon and epinephrine are markedly elevated during starvation. Glycogen storages are rapidly depleted, and gluconeogenesis becomes the primary metabolic pathway. There are abundant sources of
Pregnancy is a state of insulin resistance, accelerated starvation, and respiratory alkalosis, especially in the late second and throughout the third trimester. Insulin sensitivity has been demonstrated to decrease by as much as 56% by 36 weeks of gestation.23 Several hormones unique to pregnancy such as human placental lactogen and prolactin antagonize the effects of insulin at the cellular level. Other hormones unique to pregnancy also play a role in predisposing a diabetic pregnant woman to develop diabetic ketoacidosis. Early in
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• Inadequate circulating insulin • Increased insulin resistance
• Reduced glucose utilization or storage ◦ Muscles ◦ Liver ◦ Adipose tissue
• Increased counterregulatory hormones ◦ Glucagon ◦ Cortisol ◦ Catecholamines ◦ Growth hormone
Hyperglycemia
Fig. 1. Pathophysiology of diabetic ketoacidosis in pregnancy. Modified from Sibai BM. Management of acute obstetrics emergencies: female pelvic surgery video, atlas series. 1st ed. Philadelphia (PA): Saunders, Elsevier; 2011. p. 140. Sibai. Diabetic Ketoacidosis in Pregnancy. Obstet Gynecol 2014.
• Maternal effects ◦ Osmotic diuresis ◦ Hypovolemia ◦ Hypokalemia • Fetal effects ◦ Hypokalemia leading to arrythmias ◦ Hyperglycemia ◦ Hyperinsulinemia
Maternal and fetal acidosis
pregnancy, high levels of human chorionic gonadotropin are associated with increased nausea and vomiting,24 which may trigger a cascade of starvation, dehydration, and acidosis as well as activation of stress-related hormones (Fig. 1). Progesterone also decreases the gastrointestinal motility and enhances the carbohydrate absorption, thus promoting hyperglycemia. Diabetic pregnant women at more than 20 weeks of gestation are more prone to develop more severe and rapidly progressive episodes of diabetic ketoacidosis (usually over hours) and at lower glycemic levels (less than 300 mg/dL).22 Furthermore, diabetic pregnant women are more sensitive to starvation, infection, and extrinsic ketogenic factors such as excessive alcohol intake.25 The maternal metabolic rate increases by approximately 300 kcal/d in the third trimester.26,27 Maternal ketone body levels during fasting are elevated by 33% during the third trimester as compared with the postpartum state.21,28 Ketone bodies can be detected in the urine of pregnant women who are fasting in approximately 30% of the first morning specimens.21,29 Starvation resulting from poor nutritional status or persistent vomiting leads to reduced carbohydrate intake and both have been associated with the development of diabetic ketoa-
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• Increased hepatic glucose production ◦ Gluconeogenesis, glycogenolysis • Increased ketogenesis (liver) • Increased lipolysis
• Release of free fatty acids and conversion to ketone bodies ◦ 3β–hydroxybutirate ◦ Acetoacetate ◦ Acetone
cidosis in euglycemic diabetic pregnant women.25,30,31 Furthermore, it has been suggested that the development of diabetic ketoacidosis and starvation in the pregnant type 1 diabetic with eating disorders may not be rare.32 In addition, the increased minute alveolar ventilation places the pregnant woman in a state of respiratory alkalosis and is counterregulated by increased renal excretion of bicarbonate. This results in a lowered buffering capacity, which further contributes to the development of diabetic ketoacidosis at lower glycemic levels than those seen in nonpregnant patients.33
Euglycemic Ketoacidosis Euglycemic ketoacidosis was first described by Munro et al in 1973 and is defined as severe ketoacidosis with a serum bicarbonate of 10 mEq/L or less in the absence of pronounced hyperglycemia.34,35 All participants had type 1 DM, and blood glucose levels were less than 300 mg/dL. However, during pregnancy, euglycemic ketoacidosis has also been reported to occur in pregestational type 2 DM and GDM.18,36–38 True euglycemic ketoacidosis is exceedingly rare, occurring in 0.8–1.1% of all episodes (depending on the defining plasma bicarbonate concentration).7
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Metabolic Considerations in the Fetoplacental Compartment The mechanism of fetal loss during episodes of diabetic ketoacidosis still remains elusive. Both ketoacids and glucose readily cross the placenta. Fetoplacental demands for glucose are considerable and approach the equivalent of 150 g/d in the third trimester.39 Glucose transport to the fetus is augmented by a fivefold increase in the placental glucose transporter (GLUT-1), which increases transplacental glucose efflux even in the absence of maternal hyperglycemia.26,27 The effects of maternal acidosis, hyperglycemia, dehydration, or electrolyte imbalance on fetal status is unclear, because data are based on limited case reports of fetal heart tracings or animal models.40,41 The massive osmotic diuresis and consequent dehydration leads to volume depletion resulting in reduced uteroplacental perfusion. In addition, maternal acidemia can decrease the placental blood flow with resultant fetal hypoxia. Fetal hypoxemia can also be caused as a consequence of maternal hypophosphatemia, which causes a decrease in 2,3-diphosphoglycerate resulting in a decreased oxygen release from the red blood cells.42 Fetal hyperinsulinemia resulting from maternal hyperglycemia also increases fetal oxygen requirements by stimulating the oxidative metabolic pathway.43 Maternal hypokalemia and fetal hyperinsulinemia could potentially cause fetal hypokalemia leading to fatal arrhythmias.9,22,44
Precipitating Factors for Diabetic Ketoacidosis in Pregnancy Factors precipitating episodes of diabetic ketoacidosis in pregnant patients have been well established22,45,46 and are listed in Box 1. Vomiting and the use of betamimetic drugs accounted for 57% of the episodes of diabetic ketoacidosis in one case series.46 Schneider et al16 evaluated 888 pregnant women with diabetes using insulin over 10 years and found that 11 women (1.2%) presented with diabetic ketoacidosis. The most common causes of diabetic ketoacidosis in these patients were infections (27%) and a history of insulin therapy omission (18%). Chen et al47 compared multiple daily insulin injections with continuous subcutaneous insulin infusions in the management of type 1 DM. Patients treated with continuous subcutaneous insulin injections had a significantly higher rate of diabetic ketoacidosis episodes (13% compared with 1.6%, P5.04). Diabetic pregnant women on chronic corticosteroid therapy are at increased risk for diabetic ketoacidosis because of the effects of steroids on serum glucose values as well as increased risk for infection.48
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Box 1. Precipitating Factors for Diabetic Ketoacidosis in Pregnancy Protracted vomiting, starvation Infections (pyelonephritis, respiratory, chorioamnionitis, ear infection, cellulitis, tooth abscess) Undiagnosed diabetes Poor control of blood sugars or poor compliance with treatment Insulin pump failure Use of b-sympathomimetic agents for tocolysis Steroid use for fetal lung maturation or for chronic medical disorders Diabetic gastroparesis
In addition, the administration of corticosteroids for fetal lung maturation will result in acute elevations in serum glucose values within 6 hours after the first dose and can last up to 3 days after the last dose.49 Therefore, these women should be hospitalized for frequent serum glucose values, and the dose of insulin should be increased as needed. The effects of corticosteroids will be more pronounced when used in association with b-agonists that may be used to treat uterine contractions and preterm labor.50 Gastroparesis usually occurs in patients with longstanding diabetes in association with other microvascular complications such as nephropathy and retinopathy. It is associated with delayed gastric emptying resulting in protracted nausea, vomiting and dehydration, and persistent postprandial hyperglycemia. These metabolic abnormalities combined increase the risk of diabetic ketoacidosis.45,51
MATERNAL AND PERINATAL COMPLICATIONS Although diabetic ketoacidosis is infrequent during pregnancy, its development may result in serious maternal morbidities (acute renal failure, adult respiratory distress syndrome, myocardial ischemia, cerebral edema) and even death.9,10 The frequency of these complications depends on the severity of the maternal condition at the time of presentation and adequacy of management used (stabilization of the maternal condition before induction of labor or emergency cesarean delivery). In recent years, the reported maternal mortality in diabetic ketoacidosis has been less than 1% with a reported fetal mortality rate of 9–36%.8,16,45 However, perinatal morbidities such as
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preterm delivery, hypoxia, and acidosis still remain high. An association has been reported between elevated ketoacids during pregnancy and lower IQ scores as well as decreased mental developmental score during the second year of life.52 Furthermore, an association has also been reported between ketonuria detected during prenatal visits and adverse neurobehavioral outcomes even in nondiabetic pregnancies.53 The fetal brain is particularly susceptible to increased levels of b-hydroxybutyrate and lactate concentrations, which decrease glucose uptake by the fetal brain.54 Also, these substances are known to accumulate in the basal ganglia of children during episodes of diabetic ketoacidosis.55,56 The acidotic environment that develops has been associated with poor myelination and poor cortical connectivity as well as aberrations in the hypocampal neurons. These findings have been linked with greater deficits in expressive language among children diagnosed with autism spectrum disorder.48 Future research is thus needed to further elucidate the effect of maternal ketoacids on fetal brain injury.57,58
DIAGNOSIS OF DIABETIC KETOACIDOSIS IN PREGNANCY Clinical Presentation The signs and symptoms of diabetic ketoacidosis during pregnancy are not pathognomonic and tend to develop faster during pregnancy than in the nonpregnant state (Box 2). A high level of suspicion is required for prompt recognition and management of the disease. An episode of diabetic ketoacidosis may be the initial presentation that leads to a diagnosis of type 1 diabetes. Intractable nausea and vomiting in a known diabetic patient warrant laboratory evaluation for diabetic ketoacidosis. Abdominal pain may be severe, and the gravid patient might experience uterine contractions (Fig. 2A). Hyperglycemia leads to glucosuria, intravascular volume depletion, increased diuresis, and dehydration. Kussmaul respirations and a fruity odor in the patient’s breath might be present in advanced disease. Lethargy and central nervous system manifestations are also an effect of the buildup of ketoacids that could lead to a state of disorientation, obtundation, and even coma resulting from cerebral edema.59
Standard Laboratory Assessment Common laboratory findings in diabetic ketoacidosis are listed in Box 2. Initial laboratory testing in the symptomatic hyperglycemic patient should include a complete blood cell count with differential, liver function tests, glucose, electrolytes, blood urea nitrogen, creatinine, arterial blood gases if bicarbonate is low, and
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Box 2. Diagnosis of Diabetic Ketoacidosis Signs and Symptoms Hyperventilation–tachypnea Sinus tachycardia Hypotension or dehydration Change in sensorium, disorientation, or coma Kussmaul respirations or fruity breath Nonreassuring fetal tracing Polyuria or polydipsia Nausea or vomiting Abdominal pain or contractions Blurred vision Muscle weakness
Laboratory Findings Plasma glucose level (usually greater than 250 mg/dL)*† Arterial pH less than 7.30* Anion gap greater than 12 mEq/L* Elevated base deficit* Positive serum/urine ketones, especially 3b-hydroxybutyrate (most abundant)‡ Falsely normal potassium level might be present Low serum bicarbonate (often less than 15 mEq/L) Elevated serum blood urea nitrogen and creatinine resulting from dehydration and possible renal failure * These values are variable. † Diabetic ketoacidosis in pregnancy can present with much lower glucose levels. ‡ Siemens Multistix 10SG only detect acetoacetate.
