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KETOACIDOSIS is A RARE complication of diabetic pregnancies. It occurred at a rate of 1.73% in a recent series of pregnancies with preexisting, insulin-dependent diabetes. Ketoacidosis is an extremely rare complication of gestational diabetes, as well. In addition, ketoacidosis has been reported in two patients with previously undiagnosed diabetes. We report a case of early diabetic ketoacidosis involving a patient who had had a normal glucose tolerance test (GTT) only 10 days before presentation. generic actos

Case Report
A previously healthy, 23-year-old, gravida II, para I, Asian woman arrived at the obstetrical service in her 36th-week of pregancy, complaining of contractions every three minutes and decreased fetal movement. The patient also admitted to polyuria and polydipsia. She denied nausea, vomiting, fever and chills. She had no signs or symptoms of genitourinary, respiratory, or gastrointestinal infectious processes. Her past medical history was unremarkable. Her past obstetrical history included one prior pregnancy with delivery of malpre-senting twins at 38 weeks by cesarean section. During that pregnancy, routine screening for gestational diabetes had been negative. The present pregnancy had also been unremarkable up to this time. At 15 weeks, the patient had had a 50-gram 1-hour glucose challenge test, which was mildly elevated at 149 mg/dl. (Our facility normally screens patients upon presentation, owing to the prevalence of gestational diabetes in the population served and the fact that much of the population is transient.) A follow-up 100-gram 3-hour GTT was normal at 20 weeks, and at 35 weeks, 10 days prior to her admission, the patient had a second 50-gram 1-hour screening test, which was also normal at 106 mg/dl. Physical examination revealed an alert and oriented patient in no distress. Her vital signs included a blood pressure of 107/57, a pulse of 104, a respiratory rate of 18, and a temperature of 37.3°C. Her abdomen was not tender, there were no localizing signs of infection, and fundal height was in agreement with the estimated gestational age. Cervical examination showed the patient to be in early labor with the vertex presenting. Contractions were coming every two to three minutes.

Continuous fetal heart monitoring revealed a baseline of 150 beats per minute with good variability, but with the presence of late decelerations. Ultrasound was remarkable for oligohydramnios.

Initial laboratory investigations included a urinalysis remarkable for severe glucosuria and ketonuria, a serum sodium level of 129 mM, a potassium level of 5.2 mM, and a serum glucose level of 593 mg/dl with an elevated anion gap of 18 mmol/liter.

Based on this initial data, diabetic ketoacidosis was suspected. Arterial blood gases revealed a pH of 7.32, a PCO^2 of 28 mm Hg, a bicarbonate level of 14.2 mM, and a base excess of -10. Blood counts included a leukocyte count of 13,700/mm^3 and a hematocrit of 35.7%. Serum ketones were present, and the patient had a lactic acid level of 2.7 mmol/liter (normal range: 0.6-1.7 mmol/liter); a glycosylated hemoglobin level of 7.1% (normal range 5.0-7.3%); and a fructosamine of 232 mmol/liter (normal range 0-285 mmol/liter).
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Treatment consisted of volume expansion, correction of hyperglycemia, replacement of sodium and potassium, and oxygen therapy. The volume deficit was addressed with a rapid infusion of isotonic saline (1.5 liters in the first hour). We teated the hyperglycemia with an intravenous insulin drip. As the serum glucose approached 200 mg/dl, we added 5% dextrose to the infusion. We began potassium replacement two to three hours after we initiated therapy. Twelve hours after the initial therapy, the patient’s blood glucose level reached 181 mg/dl, and the serum ketones were negative. During this initial phase of treatment, insulin was given as a one-time, 12-unit bolus of regular insulin, followed by a continuous, intravenous drip of 5 to 6 units per hour.

At 16 hours, the patient underwent a vacuum-assisted, vaginal delivery. Apgar scores climbed from eight at one minute to nine at five minutes. Maternal arterial pH was 7.41 at delivery. Serum glucose was 160 mg/dl. It is of note that the fetal late decelerations resolved promptly with volume replacement, oxygen therapy, and left lateral positioning.

