Version May 2024
INTRODUCTION — Diabetic ketoacidosis (DKA) occurs in approximately 0.5 to 3 percent of pregnant individuals with diabetes [1]. It is characteristically associated with type 1 diabetes, but can occur in type 2 diabetes in the setting of infection, trauma, or other precipitating factors (eg, high-dose glucocorticoid therapy, vomiting), especially in patients who are "ketosis prone." DKA is an obstetric emergency because it can result in life-threatening fetal hypoxemia and acidosis, in addition to maternal morbidity (eg, cerebral edema) and, rarely, mortality.
This topic will discuss issues related specifically to DKA in pregnant patients. Issues related to DKA in nonpregnant adults are reviewed separately.
●(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment".)
PATHOGENESIS — DKA results from absolute or relative insulin deficiency combined with counterregulatory hormone excesses (ie, glucagon, glucocorticoids, catecholamines, and growth hormone). Pregnant individuals are prone to ketosis because of metabolic changes that have been referred to as "accelerated starvation." Pregnancy also induces a state of insulin resistance in late gestation that may result in greater relative insulin deficiency. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis", section on 'Pathogenesis'.)
Tocolytic therapy with a beta2 agonist and antenatal corticosteroids administered to accelerate fetal lung maturity can cause counterregulatory hormone excesses leading to DKA. Other triggers for DKA, including infection, trauma, and cardiac ischemia, are not specific to pregnancy. In addition, insulin omission, which sometimes occurs in the setting of an insulin pump system failure due to blockage or leakage in the infusion set or connectors, can also contribute to development of DKA. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Precipitating factors'.)
CLINICAL MANIFESTATIONS
Clinical presentation — The maternal clinical presentation of DKA is similar in pregnant and nonpregnant persons except that it can be seen at lower serum glucose levels and symptoms may develop more rapidly in pregnant individuals. Symptoms include nausea, vomiting, thirst, polyuria, polydipsia, abdominal pain, tachypnea, and, when DKA is severe, a change in mental status. Most, but not all, cases occur in the second or third trimester [2,3]. Rarely, DKA can be the initial presentation of new-onset diabetes, usually type 1 diabetes. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Clinical presentation' and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Diagnostic criteria'.)
Osmotic diuresis can lead to severe volume depletion and a reduction in uteroplacental blood flow. The reduced perfusion combined with the metabolic abnormalities of DKA (maternal acidosis, hyperglycemia, electrolyte imbalance) can result in life-threatening fetal hypoxemia and acidosis. In fetuses who displayed cardiac maturity (ie, heart rate variability amplitude 6 to 25 beats per minute [bpm] and accelerations ≥15 bpm above baseline) before DKA, the fetal heart rate during acute DKA often has minimal or absent variability and absent accelerations, as well as repetitive decelerations [1]. These abnormalities usually resolve with resolution of DKA, but it may take several hours before the fetal heart rate tracing is normal [4].
Laboratory findings — Laboratory findings of DKA usually include hyperglycemia, acidemia, an elevated anion gap, ketonemia (elevated serum beta-hydroxybutyrate and the presence of urine ketones), low serum bicarbonate, and renal dysfunction [5]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Laboratory findings'.)
However, when evaluating laboratory values in pregnant patients with possible DKA, it is important to consider the physiologic changes that occur during gestation, which alter these typical laboratory values used in DKA evaluation.
●Glucose levels in pregnant patients may be lower than usually expected in DKA; pregnancy is one of the known causes of "euglycemic" DKA. Hyperglycemia in nonpregnant patients with DKA is usually severe (often in the 350 to 500 mg/dL [19.4 to 27.8 mmol/L] and generally less than 800 mg/dL [44 mmol/L]). By comparison, in a series of 11 pregnant patients with DKA, more than one-third (4 out of 11) had blood glucose levels <200 mg/dL (11.1 mmol/L) [6]. In pregnant patients without markedly elevated glucose levels, it may be difficult to distinguish starvation ketosis from DKA.