anion gap or serum ketones. Acidosis is the hallmark of diabetic ketoacidosis with a serum bicarbonate concentration that is usually less than 15 mEq/L.11 Hyperglycemia (plasma glucose level greater than 300), anion gap metabolic acidosis, and ketosis (positive serum and urine ketones) are seen in virtually all cases of diabetic ketoacidosis. An anion gap is present because the acidosis is caused by unmeasured anions (ie, ketoacids and lactate). In acute diabetic ketoacidosis, the ketone body ratio (3-b-hydroxybutyrate:acetoacetate) rises from normal (1:1) to as high as 10:1. As mentioned, the plasma glucose level is usually higher than 300 mg/ dL but lower levels are not uncommon during
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pregnancy. Falsely normal or elevated potassium levels might be present; however, it is likely that the total body potassium is decreased and the patient is dehydrated and hypokalemic. Blood urea nitrogen and creatinine levels may be elevated as a result of renal dysfunction.21
MANAGEMENT OF DIABETIC KETOACIDOSIS IN PREGNANCY Diabetic ketoacidosis in pregnancy is an obstetric and medical emergency and therefore requires prompt and aggressive treatment in a specialized care unit (Fig. 3). Management should be provided by physicians with
special expertise in the area, ideally including maternalfetal medicine and medical endocrinology specialists, an obstetric anesthesiologist, and skilled nursing support. The principles of management of diabetic ketoacidosis during pregnancy are the same as that in the nonpregnant state. They consist of aggressive volume replacement, intravenous (IV) insulin therapy, correction of acidosis and abnormal electrolytes, correction of the underlying pathology, and intensive monitoring of maternal and fetal response to the treatment.
Fluid Replacement Initial fluid replacement is first accomplished with normal saline. It is imperative to establish early IV
Fig. 2. A. Fetal heart rate monitoring of a patient during an acute episode of diabetic ketoacidosis demonstrating uterine contractions, minimal variability, and late decelerations (solid arrows) after each contraction (dashed arrows). B. After correction of maternal hyperglycemia and acidosis, uterine contractions and late decelerations were resolved. In addition, there is now moderate variability. C. Fetal tracing in a patient who presented with acute diabetic ketoacidosis at 34 weeks of gestation demonstrates repetitive late decelerations (solid arrows) and minimal variability. She was rushed for an emergency cesarean delivery resulting in the delivery of a premature newborn with Apgar scores of 2, 3, and 5 at 1, 5, and 10 minutes, respectively. The arterial cord pH was 6.85. Sibai. Diabetic Ketoacidosis in Pregnancy. Obstet Gynecol 2014.
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• Confirm diagnosis (See Box 2) • Secure airway and oxygenation • Admit for intensive monitoring • Obtain adequate intravenous access* and insert indwelling catheter
Mechanical ventilation required? No
Yes Consider intensive care unit admission
No
Fluid replacement Fluid deficit (approximately 100 mL/kg)
Insulin therapy Short–acting intravenous insulin (10 units bolus)
0.9% sodium chloride 1–2 L/h x 2 h
Continue basal infusion rate of 1–2 units/hour†
Evaluate corrected serum sodium level
Corrected serum (Na+) 140 mEq/L or greater
Corrected serum (Na+) less than 140 mEq/L
0.45% sodium chloride 250–500 mL/hour
0.9% sodium chloride 250–500 mL/hour
Serum glucose 250 mg/dL or less
Add dextrose 5% in 0.45% sodium chloride or dextrose 5% in 0.9% sodium chloride
• Close monitoring first 4 hours ◦ Hourly urine output ◦ Vital signs every 15 minutes ◦ Measure arterial blood gas, capillary serum ketones, electrolytes, glucose and anion gap‡ every 1–3 hours ◦ Aggressive investigation and management of precipitating factors
Serum K+ less than 5 mEq/L and urine output more than 0.5 mL/Kg/hour
Replace K+ as per protocol (Table 1)
Continous fetal monitoring if 24 weeks of gestation or more§
Serum bicarbonate and anion gap normalize|| No Insulin drip until oral intake is tolerated
Yes Patient tolerating oral intake
• Discontinue insulin infusion 2 hours after subcutaneous longacting insulin • Initiate subcutaneous weightbased insulin • Check capillary glucose fasting and 2 hours post-prandial • Consultation to nutrition, diabetes and insulin education services
Fig. 3. An algorithm for the management of diabetic ketoacidosis in pregnancy. *Intravenous access should be obtained with two large-bore catheters or central venous catheter placement. †If serum glucose level does not fall by 50‒70 mg/dL within an hour, double the insulin infusion dose until this goal is achieved. ‡Anion gap: [Na+]–[Cl– + HCO3–], corrected serum sodium: Serum Na+ (mEq/L)+(1.6 mEq/L for each 100 mg/dL glucose level greater than 100 mg/dL). §No interventions on fetal behalf should be performed until stabilization of acute maternal condition has been achieved. kUse of bicarbonate in severe acidosis is debatable (see text). Some authors recommend administering 50 mEq of intravenous bicarbonate only if pH less than 7. Sibai. Diabetic Ketoacidosis in Pregnancy. Obstet Gynecol 2014.
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access with two large-bore catheters or central venous catheter placement. In patients with diabetic ketoacidosis, the fluid deficit is typically 100 mL/kg of body weight,60 which is equivalent to 6–10 L based on maternal weight. Immediate effects of this aggressive hydration are hemodilution and an increase in tissue perfusion resulting in a decrease of glucose and potassium levels. It is important to replace 75% of the fluid deficit during the first 24 hours of treatment and the total volume should be completed within 48 hours. Isotonic normal saline is administered at a rate of 1–2 L/h for 1–2 hours. Once this is completed, normal saline is then administered at a rate of 250– 500 mL/h and continued until glucose values are less than 250 mg/dL. Once this is achieved, administration of an IV solution with 5% dextrose is started. The subsequent choice for fluid replacement depends on the hydration state, serum electrolyte levels, and hemodynamic stability, and it should be continued until the calculated fluid deficit is corrected. If hypernatremia develops, switching to 0.45% saline until correction of hypernatremia is recommended (to replace free water loss as a result of the glucose-induced osmotic diuresis).10 Close hemodynamic monitoring should be performed during the first 4 hours; this includes hourly urine output through an indwelling catheter and vital signs surveillance every 15 minutes. Continuous oxygen saturation should be monitored and supplemental oxygen is given as needed. The patient’s response to treatment is evaluated with arterial blood gas monitoring, serum ketones, electrolytes, glucose, and anion gap every 1–3 hours. Investigation and management of the precipitating factors should be performed simultaneously and corrected promptly.22
Insulin Therapy Correction of hyperglycemia is best achieved with IV short-acting insulin. Regular insulin is administered as an 8- to 10-unit bolus followed by 0.1 units/kg/h until the serum bicarbonate and anion gap normalize and serum ketones become absent. Because correction of acidemia takes much longer than correction of hyperglycemia, insulin should be continued at a basal infusion rate of 1–2 units/h after normoglycemia is established and to be discontinued only after the first subcutaneous dose of regular insulin is administered.10
Monitoring of Acidosis and Correction of Electrolytes Correction of electrolyte imbalances, particularly hypokalemia, should start as soon as adequate renal function is documented. As mentioned, serum levels of potassium may appear deceivingly normal or
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slightly elevated, but the total body potassium is usually low. In diabetic ketoacidosis, the total potassium deficit is typically 5–10 mEq/L. During the administration of insulin, volume replacement, and correction of acidosis, potassium shifts from the extracellular to the intracellular space. To prevent fatal arrhythmias, it is important to keep serum potassium levels between 4 and 5 mEq/L. This is best accomplished by IV administration of potassium chloride (Table 1 ).60 Adequate urine output must be maintained at all times (greater than 0.5 mL/kg/h). Phosphate replacement is not usually required unless levels fall below 1 mg/dL, cardiac dysfunction ensues, or signs of obtundation are noted. Phosphorus may be replaced in conjunction with potassium by administering 10–20 mEq/L of potassium phosphate for each 10–20 mEq/L of potassium chloride.11 The need for replacement of other electrolytes including bicarbonate, magnesium, and calcium is debatable. Administration of bicarbonate may be associated with profound alkalosis or worsening acidemia secondary to increased partial pressure of carbon dioxide, leading in turn to impaired fetal oxygen transfer.10 Some authors recommend bicarbonate administration during severe acidemia (pH less than 7) or in patients complicated by cardiac dysfunction, sepsis, or shock61; however, further research is required to assess the potential risks and benefits of such therapy. In the setting of diabetic ketoacidosis in patients with type 1 DM, point-of-care b-hydroxybutyrate capillary ketone testing is routinely used.62,63 This test only measures 3-b-hydroxybutyrate, whereas the nitroprusside test for ketones in urine detects only acetoacetate.62 Point-of-care capillary testing assists in prompt detection and subsequent management of diabetic ketoacidosis. Ketone levels can be checked serially and are more accurate than urine ketone testing, because concentrations of 3-b-hydroxybutyrate are typically 10-fold higher compared with acetoacetate.64 In response to insulin, 3-b-hydroxybutyrate levels commonly decrease long before acetoacetate levels.21
Table 1. Suggested Protocol for Potassium Repletion According to Serum Levels Potassium Level Greater than 5 mEq/L 4–5 mEq/L 3–4 mEq/L 3 mEq/L or less
Intervention No treatment 20 mEq/L replacement 30–40 mEq/L replacement 40–60 mEq/L replacement
Data from Carroll MA, Yeomans ER. Diabetic ketoacidosis in pregnancy. Crit Care Med 2005;33(suppl):S347–53.
