Critical Care Medicine

Endocrine disorders of pregnancy: Gestational diabetes mellitus, Diabetic ketoacidosis in pregnancy, Acute adrenal crisis in pregnancy, Cushing's syndrome in pregnancy, Hypothyroidism in pregnancy

Related conditions: Gestational diabetes mellitus

Diabetic ketoacidosis in pregnancy

Acute adrenal crisis in pregnancy

Cushing's syndrome in pregnancy

Hypothyroidism in pregnancy

1. Description of the problem

  • Altered metabolic homeostasis in pregnancy allows for the natural growth and development of the fetus and placenta.

  • However, these adaptive metabolic changes add a level of complexity to the diagnosis and management of diseases that are either inherent to pregnancy or complicated by pregnancy.

  • The endocrine and metabolic alterations during pregnancy primarily affect the hypothalamus, pituitary, and adrenal glands.

  • Diabetic ketoacidosis

    • Nausea, vomiting, abdominal pain, ileus

    • Polyuria and polydipsia

    • Mental status changes

    • Tachycardia and hyperventilation (Kussmaul respirations)

    • Hypovolemia

    • Osmotic diuresis

  • Acute adrenal insufficiency

    • Hypotension and hypovolemic shock

    • Nonspecific symptoms such as nausea, vomiting, diarrhea, fatique, muscle weakness, abdominal pain, lethargy, confusion, and coma

  • Cushing's syndrome

    • Generalized weakness

    • Peripheral edema

    • Glucose intolerance

    • Hypertension

    • Emotional lability

    • Fatigue and muscle weakness

  • Hypothyroidism

    • Fatigue

    • Weight gain

    • Muscle weakness

    • Cold intolerance

    • Mental status changes ranging from irritability and depression to coma

  • It is important to recognize that there are many physiologic changes that occur in pregnancy, such as mild tachycardia, tachypnea, respiratory alkalosis, fatigue, muscle weakness, and peripheral edema, as well as changes in specific laboratory values, such as decreased hemoglobin and creatinine levels, that potentially may confound the diagnosis of any of the endocrine processes that occur in pregnancy.

2. Emergency Management

  • Diabetic ketoacidosis

    • Improve circulating blood volume with aggressive fluid resuscitation.

    • Decrease serum glucose with insulin administration.

    • Clear serum ketoacids (correcting acidosis) with fluid and insulin therapy.

    • Treat initiating causes of DKA .

    • Initiate therapy with 0.1 U/kg bolus, then a continuous infusion of 0.1 U/kg/hr.

  • Adrenal crisis

    • Prioritize airway, breathing, and circulation.

    • Aggressive fluid resuscitation with 5% dextrose solution and normal saline (D5NS)

    • Correct specific electrolyte abnormalities including hypoglycemia, hyponatremia, hyperkalemia, and hypercalcemia.

    • 1st dose of hydrocortisone at 100 mg intravenously

    • Administer 4-mg intravenous dose of dexamethasone initially instead of hydrocortisone if the ACTH stimulation test is performed.

    • Fludrocortisone acetate at 0.1 mg orally

  • Cushing's syndrome

    • Emergent therapy not usually required

  • Hypothyroidism

    • Gradual oral replacement with thyroxine for mild cases

    • For myxedema coma, immediate intravenous levothyroxine treatment at a dose of 500 to 800 micrograms should be administered.

    • Concomitant glucocorticoid therapy is also given in myxedema coma because of the possibility of adrenal insufficiency, especially in cases of secondary hypothyroidism.

3. Diagnosis

The normal hypermetabolic state of normal pregnancy makes it difficult to differentiate from patients who present with pathologic endocrine and metabolic disorders.

