Occurring in 1% to 2% of pregnant women with hyperthyroidism, thyroid storm is a rare but life-threatening endocrine emergency characterized by a severe hypermetabolic state precipitated by an excess of endogenous thyroid hormones. It typically has an acute onset and is diagnosed based on a constellation of symptoms, including fever, tachycardia, and central nervous system dysfunction (restlessness, altered mental status, and seizures). If not treated, it can ultimately lead to cardiac dysrhythmia, multiorgan failure and even death. Case fatality rates range from 10% to 30% in the literature.1 Given the severity of the disease process, a high clinical suspicion, rapid recognition, intervention, and supportive care are needed to maximize the maternal and fetal outcome.
Although the exact triggering mechanism is unknown, most cases are due to poorly controlled disease. Preceding events include such as preeclampsia, trauma, surgery, infection, stress, and ketoacidosis have been associated with storm.2,3 A careful search for underlying associated etiologies should be performed.
A high clinical suspicion is needed as the presenting signs and symptoms may be nonspecific enough to be confused with any number of other conditions.4 Elevated blood pressure, headaches, abdominal pain and even pulmonary edema or heart failure are features compatible with preeclampsia that may make the diagnosis of thyroid storm more difficult.5
Overt signs of hyperthyroidism such as a goiter, thyroid bruit, or exopthalmos may be discriminating physical signs that are more specific to thyroid dysfunction. Interpretation of maternal acid-base status must take into consideration the moderate compensated respiratory alkalosis that occurs in pregnancy. These metabolic changes can lead to fetal heart rate tracing abnormalities, including tachycardia, loss of variability, and late decelerations ultimately resulting in increased fetal morbidity and mortality.6
Laboratory analysis includes thyroid-stimulating hormone, free tri-iodothyronine (FT3) and free thyroxine (FT4), complete blood count, and complete metabolic panel. Thyroid-stimulating hormone is usually low/undetectable in thyroid storm, although cautious interpretation is required in the first trimester due to the human chorionic gonadotropin effect on the thyroid gland. FT4 and FT3 are often well above the upper limits of normal in pregnancy. Total hormone levels are also usually elevated. There are no generally accepted levels at which the diagnosis of thyroid storm is assured, and there may be significant laboratory overlap with simple hyperthyroidism. There is typically an associated leukocytosis as well as evidence of hyperglycemia, hypercalcemia, elevated liver enzymes, and electrolyte disturbances on metabolic panel screening.
Given a high incidence of case fatality rates and the need for early recognition, Burch and Wartofsky7 have outlined a commonly cited clinical scoring system for the probability of thyroid storm. Points are allocated for elevation in temperature, maternal pulse, and a number of organ system dysfunctions indicating a high, medium, or low probability of the diagnosis. Thyroid imaging is of limited benefit; although a chest x-rays and/or computed tomographic scan can be useful when looking for associated precipitating factors such as infections or pulmonary embolus.
A diagnosis of thyroid storm requires prompt intervention for both mother and fetus. Thyroid storm is considered a medical emergency and multidisciplinary care is required, including maternal fetal medicine, endocrinology, neonatology, and critical care specialists. In addition, preparation should be made for admission to an intensive care unit, with the availability of continuous fetal monitoring if the fetus has reached viability. Efforts to correct the underlying maternal metabolic derangement(s) are key in order to improve the underlying fetal status. It is important to exhaust all attempts to correct the underlying maternal abnormalities before intervening for the fetus, as often correction of the underlying metabolic abnormality will improve fetal status.8 The presence of a persistent fetal bradycardia or the development of category III heart rate tracing that is unresponsive to resuscitative measures may require expedited delivery.
Intravenous access should be obtained and cooling measures performed. Fluid balance and vital signs, including continuous pulse oximetry need to be carefully monitored. An initial echocardiography (EKG) and continuous telemetry is recommended, as arrhythmias, such as atrial fibrillation can occur. In addition some patients can have thyrotoxic heart failure due to the myocardial effects of excess free T4. Any cardiorespiratory complaints should be thoroughly evaluated including EKG. Treatment is generally the same for thyroid storm and thyrotoxic heart failure. Respiratory failure is generally not associated with thyroid storm; however can occur and intubation and mechanical ventilation is sometimes necessary.
In addition to supportive care, treatment of thyroid storm involves the use of several medications to decrease the level of thyroid hormone. Propylthiouracil (PTU) and methimazole (MMI) are thionamides and act within the thyroid gland to inhibit follicular growth and development, as well as the packaging of iodothyronines into T4 and T3.9 PTU has the advantage of antithyroid effects within the thyroid gland as well as inhibiting the peripheral conversion at the tissue level, limiting the active form of thyroid hormone. However, there is a significant disadvantage of the use of PTU in that there have been rare cases of fulminate liver failure and death associated with its use, including instances in pregnancy. There is a Food and Drug Administration “black box” warning for PTU concerning this link to hepatotoxicity. It is unclear how thyroid storm specifically affects this risk. MMI use in pregnancy has been linked to some teratogenic effects, specifically aplasia cutis and choanal atresia.10 In addition, rarely a life-threatening agranulocytosis may develop after MMI use. Given these conflicting risks there is no clear recommendation for which thionamide to initiate in thyroid storm.