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MANAGEMENT COMPLICATIONS AND PROGNOSIS The vast majority of patients with diabetic ketoacidosis in pregnancy recover with no sequelae. Delayed recognition and inappropriate management carry elevated maternal and fetal morbidity. Most complications result from inadequate fluid management and premature discontinuation of insulin. In addition, failure to promptly recognize and correct precipitating factors (ie, infections) is associated with a worse prognosis and higher recurrence rates (ie, inadequate home insulin administration). A rare but potentially fatal complication is cerebral edema. In most reported series, no direct association with the metabolic disturbances in diabetic ketoacidosis has been reported, although aggressive hydration (particularly with hypotonic solutions) is certainly a contributing factor.59 Furthermore, the occurrence of hyperchloremic acidosis has been reported in patients resuscitated with normal saline given its relative acidic pH of 5.5 and high chloride content. It has been proposed that the use of more physiologic, balanced crystalloid solutions such as PlasmaLyte during resuscitation may reduce the incidence of this complication given similar serum chloride concentrations and neutral pH.65 Other complications with varying degrees of severity have been described and include hypoglycemia, acute respiratory distress syndrome, pulmonary edema, and bronchial mucous plugging.66–68 Aggressive potassium replacement during the acute episode in the absence of adequate urine output may result in fatal arrhythmias.
Investigation and Management of Precipitating Factors Once hemodynamic status and metabolic abnormalities have been addressed, it is important to evaluate for and treat potential precipitating factors such as infection or use of b-sympathomimetic agents. Infections are major precipitating factors for diabetic ketoacidosis, and thus evaluation for infection should be done even in the absence of fever. The source of infection can be the urinary tract, upper airway or pneumonia, gallbladder, ear, tooth abscess, cellulitis, or wound infections in case of surgery.69 Once identified, the source of infection should be treated with appropriate antibiotics, surgery, or antibiotics and surgery as indicated. In addition, if b-agonists are being used, they should be discontinued.4
Fetal Monitoring and Timing of Delivery The metabolic derangements that take place during diabetic ketoacidosis result in fetal hypoxemia and
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acidosis, which may influence all modes of fetal testing. Fetal heart rate monitoring is recommended in patients with gestational age of 24 or more weeks.33 Fetal heart rate monitoring during the acute episode of diabetic ketoacidosis often reveals minimal or absent variability, absent accelerations, repetitive variable, and late decelerations (Fig. 2A). The fetal biophysical profile can also be abnormal, and Doppler studies may show signs of blood flow redistribution (ie, increased umbilical artery pulsatility index and reduced middle cerebral artery pulsatility index).70 The frequency and severity of these abnormalities will depend on severity and duration of diabetic ketoacidosis. After correction of the metabolic derangements in diabetic ketoacidosis and maternal stabilization, these fetal abnormalities will usually improve; however, it may take 4–8 hours for the fetal heart rate tracing to become normal.71 The decision to continue pregnancy or to proceed with delivery in the setting of diabetic ketoacidosis can be challenging, but it must be based on fetal gestational age, maternal status, fetal status, and the response to treatment. The natural inclination is to proceed with emergent cesarean delivery for concerning fetal status before stabilizing the maternal condition. Diabetic ketoacidosis per se is not an indication for emergent delivery because a premature decision to proceed with cesarean delivery increases the risk of maternal mortality and morbidity. In addition, it may lead to unnecessary preterm delivery of a hypoxic and acidotic neonate (Fig. 2C). It is imperative to stabilize the maternal condition first because this will often improve the fetal status and potentially avoid the previously mentioned complications. If fetal status does not improve or if the maternal condition continues to deteriorate despite aggressive therapy, delivery is warranted. On the other hand, if maternal condition stabilizes and the fetal abnormalities resolve, pregnancy is continued and most often patients will be discharged home safely.
PREVENTION Women with pregestational DM planning pregnancy should be educated about the risks of diabetic ketoacidosis before conception as well as during pregnancy. In addition, all pregnant women not known to be diabetic should receive screening for GDM at 24–28 weeks of gestation and earlier in pregnancy in those with certain risk factors (obesity, strong family history of type 2 DM, obesity, history of GDM, impaired glucose metabolism, or glucosuria).12,72 Those with pregestational and GDM should be instructed about the importance of compliance with diet, exercise, compliance with prenatal visits,
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measurements and recordings of glucose values, and therapy (oral agents or insulin). All pregnant patients should be vaccinated against influenza during the flu season. In addition, they need to be educated about precipitating factors, signs, and symptoms of diabetic ketoacidosis including when to seek medical help.3 Patients with either persistent blood glucose values above 200 mg/dL despite therapy, persistent vomiting, diarrhea, polyuria, drowsiness, or who have evidence of infections require prompt hospitalization. Medical providers should have a low threshold for hospitalization of patients who demonstrate repeated episodes of noncompliance with instructions and therapy, because such patients are at very high risk for diabetic ketoacidosis. In case of threatened or true preterm labor, medical providers should avoid using subcutaneous or oral terbutaline. If true preterm labor is present, the patient should be hospitalized and treated with a different class of tocolytic. In addition, if corticosteroids are used for fetal lung maturity, the dose of insulin should be adjusted accordingly.4
CONCLUSION Diabetic ketoacidosis is a rare but serious complication of diabetes in pregnancy with deleterious consequences for both the mother and the fetus. Prompt recognition of precipitating factors, aggressive correction of volume depletion and electrolyte imbalance, and insulin administration are paramount in the management of diabetic ketoacidosis. A multidisciplinary approach and continuous monitoring of the maternal response to therapy are critical to decrease the overall morbidity and mortality. After viability, fetal monitoring also is indicated, and it is imperative to correct the maternal metabolic abnormalities before considering emergent delivery, because both maternal and fetal conditions will likewise improve.73 REFERENCES 1. Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2006;29:2739–48. 2. Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone Jl, et al. Hyperglycemic crises in diabetes. Diabetes Care 2004;27(suppl 1):S94–102. 3. Landon M, Gabbe S. Gestational diabetes mellitus. Obstet Gynecol 2011;118:1379–93. 4. Gabbe S, Graves C. Management of diabetes mellitus complicating pregnancy. Obstet Gynecol 2003;102:857–68.