●Pregnant patients have a respiratory alkalosis due to increased minute ventilation, which results in lower serum bicarbonate levels and higher arterial pH (7.40 to 7.45) in normal pregnancy. The respiratory alkalosis of pregnancy may mask metabolic acidosis of DKA but the pregnancy-related reduction in serum bicarbonate may be exaggerated. (See "Maternal adaptations to pregnancy: Dyspnea and other physiologic respiratory changes".)
●Albumin levels are reduced, which can lower the anion gap [7], and this may mask the DKA-associated anion gap elevation. Measurement of serum beta-hydroxybutyrate can be helpful in evaluating whether ketosis is present in individuals whose anion gap appears to be within the normal range. (See "Serum anion gap in conditions other than metabolic acidosis".)
●Pregnancy results in a physiologic increase in glomerular filtration rate; thus, renal dysfunction may be present in those with apparently normal creatinine levels (creatinine level is <0.75 mg/dL [70.7 micromol/L] in normal pregnancy). (See "Maternal adaptations to pregnancy: Renal and urinary tract physiology".)
DIAGNOSTIC EVALUATION — Maternal diagnostic evaluation is the same as in nonpregnant adults. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Diagnostic evaluation'.)
In addition, a gestational age-appropriate evaluation of fetal wellbeing should be undertaken. (See "Overview of antepartum fetal assessment".)
DIAGNOSIS — DKA should be suspected in pregnant patients with diabetes and clinical symptoms of the disorder (eg, abdominal pain, nausea, vomiting), especially in the setting of a precipitating factor (eg, infection). The diagnosis is confirmed by characteristic abnormalities in laboratory findings. (See 'Laboratory findings' above.)
DIFFERENTIAL DIAGNOSIS — The symptoms of DKA are nonspecific. In early pregnancy, nausea and vomiting may be mistaken initially for nausea and vomiting of pregnancy. The presence or absence of hyperglycemia can help to distinguish between the two diagnoses, though euglycemic DKA is possible. (See "Nausea and vomiting of pregnancy: Clinical findings and evaluation".)
The differential diagnosis of anion gap acidosis and metabolic encephalopathy are reviewed separately. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Differential diagnosis'.)
MANAGEMENT
General principles — The general principles of DKA management are similar in pregnant and nonpregnant patients [1,8]. These include appropriate volume replacement, potassium repletion, intravenous insulin, cautious administration of bicarbonate in severe cases (eg, pH ≤6.9, potassium level >6.4 mEq/L), frequent laboratory monitoring, and a search for precipitating causes, such as infection [8]. Phosphate is repleted if hypophosphatemia is severe or symptomatic (eg, serum phosphate concentration <1 mg/dL [0.32 mmol/L], cardiac dysfunction, hemolytic anemia, and/or respiratory depression).
An algorithm for DKA treatment in pregnancy is provided (algorithm 1). Management of DKA is described in detail separately. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment".) Four key principles are:
●The glucose target in pregnant patients is 100 to 150 mg/dL (5.6 to 8.3 mmol/L).
●Initiate potassium replacement immediately if the serum potassium is <5.3 mEq/L as long as there is adequate urine output (approximately >50 mL/hour). (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Potassium replacement'.)
●Continue insulin administration until ketosis resolves – Insulin and intravenous fluids should be continued until normalization of the anion gap. If a patient has ongoing ketosis, DKA will not be adequately treated if insulin is stopped upon achieving euglycemia. The resolution of DKA should be judged based on normalization of the anion gap or lack of elevated serum ketones, rather than the serum bicarbonate level, since hyperchloremic metabolic acidosis may be induced by volume resuscitation during treatment. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Insulin'.)
●Begin dextrose-containing intravenous fluids when the glucose level is below 200 mg/dL (11.1 mmol/L) – Administration of dextrose-containing intravenous fluids in addition to insulin is important when the glucose level is falling and below 200 mg/dL (11.1 mmol/L) to avoid interruption of insulin because of impending hypoglycemia and to facilitate continued insulin administration and normalization of the anion gap. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Fluid replacement'.)
Obstetric management
●Medications to avoid – Glucocorticoids (eg, betamethasone for fetal lung maturation) and beta-mimetics (eg, terbutaline for tocolysis) should be avoided during DKA, if possible, as they will worsen hyperglycemia.