In the immediate postpartum period, the patient regained good glycemic control with relatively modest doses of insulin (10 units of regular, 10 units of NPH per day). Three months after discharge, the patient was readmitted with a second episode of diabetic ketoacidosis. On admission, she had a serum glucose level of 534 mg/dl. This episode was felt to be due to increasing insulin requirements and poor compliance. After this hospitalization, the patient became pregnant again. This pregnancy has been complicated by increasing insulin requirements. The patient has been admitted to the hospital on several occasions for hyperglycemia and has also experienced severe symptomatic episodes of hypoglycemia. There have been no episodes of ketoacidosis in this most recent pregnancy.

Discussion
In rare instances, diabetes mellitus can present initially as diabetic ketoacidosis during pregnancy. In the case we are discussing, the patient had had a screening test for gestational diabetes with normal results only 10 days prior to her admission for ketoacidosis. Laboratory records reflect proper administration of the glucose load and make no mention of any emesis during the testing period. This, however, does not rule out the possiblity of laboratory error or poor patient compliance with the test protocol.

As we mentioned previously, our facility normally screens for diabetes upon presentation for prenatal care. This patient’s abnormal screening at the early gestational age of 15 weeks is interesting, but of uncertain significance. The 100-gram 3-hour GTT, however, is the diagnostic test for gestational diabetes, and the patient’s test was normal.

A normal glycosylated hemoglobin level and fructosamine show that the patient had not had any significant disturbances in glucose metabolism during the months prior to presentation. This may represent a case of pancreatic islet-cell failure of relatively acute onset. Rapid depletion of insulin, coupled with the stress of labor, precipitated diabetic ketoacidosis. A brief review of the genesis of diabetic ketoacidosis, the effects of pregnancy on the disease process, and the disease’s effects on the fetus follows.

Diabetic ketoacidosis is a state of relative or absolute lack of insulin, which leads to major changes in metabolic pathways. A lack of insulin seriously impairs the body’s ability to use glucose as a peripheral energy source. The organism must continue to produce glucose in order to support brain function, but must also provide an alternative energy source for peripheral use. Protein catabolism provides a substrate for hepatic gluconeogenesis, which supports central nervous system function, but, unfortunately, also contributes to the overall state of hyperglycemia. Hyperglycemia in turn helps to stimulate increasing lipolysis with the release of free fatty acids. Oxidation of free fatty acids in the liver produces ketonemia and, eventually, metabolic acidosis. Hyperglycemia also results in glucosuria and osmotic diuresis. Free water and electrolytes are lost in the urine, leading to dehydration and electrolyte imbalances. Water shifts from the intracellular space to replenish the intravascular volume, and, eventually, with continued diuresis, all body compartments can become dehydrated. Serum hyperosmolarity results in the increased secretion of counter-regulatory hormones, such as glucagon, catecholamines, growth hormone and Cortisol. These hormones, in turn, contribute to the overall state of hyperglycemia and increase the maladaptive attempt to use large amounts of free fatty acids as an energy source.

Pregnancy in particular can predispose a patient to ketoacidosis in several ways. In the fasting state, the increased use of glucose by both the fetal and maternal units can lead relatively quickly to conversion to a cata-bolic metabolism. This condition of accelerated starvation is further characterized by hypoinsulinemia, hypoglycemia and, more importantly, hyperketonemia and protein catabolism. Pregnancy-associated nausea and vomiting can contribute as well.

Relative respiratory alkalosis associated with increased alveolar minute-ventilation causes a compensatory increase in renal bicarbonate excretion. As a consequence, a deficit in buffering capacity develops, which becomes especially important in the presence of an acid load, as is the case in ketonemia.

The production of diabetogenic hormones, such as human placental lactogen, prolactin and Cortisol, increases over the course of gestation, thereby predisposing the patient to ketoacidosis.
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During pregnancy, miscellaneous conditions, such as infection, beta-sympathomimetic therapy, and labor can increase endogenous catecholamine release, thereby contributing to the onset of diabetic ketoacidosis.
As we discussed earlier, metabolic, acid-base, and hormonal conditions normal to pregnancy can predispose the diabetic patient to ketoacidosis. In addition, it has been demonstrated that, during pregnancy, diabetic ketoacidosis can occur at glucose levels as low as 200 mg/dl.

The precise effects of diabetic ketoacidosis on the fetus are unknown, although abnormal heart-rate patterns consistent with fetal acidosis have been reported. In severe cases of ketoacidosis, especially those associated with maternal coma, fetal demise is common. Most series report good outcomes for the fetus, if it is alive upon presentation to the hospital and prompt, appropriate, maternal interventions are initiated. We cannot overemphasize the importance of continuous fetal heart-rate monitoring in this setting.