7. Chauhan SP, Perry KG, McLaughlin BN, Roberts WE, Sullivan CA, Morrison JC. Diabetic ketoacidosis complicating pregnancy. J Perinatol 1996;16:173–5. 8. Cullen MT, Reece EA, Homko CJ, Civan E. The changing presentations of diabetic ketoacidosis during pregnancy. Am J Perinatol 1996;13:449–51. 9. Kamalakannan D, Baskar V, Barton DM, Abdu TA. Diabetic ketoacidosis in pregnancy. Postgrad Med J 2003;79:454–7. 10. Parker JA, Conway DL. Diabetic ketoacidosis in pregnancy. Obstet Gynecol Clin North Am 2007;34:533–43, xii. 11. Ramin KD. Diabetic ketoacidosis in pregnancy. Obstet Gynecol Clin North Am 1999;26:481–8, viii. 12. Gestational diabetes mellitus. Practice Bulletin No. 137. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;122:406–16. 13. Wier LM, Witt E., Burgess J, Elixhauser A (AHRQ). Hospitalizations related to diabetes in pregnancy, 2008. HCUP Statistical Brief #102. Rockville (MD): Agency for Healthcare Research and Quality; 2010. Available at: http://www.hcup-us.ahrq.gov/ reports/statbriefs/sb102.pdf. Retrieved August 17, 2013. 14. World Diabetes Foundation, Global Alliance for Women’s Health. Diabetes, Women, and Development: meeting summary, expert recommendations for policy action, conclusions, and follow-up actions, Int J Gynecol Obstet 2009;104(suppl 1): S46–50. 15. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta (GA): U.S. Department of Health and Human Services; 2011. 16. Schneider M, Umpierrez G, Ramsey R, Mabie W, Bennett K. Pregnancy complicated by diabetic ketoacidosis: maternal and fetal outcomes. Diabetes Care 2003;26:958–9. 17. Maislos M, Harman-Bohem I, Weitzman S. Diabetic ketoacidosis: a rare complication of gestational diabetes. Diabetes Care 1992;15:968–70. 18. Madaan M, Aggarwal K, Sharma R, Trivedi S. Diabetic ketoacidosis occurring with lower blood glucose levels in pregnancy: a report of two cases. J Reprod Med 2012;57:452–5. 19. Young BC, Wylie BJ. Effects of twin gestation on maternal morbidity. Semin Perinatol 2012;36:162–8. 20. Schwartz D, Daoud Y, Zazula P, Goyert G, Bronsteen R, Wright D, et al. Gestational diabetes mellitus: metabolic and blood glucose parameters in singleton versus twin pregnancies. Am J Obstet Gynecol 1999;181:912–4. 21. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999;15:412–26. 22. Sibai BM. Management of acute obstetrics emergencies: female pelvic surgery video atlas series. 1st ed. Philadelphia (PA): Saunders Elsevier; 2011. p. 137–41. 23. Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol 1991;165: 1667–72. 24. Tamay A, Kus¸çu N. Hyperemesis gravidarum: current aspect. J Obstet Gynaecol 2011;31:708–12.
5. Kilvert JA, Nicholson HO, Wright AD. Ketoacidosis in diabetic pregnancy. Diabet Med 1993;10:278–81.
25. Deepak D, Ingham D, Reynolds RM, Walker JD. A case of euglycaemic ketoacidosis in pregnancy—a reply. Diabet Med 2002;19:699.
6. 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.
26. Shinagawa S, Suzuki S, Chihara H, Otsubo Y, Takeshita T, Araki T. Maternal basal metabolic rate in twin pregnancy. Gynecol Obstet Invest 2005;60:145–8.
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27. Butte N, Wong W, Treuth M, Ellis K, O’Brian Smith E. Energy requirements during pregnancy based on total energy expenditure and energy deposition. Am J Clin Nutr 2004;79:1078–87. 28. Montelongo A, Lasunción MA, Pallardo LF, Herrera E. Longitudinal study of plasma lipoproteins and hormones during pregnancy in normal and diabetic women. Diabetes 1992; 41:1651–9. 29. Jovanovic-Peterson L, Peterson C. Sweet success, but an acid aftertaste? N Engl J Med 1991;325:959–60. 30. Franke B, Carr D, Hatem MH. A case of euglycaemic diabetic ketoacidosis in pregnancy. Diabet Med 2001;18:858–9. 31. Oliver R, Jagadeesan P, Howard RJ, Nikookam K. Euglycaemic diabetic ketoacidosis in pregnancy: an unusual presentation. J Obstet Gynaecol 2007;27:308. 32. Napoli A, Framarino M, Colatrella A, Merola G, Trappolini M, Toscano V, et al. Eating disorders and diabetic ketoacidosis in pregnant woman with type 1 diabetes: a case report. Eat Weight Disord 2011;16:e146–9. 33. Moore TR. Diabetes in pregnancy. In: Creasy RK, Resnik R, Iams JD, editors. Maternal-fetal medicine. 5th ed. Philadelphia (PA): Saunders; 2004. p. 1031–2. 34. Munro JF, Campbell IW, McCuish AC, Duncan LJ. Euglycemic diabetic ketoacidosis. Br Med J 1973;2:578–80. 35. Darbhamulla S, Shah N, Bosio P. Euglycaemic ketoacidosis in a patient with gestational diabetes. Eur J Obstet Gynecol Reprod Biol 2012;163:118–9. 36. Guo R, Yang L, Li L, Zhao X. Diabetic ketoacidosis in pregnancy tends to occur at lower blood glucose levels: case-control study and a case report of euglycemic diabetic ketoacidosis in pregnancy. J Obstet Gynaecol Res 2008;34:324–30. 37. Tarif N, Al Badr W. Euglycemic diabetic ketoacidosis in pregnancy. Saudi J Kidney Dis Transpl 2007;18:590–3. 38. Pinto M, Villena J. Diabetic ketoacidosis during gestational diabetes. A case report. Diabetes Res Clin Pract 2011;93:e92–4. 39. Aldoretta PW, Hay WW Jr. Metabolic substrates for fetal energy metabolism and growth. Clin Perinatol 1995;22:15–36. 40. Hughes AB. Fetal heart rate changes during diabetic ketosis. Acta Obstet Gynecol Scand 1987;66:71–3. 41. Chauhan SP, Perry KG Jr. Management of diabetic ketoacidosis in the obstetric patient. Obstet Gynecol Clin North Am 1995; 22:143–55. 42. Ditzel J, Standl E. The oxygen transport system of red blood cells during diabetic ketoacidosis and recovery. Diabetologia 1975;11:255–60. 43. Philipps AF, Rosenkrantz TS, Raye J. Consequences of perturbations of fetal fuels in ovine pregnancy. Diabetes 1985;34 (suppl 2):32–5. 44. Kitzmiller JL. Diabetic ketoacidosis and pregnancy. Contemp Obstet Gynecol 1982;20:141–7. 45. Hawthorne G. Maternal complications in diabetic pregnancy. Best Pract Res Clin Obstet Gynaecol 2011;25:77–90. 46. Rodgers BD, Rodgers DE. Clinical variables associated with diabetic ketoacidosis during pregnancy. J Reprod Med 1991; 36:797–800. 47. Chen R, Ben-Haroush A, Weissmann-Brenner A, Melamed N, Hod M, Yogev Y. Level of glycemic control and pregnancy outcome in type 1 diabetes: a comparison between multiple daily insulin injections and continuous subcutaneous insulin infusions. Am J Obstet Gynecol 2007;197:404.e1–5. 48. Bedalow A, Balasubramnyam A. Glucocorticoid-induced ketoacidosis in gestational diabetes: sequelae of the acute treatment of preterm labor. Diabetes Care 1997;20:922–4.
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49. Mathiesen ER, Christensen AB, Hellmuth E, Hornnes P, Stage E, Damm P. Insulin dose during glucocorticoid treatment for fetal lung maturation in diabetic pregnancy: test of an algorithm [correction of analgoritm]. Acta Obstet Gynecol Scand 2002;81:835–9. 50. Bernstein IM, Catalano PM. Ketoacidosis in pregnancy associated with parenteral administration of terbutaline and betamethasone. A case report. J Reprod Med 1990;35:818–20. 51. Kitzmiller JL, Block JM, Brown FM, Catalano PM, Conway DL, Coustan DR, et al. Managing preexisting diabetes in pregnancy. Diabetes Care 2008;31:1060–79. 52. Rizzo T, Metzger BE, Burns WJ, Burns K. Correlations between antepartum maternal metabolism and child intelligence. N Engl J Med 1991;325:911–6. 53. Churchill JA, Berendes HW, Nemore J. Neuropsychological deficits in children of diabetic mothers. A report from the Collaborative Sdy of Cerebral Palsy. Am J Obstet Gynecol 1969; 105:257–68. 54. Harding JE, Charlton VE. Effect of lactate and betahydroxybutyrate infusions on brain metabolism in the fetal sheep. J Dev Physiol 1990;14:139–46. 55. Wooton-Gorges SL, Buoconore MH, Kuppermann N, Marcin J, Dicarlo J, Neely EK, et al. Detection of cerebral {beta}-hydroxy butyrate, acetoacetate, and lactate on proton MR spectroscopy in children with diabetic ketoacidosis. AJNR Am J Neuroradiol 2005;26:1286–91. 56. Wooton-Gorges SL, Buoconore MH, Kuppermann N, Marcin JP, Barnes PD, Neely EK, et al. Cerebral proton magnetic resonance spectroscopy in children with diabetic ketoacidosis. AJNR Am J Neuroradiol 2007;28:895–9. 57. Krakowiak P, Walker C, Bremer A, Baker AS, Ozonoff S, Hansen RL, et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics 2012;129:e1121–8. 58. Stenerson MB, Collura CA, Rose CH, Lteif AN, Carey WA. Bilateral basal ganglia infarctions in a neonate born during maternal diabetic ketoacidosis. Pediatrics 2011;128:e707–10. 59. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care 1990;13:22–33. 60. Carroll MA, Yeomans ER. Diabetic ketoacidosis in pregnancy. Crit Care Med 2005;33(suppl):S347–53. 61. Gabbe SG, Holing E, Temple P, Brown Z. Benefits, risks, costs and patient satisfaction associated with insulin pump therapy for the pregnancy complicated by type I diabetes mellitus. Am J Obstet Gynecol 2000;182:1283–91. 62. Arora S, Henderson SO, Long T, Menchine M. Diagnostic accuracy of point of care testing for diabetic ketoacidosis at emergency department triage: {beta}-hydroxybutyrate versus dipstick. Diabetes Care 2011;34:852–4. 63. Wallace TM, Mathews DR. Recent advances in the monitoring and management of diabetic ketoacidosis. QJM 2004;97: 773–80. 64. Frise C, Mackillop L, Joash K, Williamson C. Starvation ketoacidosis in pregnancy. Eur J Obstet Gynecol Reprod Biol 2013; 167:1–7. 65. Mahler SA, Conrad SA, Wang H, Arnold TC. Resuscitation with balanced electrolyte solution prevent hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med 2011;29:670–4. 66. Brun-Buisson CJ, Bonnet F, Bergeret S, Lemaire F, Rapin M. Recurrent high-permeability pulmonary edema associated with diabetic ketoacidosis. Crit Care Med 1985;13:55–6.