  • Diabetic ketoacidosis

    • Electrolytes with low bicarbonate level of <15 mEq/L

    • Serum glucose level usually > 250 mg/dL, although lower levels have been reported in pregnancy

    • Serum ketones elevated with ≥1:2 dilution

    • Arterial blood gas with pH <7.3 and anion gap >12 mEq/L

    • Elevated base deficit > 4 mEq/L

    • Ketonemia ≥1:2 dilution

  • Adrenal crisis

    • Serum electrolytes

    • Serum glucose level

    • Complete blood count

    • Blood urea nitrogen and creatinine levels

    • Serum cortisol level

    • Serum calcium or ionized calcium levels

    • ACTH Cosyntropin stimulation test

  • Cushing's syndrome

    • Serum electrolytes

    • Serum cortisol level

    • 24-hour urinary cortisol test - the most definitive test, with values of greater than 50 micrograms daily suggestive of the diagnosis

    • Dexamethasone suppression test

    • CRH (corticotropin-releasing hormone) stimulation test

    • CT and MRI scans to evaluate for pituitary or adrenal tumors

    • inferior petrosal sinus catheterization

  • Hypothyroidism

    • Thyroid function tests of T4, T3 and TSH serum levels

    • Thyroid-releasing hormone (TRH) stimulation test

  • Diabetic ketoacidosis

    • High anion gap metabolic acidosis

    • Elevated blood glucose levels - every 1 to 2 hours

    • Elevated serum ketones - every 1 to 2 hours

  • Acute adrenal insufficiency

    • Low to low-normal cortisol levels

    • No increase in the plasma cortisol level with the ACTH stimulation test

  • Cushing's syndrome

    • Increased serum cortisol level

    • Increased 24-hour urinary free cortisol level of >50 to 100 micrograms/day

    • Radiographs of the adrenal and pituitary glands to locate tumors

    • Dexamethasone suppression test will differentiate between excess ACTH production for pituitary adenomas from those with ectopic ACTH-producing tumors.

  • Hypothyroidism

    • Increased TSH levels with low serum levels of T4 and T3 hormones

    • In secondary hypothyroidism, TSH levels will be normal. A TRH stimulation test should be done in these cases to make the appropriate diagnosis.

4. Specific Treatment

  • Diabetic ketoacidosis

    • Continue insulin until bicarbonate and anion gap normalize and serum ketones are cleared.

  • Adrenal crisis

    • Continue 100 mg IV hydrocortisone until acute signs of adrenal crisis resolve, and then transition to oral prednisone if required.

    • Continue with oral fludrocortisone at 0.1 to 0.2 mg orally daily if signs of adrenal insufficiency persist.

  • Cushing's syndrome

    • Treatment will depend on the etiology of the cortoisol excess and may include surgery, radiotherapy, chemotherapy, and/or cortisol-inhibiting medications, such as metyrapone, ketoconazole, or aminoglutethimide.

  • Hypothyroidism

    • Thryroxine (T4) dosing should be titrated rapidly to reach and then maintain serum TSH concentrations of <2.5 microunits/mL in the 1st trimester or to 3 microunits/mL in the 2nd or 3rd trimester or to trimester-specific TSH ranges.

5. Disease monitoring, follow-up and disposition

  • Diabetic ketoacidosis

    • Evaluate serum glucose levels and ketones and electrolytes every 2 to 4 hours initally.

    • Maintain serum potassium levels at 4 to 5 mEq/L.

    • Anticipate potassium deficit of 5 to 10 mEq/kg body weight.

    • Replace potassium with either potassium chloride or potassium phosphate.

    • Correct 75% of fluid deficit over the 1st 24 hours with a normal saline infusion for initial replacement and then add dextrose to the solution when the glucose level is at 250 mg/dL.

  • Hypothyroidism

    • The thyroxine dose needs to be increased by 4 to 6 weeks of gestation and may require a 30% to 50% increase in dosage during the pregnancy. When changes are made in thyroxine dosing, thyroid function tests should be measured within 30 to 40 days.

    • Women with autoimmune thyroid disease should be closely monitored throughout the pregnancy, especially during the 1st trimester, because of the risk of developing hypothyroidism later in the pregnancy.

    • Women with subclinical hypothyroidism with normal free T4 levels but increased TSH levels should be treated with T4 therapy during the pregnancy.

Pathophysiology

  • Changes in glucose metabolism

    • Variable glucose and insulin levels are seen in pregnancy depending upon the mother's nutritional state.

    • Fasting glucose levels can decrease by 10% to 20%.

    • There is increased insulin secretion but a relative state of insulin resistance is present in pregnancy.