In cases of maternal diabetic ketoacidosis, a number of factors most likely contribute to the development of fetal acidosis. Maternal hypovolemia and catecholamine excess may result in decreased, uterine blood flow. Fetal hyperinsulinemia, resulting from hyperglycemic conditions, will increase fetal oxygen demands. Maternal phosphate deficiency may deplete erythrocytes of 2,3-diphosphoglycerate, thereby impairing oxygen delivery to the fetus. Hyperglycemia has been shown to decrease myocardial contractility in animal models. Finally, maternal metabolic acidosis and electrolyte disturbances will be directly reflected in the fetal compartment. For example, fetal cardiac arrest has been reported in connection with severe, maternal hypokalemia.

In our case, the patient presented with late decelerations and oligohydramnios. These findings were probably manifestations of uteroplacental insufficiency, secondary to maternal dehydration and metabolic acidosis. Correction of maternal fluid deficits and acidosis resulted in the normalization of the fetal heart-rate pattern.
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The genesis of rapid-onset, islet-cell failure and resultant diabetes remains a controversial topic. Research suggests, however, that the genesis may be related to recent viral infection. Considerable animal data link diabetes with particular strains of common viruses. The data on humans, however, is less certain. We do not know whether pancreatic viral infection would result in transient or permanent pathology. In several studies, evidence of viral infection in the peripheral blood or pancreatic tissue was found no more commonly in insulin-dependent, diabetic patients than in non-diabetic individuals. This finding, however, may reflect either the elimination of the diabetogenic viruses by the time of diagnosis or their behavior as nonspecific agents to which the host has an abnormal immune response. Indeed, viruses may induce changes in cell proteins, which the immune system subsequently identifies as foreign.

There is some evidence that susceptibility to the diabetogenic effects of viruses may be genetic. Certain viral strains seem to be more tropic for beta cells than others. Furthermore, in rare instances, toxins, such as lead, have been implicated in rapid-onset diabetes.

We could obtain no clear history of antecedent viral infection or toxin exposure for the patient under discussion. A subclinical or minimally symptomatic infection could have been present. We should emphasize that the association of acute islet-cell failure with recent viral infection in humans remains purely theoretical. Furthermore, in the present case, titers for islet-cell antibodies or for antibodies to suspected diabetogenic viruses were, unfortunately, not obtained at the time of presentation. Although not critical to the management of this patient, this information may have added to our understanding of this case.

The patient’s course, since the index pregnancy, has been notable for waxing and waning pancreatic function with corresponding wide swings in glycemic control. Since the initial presentation, she has continued to require insulin, as is clearly evidenced by a hospital admission for diabetic ketoacidosis three to four weeks postpartum and by admissions for poorly controlled diabetes early in a subsequent pregnancy.

It is of note that the patient’s diabetes was easily controlled in the immediate postpartum period with low doses of insulin. This “honeymoon period” of improved glycemic status following delivery of the fetus and placenta results from falling levels of diabetogenic hormones, particularly human placental lactogen. In the typical insulin-dependent diabetic individual, insulin requirements will usually increase to prepregnancy levels within four to six days after delivery. We do not know, however, what the pregnant, newly diagnosed, diabetic patient’s true insulin requirements will be after delivery. We believe that failure to recognize increasing insulin requirements in the weeks following delivery may have contributed to this patient’s postpartum episode of ketoacidosis. rosiglitazone drug

In summary, diabetic ketoacidosis can be managed successfully during pregnancy, if certain basic principles are kept in mind. Volume deficits must be quickly corrected in order to improve tissue perfusion and dilute plasma glucose concentrations. Hyperglycemia must be treated with insulin replacement. Once plasma glucose levels are clearly falling, carbohydrates should be provided to the patient via intravenous infusion in order to insure normal cellular metabolism. Electrolyte disturbances must be corrected. Serum potassium levels may be normal or mildly elevated on presentation, but intracellular levels may be low. Upon correction of the acidosis and institution of insulin therapy, the intracellular influx of potassium will result in falling serum levels. Finally, the search for and correction of precipitating factors, such as infection, emesis, and beta-agonist use, should be undertaken.

Sudden islet-cell failure can occur in pregnancy with the acute onset of hyperglycemia and diabetic ketoacidosis. Certain viruses may be direct or indirect precipitants of this disorder, although we lack conclusive evidence of this in humans.