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67. Brandstetter RD, Tamarin FM, Washington D, Wing M, Eufemio M. Occult mucous airway obstruction in diabetic ketoacidosis. Chest 1987;91:575–8.
ketoacidosis diagnosed by Doppler ultrasonography. Prenat Diagn 2000;20:524–5.
68. Hansen LA, Prakash UB, Colby TV. Pulmonary complications in diabetes mellitus. Mayo Clin Proc 1989;64:791–9.
71. Hagay ZJ, Weissman A, Laurie S, Insler V. Reversal of fetal distress following intensive treatment of maternal diabetic ketoacidosis. Am J Perinatol 1994;11:430–2.
69. Gabbe S, Carpenter L, Garrison E. New strategies for glucose control in patients with type 1 and type 2 diabetes mellitus during pregnancy. Clin Obstet Gynecol 2007;50: 1014–24.
72. Metzger BE, Buchanan TA, Coustan DR, de Leiva A, Dunger DB, Hadden DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 2007;30(suppl 2):S251–60.
70. Takahashi Y, Kawabata I, Shinohara A, Tamaya T. Transient fetal blood flow redistribution induced by maternal diabetic
73. LoBue C, Goodlin RC. Treatment of fetal distress during diabetic keto-acidosis. J Reprod Med 1978;20:101–4.
Continuing Medical Education Credits Available for the Clinical Expert Series Continuing medical education (CME) credits are available for reading the Clinical Expert Series. Visit http://www.greenjournal.org and click on the “CME” tab to read the articles and complete their associated quizzes. ACCME Accreditation The American College of Obstetricians and Gynecologists is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. AMA PRA Category 1 Credit(s)™ The American College of Obstetricians and Gynecologists designates this journal-based CME activity for a maximum of 2 AMA PRA Category 1 Credits.™ Physicians should claim only the credit commensurate with the extent of their participation in the activity. College Cognate Credit(s) The American College of Obstetricians and Gynecologists designates this journal-based CME activity for a maximum of 2 Category 1 College Cognate Credits. The College has a reciprocity agreement with the AMA that allows AMA PRA Category 1 Credits™ to be equivalent to College Cognate Credits. rev 7/2013
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Diabetic Ketoacidosis in Pregnancy Baha M. Sibai,
MD,
and Oscar A. Viteri,
MD
Pregnancies complicated by diabetic ketoacidosis are associated with increased rates of perinatal morbidity and mortality. A high index of suspicion is required, because diabetic ketoacidosis onset in pregnancy can be insidious, usually at lower glucose levels, and often progresses more rapidly as compared with nonpregnancy. Morbidity and mortality can be reduced with early detection of precipitating factors (ie, infection, intractable vomiting, inadequate insulin management or inappropriate insulin cessation, b-sympathomimetic use, steroid administration for fetal lung maturation), prompt hospitalization, and targeted therapy with intensive monitoring. A multidisciplinary approach including a maternal-fetal medicine physician, medical endocrinology specialists familiar with the physiologic changes in pregnancy, an obstetric anesthesiologist, and skilled nursing is paramount. Management principles include aggressive volume replacement, initiation of intravenous insulin therapy, correction of acidosis, correction of electrolyte abnormalities and management of precipitating factors, as well as monitoring of maternal-fetal response to treatment. When diabetic ketoacidosis occurs after 24 weeks of gestation, fetal status should be continuously monitored given associated fetal hypoxemia and acidosis. The decision for delivery can be challenging and must be based on gestational age as well as maternal-fetal responses to therapy. The natural inclination is to proceed with emergent delivery for nonreassuring fetal status that is frequently present during the acute episode, but it is imperative to correct the maternal metabolic abnormalities first, because both maternal and fetal conditions will likewise improve. Prevention strategies should include education of diabetic pregnant women about the risks of diabetic ketoacidosis, precipitating factors, and the importance of reporting signs and symptoms in a timely fashion. (Obstet Gynecol 2014;123:167–78) DOI: 10.1097/AOG.0000000000000060
D
iabetic ketoacidosis is one of the most serious acute complications of diabetes and is characterized by the triad of uncontrolled hyperglycemia, anion gap metabolic acidosis, and ketosis.1,2 Diabetic ketoacidosis is an infrequent complication of pregestational or gestational diabetes mellitus (GDM) during pregnancy, but in the absence of prompt diagnosis and treatment, it can be life-threatening to the mother From the Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, the University of Texas Health Science Center at Houston, Houston, Texas. Continuing medical education for this article is available at http://links.lww. com/AOG/A457. Corresponding author: Baha M. Sibai, MD, 6410 Fannin Street, Suite 210, Houston, TX 77030; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2013 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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and fetus. The worldwide prevalence of diabetes has risen dramatically over the past two decades, corresponding with increasing trends to higher-calorie diets as well as decreased physical activity leading to obesity. Furthermore, the increased rates of obese women and the continued immigration to the United States among populations with high prevalence of type 2 diabetes mellitus (DM) have all significantly contributed to the increasing incidence of gestational and type 2 DM in pregnancy.3 During the past decade, there has been considerable effort to improve pregnancy outcomes in women with type 1 and type 2 DM as well as GDM with preconception and first-trimester control of maternal hyperglycemia, early detection of type 2 DM and GDM (universal screening), nutritional counseling, frequent glucose monitoring, proper oral hypoglycemic or insulin therapy, and timely hospitalization and delivery.3,4 Nevertheless, diabetic ketoacidosis continues to occur in a small percentage of patients with diabetes in pregnancy.
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The purpose of this report is to review the English literature regarding the incidence, pathophysiology, risk factors, diagnosis, management, outcome, and prevention of diabetic ketoacidosis in pregnancy.
INCIDENCE The true incidence of diabetic ketoacidosis in pregnancy is difficult to ascertain and epidemiologic data are based mainly on case reports, retrospective studies with small numbers, and review articles.5–11 Historically, the reported incidence of diabetes in pregnancy ranges from 6% to 7% with 90% of these cases representing women with GDM.12,13 The two populations with the highest risk of diabetes in pregnancy are obese African Americans and those of Hispanic or Latino descent with an overall prevalence as high as 30%.12,14–16 Diabetic ketoacidosis occurrence during pregnancy is exceedingly rare with a reported incidence between 0.5% and 3% of all diabetic gestations.6,11 Formerly considered a hallmark of type 1 DM, diabetic ketoacidosis is now increasingly being reported in individuals with poorly controlled type 2 DM or GDM.17,18 The incidence of diabetic ketoacidosis in pregnancy is expected to increase because of the increased frequency of type 2 DM and gestational diabetes during pregnancy as a result of the change in demographics of women who are pregnant. Pregnancies in women 35 years or older are much more common than a decade ago. Advanced maternal age is associated with increased rates of obesity and both type 2 DM and GDM. Some of these women will also conceive by assisted reproductive technology, resulting in multifetal pregnancies. Indeed, higher order gestations are associated with increased rates of GDM; however, the magnitude of this risk is unclear.19,20 In addition, multifetal gestations are associated with increased rates of preterm labor or premature rupture of membranes,19 resulting in the need for corticosteroids for fetal lung maturation, which, if complicated by diabetes, may increase the maternal risk of diabetic ketoacidosis.
glucose precursors: lipolysis results in excess amounts of glycerol released to the circulation and muscle breakdown results in the release of amino acids, both of which are readily available as sources of energy. Furthermore, as a result of the state of insulin resistance, there is increased lipolysis, which in turn decreases adipocyte storage of free fatty acids.10 The metabolic derangements during an episode of diabetic ketoacidosis result in a chain of events that selfperpetuate the process in a vicious cycle. The elevated glucose levels in the intravascular space create an osmotic gradient, resulting in marked diuresis that in turn leads to a profound state of dehydration and hypovolemia. This further exacerbates the hyperglycemia and acidosis because it promotes the activation of other counterregulatory stress hormones (ie, growth hormone, cortisol). Furthermore, measured sodium levels can become abnormally low as a result of the osmotic diuresis. Additionally, electrolyte salts containing sodium, potassium, and phosphorus become bound to anions from ketoacids in the bloodstream and are excreted in the urine.9 Protein breakdown (as a consequence of the perceived state of starvation) and decreased potassium cellular uptake resulting from the lack of insulin result in normal or elevated serum potassium levels in the presence of diminished total body potassium. During diabetic ketoacidosis, increased b-oxidation of fatty acids resulting from insulin deficiency and concomitant elevations of counterregulatory hormones increase production of acetyl CoA, which in turn is converted by the liver to ketone bodies (3b-hydroxybutyrate and acetoacetate).21 Acetoacetate can undergo decarboxylation and conversion to acetone (which presents as a fruity odor in the patient’s breath). Increasing amounts of ketone bodies in the bloodstream along with lactic acid (which also serves as a gluconeogenesis precursor) are the principal contributors to the metabolic acidosis seen in patients with diabetic ketoacidosis (Fig. 1).22
PATHOPHYSIOLOGY
METABOLIC CONSIDERATIONS UNIQUE TO PREGNANCY
The metabolic profile of diabetic ketoacidosis is the result of an exaggerated counterregulatory response to a perceived lack of glucose supply at the cellular level. In the absence of adequate insulin availability, cells enter a state of starvation, which in turn activates alternative energy-producing pathways. Levels of glucagon and epinephrine are markedly elevated during starvation. Glycogen storages are rapidly depleted, and gluconeogenesis becomes the primary metabolic pathway. There are abundant sources of
Pregnancy is a state of insulin resistance, accelerated starvation, and respiratory alkalosis, especially in the late second and throughout the third trimester. Insulin sensitivity has been demonstrated to decrease by as much as 56% by 36 weeks of gestation.23 Several hormones unique to pregnancy such as human placental lactogen and prolactin antagonize the effects of insulin at the cellular level. Other hormones unique to pregnancy also play a role in predisposing a diabetic pregnant woman to develop diabetic ketoacidosis. Early in
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• Inadequate circulating insulin • Increased insulin resistance
• Reduced glucose utilization or storage ◦ Muscles ◦ Liver ◦ Adipose tissue
• Increased counterregulatory hormones ◦ Glucagon ◦ Cortisol ◦ Catecholamines ◦ Growth hormone
Hyperglycemia
Fig. 1. Pathophysiology of diabetic ketoacidosis in pregnancy. Modified from Sibai BM. Management of acute obstetrics emergencies: female pelvic surgery video, atlas series. 1st ed. Philadelphia (PA): Saunders, Elsevier; 2011. p. 140. Sibai. Diabetic Ketoacidosis in Pregnancy. Obstet Gynecol 2014.