    • Obese pregnant women with preexisting insulin resistance and women with marginal pancreatic reserve are at risk for developing gestational diabetes.

    • The compensatory respiratory alkalosis of normal pregnancy

  • Changes in hypothalamic and pituitary metabolism

    • Both ACTH and cortisol levels are significantly increased in pregnancy, and Cushing's syndrome can be exacerbated.

    • Acute adrenal crisis may occur precipitated by the stress of labor and delivery in patients with previously undiagnosed adrenal insufficiency.

    • Thyroid hormones are increased during pregnancy but free levels are normal. TSH levels are decreased but thyroid hormones increase as a result of increased synthesis of thyroxine-binding globulin. Hypothyroidism may occur if if the pregnant woman does not ingest sufficient dietary iodine (200 micrograms daily).

    • Transient diabetes insipidus can occur during pregnancy from vasopressin resistance. Plasma osmolality decreases in pregnancy by 5 to 10 mOsm/kg.

Epidemiology

  • Diabetic ketoacidosis

    • Incidence of DKA is approximately 2% to 3% in pregnancy with an associated 10% perinatal mortality rate.

    • In pregnancy, DKA is precipitated by in 40% of cases cessation of insulin therapy and in 20% of cases from infection; 30% of women presented in DKA with no prior antecedent history of diabetes mellitus.

    • Beta-mimetic tocolytic agents and corticosteroids during pregnancy can also precipitate DKA in pregnancy.

  • Acute adrenal crisis

    • Most cases in pregnancy result from abrupt cessation of chronic corticosteroid therapy for prepartum conditions, particularly at the time of labor and delivery.

  • Cushing's syndrome

    • Occurs rarely during pregnancy

    • The frequency of ACTH-independent cases of Cushing's syndrome is as high as 60% in pregnant women, with 48% having adenomas and 10% with carcinomas, compared to lower frequency rates in nonpregnant patients. Less frequent causes are secondary to Cushing's disease or bilateral adrenal hyperplasia.

  • Hypothyroidism

    • The most common thyroid disease during pregnancy is hypothyroidism. One percent of pregnant women will present with overt hypothyroidism, 2% to 3% will present with subclinical hypothyroidism, and 10% to 15% will have evidence of autoimmune thyroid disease.

    • Although rare, myxedema coma may be precipitated by infection during pregnancy coupled with the metabolic-related stresses of pregnancy.

Prognosis

  • DKA represents an acute emergency to both maternal and fetal well-being. Prompt initiation of treatment will correct the associated maternal and fetal metabolic acidosis, hyperglycemia, ketosis, and volume depletion..

  • Adrenal crisis represents another true emergency for both the mother and the fetus. Prompt treatment with glucocorticoid and mineralocorticoid therapies will restore homeostasis.

  • The symptoms of Cushing's disease are exacerbated by pregnancy but usually resolve after pregnancy. Improved outcomes are seen with surgery during pregnancy if pituitary or adrenal tumors are detected.

  • In addition to the maternal manifestations of overt hypothyroidism during pregnancy, hypothyroidism has been associated with damage to fetal intellectual development. T4 therapy has been shown to improve obstetrical outcome but may increase the risk of long-term sequelae in the offspring.

What's the evidence?

Carroll, MA, Yeomans, ER. "Diabetic ketoacidosis in pregnancy". Crit Care Med. vol. 33. 2005. pp. S347-53.

"American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 30: Gestational Diabetes". Obstet Gynecol. vol. 98. 2001. pp. 525-38.

Kamalakannan, D, Baskar, V, Barton, DM. "Diabetic ketoacidosis in pregnancy". Postgrad Med. vol. 79. 2003. pp. 699-714.

LIndsay, JR, Jonklaas, J, Oldfield, EH. "Cushing's syndrome during pregnancy; personal experience and review of the literature". J Clin Endocrinol Metabol. vol. 90. 2005. pp. 3077.

"The Endocrine Society's Clinical Guidelines. Management of thyroid dysfunction during pregnancy and postpartum". J Clin Endocrinol Metab. vol. 92. 2007. pp. S1-47.

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