●Fetal monitoring and timing of delivery – In fetuses with cardiac maturity before DKA, the fetal heart rate is continuously monitored. The pattern may be nonreassuring (no or minimal variability, absent acceleration, deceleration), but the abnormal pattern usually resolves as DKA is treated and maternal metabolic abnormalities improve [1].
Emergency delivery before maternal stabilization usually should be avoided because it increases the risk of maternal morbidity and mortality and may result in delivery of a hypoxic, acidotic preterm newborn for whom in utero resuscitation may have resulted in a better outcome. The timing of delivery needs to be individualized based on multiple factors, including gestational age, maternal condition (whether the mother is responding to aggressive therapy or deteriorating), and fetal condition (whether the fetal heart rate pattern is improving or deteriorating).
OUTCOME — Maternal mortality is less than 1 percent, but fetal mortality rates of 9 to 36 percent have been reported, as well as increased risks of preterm birth [1]. Data regarding other fetal outcomes is limited.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in pregnancy".)
SUMMARY AND RECOMMENDATIONS
●Clinical findings – Diabetic ketoacidosis (DKA) occurs in approximately 0.5 to 3 percent of pregnant individuals with diabetes, usually in the second or third trimester. The maternal clinical presentation of DKA is similar in pregnant and nonpregnant persons, but symptoms may develop more rapidly in pregnancy. Symptoms include nausea, vomiting, thirst, polyuria, polydipsia, abdominal pain, tachypnea, and, when DKA is severe, a change in mental status. DKA can result in life-threatening fetal hypoxemia and acidosis. (See 'Clinical manifestations' above.)
●Diagnosis – DKA should be suspected in pregnant patients with diabetes and clinical symptoms of the disorder (eg, abdominal pain, nausea, vomiting), especially in the setting of a precipitating factor (eg, infection, antenatal corticosteroid administration, betamimetic tocolytic therapy). The diagnosis is confirmed by characteristic abnormalities in laboratory findings (hyperglycemia, acidemia, an elevated anion gap, ketonemia [elevated serum beta-hydroxybutyrate and the presence of urine ketones]), low serum bicarbonate, and renal dysfunction. (See 'Diagnosis' above.)
The degree of hyperglycemia may be lower than in nonpregnant patients in DKA, and may be <200 mg/dL (11.1 mmol/L).
●Differential diagnosis – In early pregnancy, nausea and vomiting may be mistaken initially for nausea and vomiting of pregnancy. The presence or absence of hyperglycemia can help to distinguish between the two diagnoses, though euglycemic DKA is possible. (See 'Differential diagnosis' above.)
●Management – The general principles of DKA management are similar in pregnant and nonpregnant patients: appropriate volume replacement, potassium repletion (prior to insulin administration), intravenous insulin, administration of bicarbonate in severe cases, frequent laboratory monitoring, and a search for precipitating causes, such as infection. Phosphate is repleted if hypophosphatemia is severe or symptomatic. An algorithm for DKA treatment in pregnancy is provided (algorithm 1). Four key principles are (see 'General principles' above):
•The glucose target in pregnant patients is 100 to 150 mg/dL (5.6 to 8.3 mmol/L)
•Initiate potassium replacement immediately if the serum potassium is <5.3 mEq/L
•Continue insulin administration until normalization of the anion gap
•Administer dextrose-containing intravenous fluids in addition to insulin when the glucose level is falling and below 200 mg/dL (11.1 mmol/L) to avoid interruption of insulin because of impending hypoglycemia
●Obstetric issues – The fetal heart rate pattern may be nonreassuring (no or minimal variability, absent acceleration, deceleration), but the abnormal pattern usually resolves as maternal metabolic abnormalities improve with treatment. Delivery timing is individualized based on multiple factors, including gestational age, maternal condition (whether the mother is responding to aggressive therapy or deteriorating), and fetal condition (whether the fetal heart rate pattern is improving or deteriorating). (See 'Obstetric management' above.)
ACKNOWLEDGEMENT — The UpToDate editorial staff acknowledges Michael F Greene, MD, who contributed to an earlier version of this topic review.
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