• Maternal effects ◦ Osmotic diuresis ◦ Hypovolemia ◦ Hypokalemia • Fetal effects ◦ Hypokalemia leading to arrythmias ◦ Hyperglycemia ◦ Hyperinsulinemia
Maternal and fetal acidosis
pregnancy, high levels of human chorionic gonadotropin are associated with increased nausea and vomiting,24 which may trigger a cascade of starvation, dehydration, and acidosis as well as activation of stress-related hormones (Fig. 1). Progesterone also decreases the gastrointestinal motility and enhances the carbohydrate absorption, thus promoting hyperglycemia. Diabetic pregnant women at more than 20 weeks of gestation are more prone to develop more severe and rapidly progressive episodes of diabetic ketoacidosis (usually over hours) and at lower glycemic levels (less than 300 mg/dL).22 Furthermore, diabetic pregnant women are more sensitive to starvation, infection, and extrinsic ketogenic factors such as excessive alcohol intake.25 The maternal metabolic rate increases by approximately 300 kcal/d in the third trimester.26,27 Maternal ketone body levels during fasting are elevated by 33% during the third trimester as compared with the postpartum state.21,28 Ketone bodies can be detected in the urine of pregnant women who are fasting in approximately 30% of the first morning specimens.21,29 Starvation resulting from poor nutritional status or persistent vomiting leads to reduced carbohydrate intake and both have been associated with the development of diabetic ketoa-
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• Increased hepatic glucose production ◦ Gluconeogenesis, glycogenolysis • Increased ketogenesis (liver) • Increased lipolysis
• Release of free fatty acids and conversion to ketone bodies ◦ 3β–hydroxybutirate ◦ Acetoacetate ◦ Acetone
cidosis in euglycemic diabetic pregnant women.25,30,31 Furthermore, it has been suggested that the development of diabetic ketoacidosis and starvation in the pregnant type 1 diabetic with eating disorders may not be rare.32 In addition, the increased minute alveolar ventilation places the pregnant woman in a state of respiratory alkalosis and is counterregulated by increased renal excretion of bicarbonate. This results in a lowered buffering capacity, which further contributes to the development of diabetic ketoacidosis at lower glycemic levels than those seen in nonpregnant patients.33
Euglycemic Ketoacidosis Euglycemic ketoacidosis was first described by Munro et al in 1973 and is defined as severe ketoacidosis with a serum bicarbonate of 10 mEq/L or less in the absence of pronounced hyperglycemia.34,35 All participants had type 1 DM, and blood glucose levels were less than 300 mg/dL. However, during pregnancy, euglycemic ketoacidosis has also been reported to occur in pregestational type 2 DM and GDM.18,36–38 True euglycemic ketoacidosis is exceedingly rare, occurring in 0.8–1.1% of all episodes (depending on the defining plasma bicarbonate concentration).7
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Metabolic Considerations in the Fetoplacental Compartment The mechanism of fetal loss during episodes of diabetic ketoacidosis still remains elusive. Both ketoacids and glucose readily cross the placenta. Fetoplacental demands for glucose are considerable and approach the equivalent of 150 g/d in the third trimester.39 Glucose transport to the fetus is augmented by a fivefold increase in the placental glucose transporter (GLUT-1), which increases transplacental glucose efflux even in the absence of maternal hyperglycemia.26,27 The effects of maternal acidosis, hyperglycemia, dehydration, or electrolyte imbalance on fetal status is unclear, because data are based on limited case reports of fetal heart tracings or animal models.40,41 The massive osmotic diuresis and consequent dehydration leads to volume depletion resulting in reduced uteroplacental perfusion. In addition, maternal acidemia can decrease the placental blood flow with resultant fetal hypoxia. Fetal hypoxemia can also be caused as a consequence of maternal hypophosphatemia, which causes a decrease in 2,3-diphosphoglycerate resulting in a decreased oxygen release from the red blood cells.42 Fetal hyperinsulinemia resulting from maternal hyperglycemia also increases fetal oxygen requirements by stimulating the oxidative metabolic pathway.43 Maternal hypokalemia and fetal hyperinsulinemia could potentially cause fetal hypokalemia leading to fatal arrhythmias.9,22,44
Precipitating Factors for Diabetic Ketoacidosis in Pregnancy Factors precipitating episodes of diabetic ketoacidosis in pregnant patients have been well established22,45,46 and are listed in Box 1. Vomiting and the use of betamimetic drugs accounted for 57% of the episodes of diabetic ketoacidosis in one case series.46 Schneider et al16 evaluated 888 pregnant women with diabetes using insulin over 10 years and found that 11 women (1.2%) presented with diabetic ketoacidosis. The most common causes of diabetic ketoacidosis in these patients were infections (27%) and a history of insulin therapy omission (18%). Chen et al47 compared multiple daily insulin injections with continuous subcutaneous insulin infusions in the management of type 1 DM. Patients treated with continuous subcutaneous insulin injections had a significantly higher rate of diabetic ketoacidosis episodes (13% compared with 1.6%, P5.04). Diabetic pregnant women on chronic corticosteroid therapy are at increased risk for diabetic ketoacidosis because of the effects of steroids on serum glucose values as well as increased risk for infection.48
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Box 1. Precipitating Factors for Diabetic Ketoacidosis in Pregnancy Protracted vomiting, starvation Infections (pyelonephritis, respiratory, chorioamnionitis, ear infection, cellulitis, tooth abscess) Undiagnosed diabetes Poor control of blood sugars or poor compliance with treatment Insulin pump failure Use of b-sympathomimetic agents for tocolysis Steroid use for fetal lung maturation or for chronic medical disorders Diabetic gastroparesis
In addition, the administration of corticosteroids for fetal lung maturation will result in acute elevations in serum glucose values within 6 hours after the first dose and can last up to 3 days after the last dose.49 Therefore, these women should be hospitalized for frequent serum glucose values, and the dose of insulin should be increased as needed. The effects of corticosteroids will be more pronounced when used in association with b-agonists that may be used to treat uterine contractions and preterm labor.50 Gastroparesis usually occurs in patients with longstanding diabetes in association with other microvascular complications such as nephropathy and retinopathy. It is associated with delayed gastric emptying resulting in protracted nausea, vomiting and dehydration, and persistent postprandial hyperglycemia. These metabolic abnormalities combined increase the risk of diabetic ketoacidosis.45,51
MATERNAL AND PERINATAL COMPLICATIONS Although diabetic ketoacidosis is infrequent during pregnancy, its development may result in serious maternal morbidities (acute renal failure, adult respiratory distress syndrome, myocardial ischemia, cerebral edema) and even death.9,10 The frequency of these complications depends on the severity of the maternal condition at the time of presentation and adequacy of management used (stabilization of the maternal condition before induction of labor or emergency cesarean delivery). In recent years, the reported maternal mortality in diabetic ketoacidosis has been less than 1% with a reported fetal mortality rate of 9–36%.8,16,45 However, perinatal morbidities such as
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preterm delivery, hypoxia, and acidosis still remain high. An association has been reported between elevated ketoacids during pregnancy and lower IQ scores as well as decreased mental developmental score during the second year of life.52 Furthermore, an association has also been reported between ketonuria detected during prenatal visits and adverse neurobehavioral outcomes even in nondiabetic pregnancies.53 The fetal brain is particularly susceptible to increased levels of b-hydroxybutyrate and lactate concentrations, which decrease glucose uptake by the fetal brain.54 Also, these substances are known to accumulate in the basal ganglia of children during episodes of diabetic ketoacidosis.55,56 The acidotic environment that develops has been associated with poor myelination and poor cortical connectivity as well as aberrations in the hypocampal neurons. These findings have been linked with greater deficits in expressive language among children diagnosed with autism spectrum disorder.48 Future research is thus needed to further elucidate the effect of maternal ketoacids on fetal brain injury.57,58
DIAGNOSIS OF DIABETIC KETOACIDOSIS IN PREGNANCY Clinical Presentation The signs and symptoms of diabetic ketoacidosis during pregnancy are not pathognomonic and tend to develop faster during pregnancy than in the nonpregnant state (Box 2). A high level of suspicion is required for prompt recognition and management of the disease. An episode of diabetic ketoacidosis may be the initial presentation that leads to a diagnosis of type 1 diabetes. Intractable nausea and vomiting in a known diabetic patient warrant laboratory evaluation for diabetic ketoacidosis. Abdominal pain may be severe, and the gravid patient might experience uterine contractions (Fig. 2A). Hyperglycemia leads to glucosuria, intravascular volume depletion, increased diuresis, and dehydration. Kussmaul respirations and a fruity odor in the patient’s breath might be present in advanced disease. Lethargy and central nervous system manifestations are also an effect of the buildup of ketoacids that could lead to a state of disorientation, obtundation, and even coma resulting from cerebral edema.59
Standard Laboratory Assessment Common laboratory findings in diabetic ketoacidosis are listed in Box 2. Initial laboratory testing in the symptomatic hyperglycemic patient should include a complete blood cell count with differential, liver function tests, glucose, electrolytes, blood urea nitrogen, creatinine, arterial blood gases if bicarbonate is low, and
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Box 2. Diagnosis of Diabetic Ketoacidosis Signs and Symptoms Hyperventilation–tachypnea Sinus tachycardia Hypotension or dehydration Change in sensorium, disorientation, or coma Kussmaul respirations or fruity breath Nonreassuring fetal tracing Polyuria or polydipsia Nausea or vomiting Abdominal pain or contractions Blurred vision Muscle weakness
Laboratory Findings Plasma glucose level (usually greater than 250 mg/dL)*† Arterial pH less than 7.30* Anion gap greater than 12 mEq/L* Elevated base deficit* Positive serum/urine ketones, especially 3b-hydroxybutyrate (most abundant)‡ Falsely normal potassium level might be present Low serum bicarbonate (often less than 15 mEq/L) Elevated serum blood urea nitrogen and creatinine resulting from dehydration and possible renal failure * These values are variable. † Diabetic ketoacidosis in pregnancy can present with much lower glucose levels. ‡ Siemens Multistix 10SG only detect acetoacetate.
anion gap or serum ketones. Acidosis is the hallmark of diabetic ketoacidosis with a serum bicarbonate concentration that is usually less than 15 mEq/L.11 Hyperglycemia (plasma glucose level greater than 300), anion gap metabolic acidosis, and ketosis (positive serum and urine ketones) are seen in virtually all cases of diabetic ketoacidosis. An anion gap is present because the acidosis is caused by unmeasured anions (ie, ketoacids and lactate). In acute diabetic ketoacidosis, the ketone body ratio (3-b-hydroxybutyrate:acetoacetate) rises from normal (1:1) to as high as 10:1. As mentioned, the plasma glucose level is usually higher than 300 mg/ dL but lower levels are not uncommon during
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pregnancy. Falsely normal or elevated potassium levels might be present; however, it is likely that the total body potassium is decreased and the patient is dehydrated and hypokalemic. Blood urea nitrogen and creatinine levels may be elevated as a result of renal dysfunction.21
MANAGEMENT OF DIABETIC KETOACIDOSIS IN PREGNANCY Diabetic ketoacidosis in pregnancy is an obstetric and medical emergency and therefore requires prompt and aggressive treatment in a specialized care unit (Fig. 3). Management should be provided by physicians with
special expertise in the area, ideally including maternalfetal medicine and medical endocrinology specialists, an obstetric anesthesiologist, and skilled nursing support. The principles of management of diabetic ketoacidosis during pregnancy are the same as that in the nonpregnant state. They consist of aggressive volume replacement, intravenous (IV) insulin therapy, correction of acidosis and abnormal electrolytes, correction of the underlying pathology, and intensive monitoring of maternal and fetal response to the treatment.
Fluid Replacement Initial fluid replacement is first accomplished with normal saline. It is imperative to establish early IV
Fig. 2. A. Fetal heart rate monitoring of a patient during an acute episode of diabetic ketoacidosis demonstrating uterine contractions, minimal variability, and late decelerations (solid arrows) after each contraction (dashed arrows). B. After correction of maternal hyperglycemia and acidosis, uterine contractions and late decelerations were resolved. In addition, there is now moderate variability. C. Fetal tracing in a patient who presented with acute diabetic ketoacidosis at 34 weeks of gestation demonstrates repetitive late decelerations (solid arrows) and minimal variability. She was rushed for an emergency cesarean delivery resulting in the delivery of a premature newborn with Apgar scores of 2, 3, and 5 at 1, 5, and 10 minutes, respectively. The arterial cord pH was 6.85. Sibai. Diabetic Ketoacidosis in Pregnancy. Obstet Gynecol 2014.
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• Confirm diagnosis (See Box 2) • Secure airway and oxygenation • Admit for intensive monitoring • Obtain adequate intravenous access* and insert indwelling catheter
Mechanical ventilation required? No
Yes Consider intensive care unit admission
No
Fluid replacement Fluid deficit (approximately 100 mL/kg)
Insulin therapy Short–acting intravenous insulin (10 units bolus)
0.9% sodium chloride 1–2 L/h x 2 h
Continue basal infusion rate of 1–2 units/hour†
Evaluate corrected serum sodium level
Corrected serum (Na+) 140 mEq/L or greater
Corrected serum (Na+) less than 140 mEq/L
0.45% sodium chloride 250–500 mL/hour
0.9% sodium chloride 250–500 mL/hour
Serum glucose 250 mg/dL or less
Add dextrose 5% in 0.45% sodium chloride or dextrose 5% in 0.9% sodium chloride
• Close monitoring first 4 hours ◦ Hourly urine output ◦ Vital signs every 15 minutes ◦ Measure arterial blood gas, capillary serum ketones, electrolytes, glucose and anion gap‡ every 1–3 hours ◦ Aggressive investigation and management of precipitating factors
Serum K+ less than 5 mEq/L and urine output more than 0.5 mL/Kg/hour
Replace K+ as per protocol (Table 1)
Continous fetal monitoring if 24 weeks of gestation or more§
Serum bicarbonate and anion gap normalize|| No Insulin drip until oral intake is tolerated
Yes Patient tolerating oral intake
• Discontinue insulin infusion 2 hours after subcutaneous longacting insulin • Initiate subcutaneous weightbased insulin • Check capillary glucose fasting and 2 hours post-prandial • Consultation to nutrition, diabetes and insulin education services
Fig. 3. An algorithm for the management of diabetic ketoacidosis in pregnancy. *Intravenous access should be obtained with two large-bore catheters or central venous catheter placement. †If serum glucose level does not fall by 50‒70 mg/dL within an hour, double the insulin infusion dose until this goal is achieved. ‡Anion gap: [Na+]–[Cl– + HCO3–], corrected serum sodium: Serum Na+ (mEq/L)+(1.6 mEq/L for each 100 mg/dL glucose level greater than 100 mg/dL). §No interventions on fetal behalf should be performed until stabilization of acute maternal condition has been achieved. kUse of bicarbonate in severe acidosis is debatable (see text). Some authors recommend administering 50 mEq of intravenous bicarbonate only if pH less than 7. Sibai. Diabetic Ketoacidosis in Pregnancy. Obstet Gynecol 2014.
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access with two large-bore catheters or central venous catheter placement. In patients with diabetic ketoacidosis, the fluid deficit is typically 100 mL/kg of body weight,60 which is equivalent to 6–10 L based on maternal weight. Immediate effects of this aggressive hydration are hemodilution and an increase in tissue perfusion resulting in a decrease of glucose and potassium levels. It is important to replace 75% of the fluid deficit during the first 24 hours of treatment and the total volume should be completed within 48 hours. Isotonic normal saline is administered at a rate of 1–2 L/h for 1–2 hours. Once this is completed, normal saline is then administered at a rate of 250– 500 mL/h and continued until glucose values are less than 250 mg/dL. Once this is achieved, administration of an IV solution with 5% dextrose is started. The subsequent choice for fluid replacement depends on the hydration state, serum electrolyte levels, and hemodynamic stability, and it should be continued until the calculated fluid deficit is corrected. If hypernatremia develops, switching to 0.45% saline until correction of hypernatremia is recommended (to replace free water loss as a result of the glucose-induced osmotic diuresis).10 Close hemodynamic monitoring should be performed during the first 4 hours; this includes hourly urine output through an indwelling catheter and vital signs surveillance every 15 minutes. Continuous oxygen saturation should be monitored and supplemental oxygen is given as needed. The patient’s response to treatment is evaluated with arterial blood gas monitoring, serum ketones, electrolytes, glucose, and anion gap every 1–3 hours. Investigation and management of the precipitating factors should be performed simultaneously and corrected promptly.22
Insulin Therapy Correction of hyperglycemia is best achieved with IV short-acting insulin. Regular insulin is administered as an 8- to 10-unit bolus followed by 0.1 units/kg/h until the serum bicarbonate and anion gap normalize and serum ketones become absent. Because correction of acidemia takes much longer than correction of hyperglycemia, insulin should be continued at a basal infusion rate of 1–2 units/h after normoglycemia is established and to be discontinued only after the first subcutaneous dose of regular insulin is administered.10
Monitoring of Acidosis and Correction of Electrolytes Correction of electrolyte imbalances, particularly hypokalemia, should start as soon as adequate renal function is documented. As mentioned, serum levels of potassium may appear deceivingly normal or
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slightly elevated, but the total body potassium is usually low. In diabetic ketoacidosis, the total potassium deficit is typically 5–10 mEq/L. During the administration of insulin, volume replacement, and correction of acidosis, potassium shifts from the extracellular to the intracellular space. To prevent fatal arrhythmias, it is important to keep serum potassium levels between 4 and 5 mEq/L. This is best accomplished by IV administration of potassium chloride (Table 1 ).60 Adequate urine output must be maintained at all times (greater than 0.5 mL/kg/h). Phosphate replacement is not usually required unless levels fall below 1 mg/dL, cardiac dysfunction ensues, or signs of obtundation are noted. Phosphorus may be replaced in conjunction with potassium by administering 10–20 mEq/L of potassium phosphate for each 10–20 mEq/L of potassium chloride.11 The need for replacement of other electrolytes including bicarbonate, magnesium, and calcium is debatable. Administration of bicarbonate may be associated with profound alkalosis or worsening acidemia secondary to increased partial pressure of carbon dioxide, leading in turn to impaired fetal oxygen transfer.10 Some authors recommend bicarbonate administration during severe acidemia (pH less than 7) or in patients complicated by cardiac dysfunction, sepsis, or shock61; however, further research is required to assess the potential risks and benefits of such therapy. In the setting of diabetic ketoacidosis in patients with type 1 DM, point-of-care b-hydroxybutyrate capillary ketone testing is routinely used.62,63 This test only measures 3-b-hydroxybutyrate, whereas the nitroprusside test for ketones in urine detects only acetoacetate.62 Point-of-care capillary testing assists in prompt detection and subsequent management of diabetic ketoacidosis. Ketone levels can be checked serially and are more accurate than urine ketone testing, because concentrations of 3-b-hydroxybutyrate are typically 10-fold higher compared with acetoacetate.64 In response to insulin, 3-b-hydroxybutyrate levels commonly decrease long before acetoacetate levels.21
Table 1. Suggested Protocol for Potassium Repletion According to Serum Levels Potassium Level Greater than 5 mEq/L 4–5 mEq/L 3–4 mEq/L 3 mEq/L or less
Intervention No treatment 20 mEq/L replacement 30–40 mEq/L replacement 40–60 mEq/L replacement
Data from Carroll MA, Yeomans ER. Diabetic ketoacidosis in pregnancy. Crit Care Med 2005;33(suppl):S347–53.
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MANAGEMENT COMPLICATIONS AND PROGNOSIS The vast majority of patients with diabetic ketoacidosis in pregnancy recover with no sequelae. Delayed recognition and inappropriate management carry elevated maternal and fetal morbidity. Most complications result from inadequate fluid management and premature discontinuation of insulin. In addition, failure to promptly recognize and correct precipitating factors (ie, infections) is associated with a worse prognosis and higher recurrence rates (ie, inadequate home insulin administration). A rare but potentially fatal complication is cerebral edema. In most reported series, no direct association with the metabolic disturbances in diabetic ketoacidosis has been reported, although aggressive hydration (particularly with hypotonic solutions) is certainly a contributing factor.59 Furthermore, the occurrence of hyperchloremic acidosis has been reported in patients resuscitated with normal saline given its relative acidic pH of 5.5 and high chloride content. It has been proposed that the use of more physiologic, balanced crystalloid solutions such as PlasmaLyte during resuscitation may reduce the incidence of this complication given similar serum chloride concentrations and neutral pH.65 Other complications with varying degrees of severity have been described and include hypoglycemia, acute respiratory distress syndrome, pulmonary edema, and bronchial mucous plugging.66–68 Aggressive potassium replacement during the acute episode in the absence of adequate urine output may result in fatal arrhythmias.
Investigation and Management of Precipitating Factors Once hemodynamic status and metabolic abnormalities have been addressed, it is important to evaluate for and treat potential precipitating factors such as infection or use of b-sympathomimetic agents. Infections are major precipitating factors for diabetic ketoacidosis, and thus evaluation for infection should be done even in the absence of fever. The source of infection can be the urinary tract, upper airway or pneumonia, gallbladder, ear, tooth abscess, cellulitis, or wound infections in case of surgery.69 Once identified, the source of infection should be treated with appropriate antibiotics, surgery, or antibiotics and surgery as indicated. In addition, if b-agonists are being used, they should be discontinued.4
Fetal Monitoring and Timing of Delivery The metabolic derangements that take place during diabetic ketoacidosis result in fetal hypoxemia and
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acidosis, which may influence all modes of fetal testing. Fetal heart rate monitoring is recommended in patients with gestational age of 24 or more weeks.33 Fetal heart rate monitoring during the acute episode of diabetic ketoacidosis often reveals minimal or absent variability, absent accelerations, repetitive variable, and late decelerations (Fig. 2A). The fetal biophysical profile can also be abnormal, and Doppler studies may show signs of blood flow redistribution (ie, increased umbilical artery pulsatility index and reduced middle cerebral artery pulsatility index).70 The frequency and severity of these abnormalities will depend on severity and duration of diabetic ketoacidosis. After correction of the metabolic derangements in diabetic ketoacidosis and maternal stabilization, these fetal abnormalities will usually improve; however, it may take 4–8 hours for the fetal heart rate tracing to become normal.71 The decision to continue pregnancy or to proceed with delivery in the setting of diabetic ketoacidosis can be challenging, but it must be based on fetal gestational age, maternal status, fetal status, and the response to treatment. The natural inclination is to proceed with emergent cesarean delivery for concerning fetal status before stabilizing the maternal condition. Diabetic ketoacidosis per se is not an indication for emergent delivery because a premature decision to proceed with cesarean delivery increases the risk of maternal mortality and morbidity. In addition, it may lead to unnecessary preterm delivery of a hypoxic and acidotic neonate (Fig. 2C). It is imperative to stabilize the maternal condition first because this will often improve the fetal status and potentially avoid the previously mentioned complications. If fetal status does not improve or if the maternal condition continues to deteriorate despite aggressive therapy, delivery is warranted. On the other hand, if maternal condition stabilizes and the fetal abnormalities resolve, pregnancy is continued and most often patients will be discharged home safely.
PREVENTION Women with pregestational DM planning pregnancy should be educated about the risks of diabetic ketoacidosis before conception as well as during pregnancy. In addition, all pregnant women not known to be diabetic should receive screening for GDM at 24–28 weeks of gestation and earlier in pregnancy in those with certain risk factors (obesity, strong family history of type 2 DM, obesity, history of GDM, impaired glucose metabolism, or glucosuria).12,72 Those with pregestational and GDM should be instructed about the importance of compliance with diet, exercise, compliance with prenatal visits,
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measurements and recordings of glucose values, and therapy (oral agents or insulin). All pregnant patients should be vaccinated against influenza during the flu season. In addition, they need to be educated about precipitating factors, signs, and symptoms of diabetic ketoacidosis including when to seek medical help.3 Patients with either persistent blood glucose values above 200 mg/dL despite therapy, persistent vomiting, diarrhea, polyuria, drowsiness, or who have evidence of infections require prompt hospitalization. Medical providers should have a low threshold for hospitalization of patients who demonstrate repeated episodes of noncompliance with instructions and therapy, because such patients are at very high risk for diabetic ketoacidosis. In case of threatened or true preterm labor, medical providers should avoid using subcutaneous or oral terbutaline. If true preterm labor is present, the patient should be hospitalized and treated with a different class of tocolytic. In addition, if corticosteroids are used for fetal lung maturity, the dose of insulin should be adjusted accordingly.4
CONCLUSION Diabetic ketoacidosis is a rare but serious complication of diabetes in pregnancy with deleterious consequences for both the mother and the fetus. Prompt recognition of precipitating factors, aggressive correction of volume depletion and electrolyte imbalance, and insulin administration are paramount in the management of diabetic ketoacidosis. A multidisciplinary approach and continuous monitoring of the maternal response to therapy are critical to decrease the overall morbidity and mortality. After viability, fetal monitoring also is indicated, and it is imperative to correct the maternal metabolic abnormalities before considering emergent delivery, because both maternal and fetal conditions will likewise improve.73 REFERENCES 1. Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2006;29:2739–48. 2. Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone Jl, et al. Hyperglycemic crises in diabetes. Diabetes Care 2004;27(suppl 1):S94–102. 3. Landon M, Gabbe S. Gestational diabetes mellitus. Obstet Gynecol 2011;118:1379–93. 4. Gabbe S, Graves C. Management of diabetes mellitus complicating pregnancy. Obstet Gynecol 2003;102:857–68.
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Continuing Medical Education Credits Available for the Clinical Expert Series Continuing medical education (CME) credits are available for reading the Clinical Expert Series. Visit http://www.greenjournal.org and click on the “CME” tab to read the articles and complete their associated quizzes. ACCME Accreditation The American College of Obstetricians and Gynecologists is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. AMA PRA Category 1 Credit(s)™ The American College of Obstetricians and Gynecologists designates this journal-based CME activity for a maximum of 2 AMA PRA Category 1 Credits.™ Physicians should claim only the credit commensurate with the extent of their participation in the activity. College Cognate Credit(s) The American College of Obstetricians and Gynecologists designates this journal-based CME activity for a maximum of 2 Category 1 College Cognate Credits. The College has a reciprocity agreement with the AMA that allows AMA PRA Category 1 Credits™ to be equivalent to College Cognate Credits. rev 7/2013
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Diabetic Ketoacidosis in Pregnancy
OBSTETRICS & GYNECOLOGY