The use of an iodide-containing medication inhibits the further release of active thyroid hormone from the thyroid gland. Oral potassium iodide, 5 drops every 8 hours, or IV sodium iodide 500 to 1000 mg every 8 to 12 hours may be used. One of the side effects of iodine agents is the paradoxical release of thyroid hormone from the thyroid gland, thus it is important to start iodine administration ~1 hour after the use of thionamides.9 Corticosteroids are also important in the treatment of thyroid storm due to the effect of decreasing systemic inflammation as well as peripheral effects of decreasing T4 to T3 conversion. Beta-blockers such as propranolol will reduce peripheral conversion of T4 to T3, and lessen the complications of tachycardia including high output cardiac failure. Long-term use of beta-blockers has been associated with fetal growth restriction, but is generally considered safe in a risk/benefit consideration. Other supportive medications include antipyretics such as acetaminophen (Table 1).
Conventional treatments may fail after trials of medical management in the most severe cases. There also may be adverse reactions to the thionamides which may require discontinuation. Emergency thyroidectomy, with or without plasmaphoresis has been described successfully in thyroid storm, but must be considered high risk and last line treatment.11
In summary, thyroid storm is a rare, life-threatening condition which requires early recognition, multidisciplinary care, and aggressive therapy.
Diabetic Ketoacidosis (DKA)
DKA is a medical emergency, which can result in both maternal and fetal morbidity and mortality. Before the discovery of insulin it was uniformly fatal. With early recognition and aggressive multidisciplinary management, the overall incidence has decreased from ~10% to 20% in the late 1970s to ~1% to 2% in most recent reports,3,12,13 resulting in improved maternal and fetal mortality. Preterm birth, both from premature labor and from medical intervention, is a common occurrence after DKA.
The pathophysiology of DKA occurs due to the lack of insulin resulting in a perceived hypoglycemia at target cells such as those in the liver, adipose, and muscle tissues. As a result, stores of glucagon are released, worsening the hyperglycemia and causing osmotic diuresis, hypovolemia, and electrolyte depletion.
Counter regulatory hormones in the adipose tissue cause the release of free fatty acids into the circulation which are then oxidized to ketone bodies. Ultimately a metabolic acidosis ensues which manifests as an anion gap on blood chemistry. Ketoacids bind sodium and potassium, which are excreted in the urine, further worsening the electrolyte balance. If untreated, patients can experience cardiac dysfunction, decreased tissue perfusion, and worsened real function leading to shock, coma, and death.3,14
The normal physiological changes of pregnancy increase the susceptibility to DKA. Insulin resistance primarily attributable to human placental lactogen causes insulin requirements to increase with advancing gestation. Respiratory adaptations during pregnancy result in a compensated maternal respiratory alkalosis. The compensatory decrease in serum bicarbonate reduces the body’s normal buffering capacity, thus predisposing the patient to DKA.3,12,14
Patients generally present with abdominal pain, malaise, persistent vomiting, increased thirst, hyperventilation, tachycardia, dehydration, and polyuria. As the level of acidosis worsens altered mental status can occur. The diagnosis is confirmed with documentation of hyperglycemia, acidosis, and ketonuria. Other laboratory findings include anion gap, ketonemia, renal dysfunction, and possible electrolyte abnormalities.12,14 Typically patients present with severely elevated serum glucose levels; however DKA can occur with levels <200 mg/dL in pregnancy.13
Common precipitating factors in pregnancy include emesis, infection, beta-sympathomimetic tocolytic agents, corticosteroids, poor compliance, and medical errors.15,16 Although beta-sympathomimetics (eg, terbutaline) are not routinely used for prolonged (>48 h) tocolysis due to the Food and Drug Administration safety communication in 2011, it is important to remember that they should be used very cautiously, if ever, for patients with diabetes.3
Although the mechanism is not clearly understood, DKA presents a significant risk to overall fetal well-being. The likely mechanism is related to maternal ketoacids which cross the placenta leading to decreased fetal tissue perfusion and oxygenation.14 The fetus has a limited ability to buffer significant acidemia, and therefore is quite sensitive to maternal acidosis.
This often results in alterations of the fetal heart rate tracing, including decreased variability and/or late decelerations. It is important to exhaust all attempts to correct the underlying maternal abnormalities before intervening for the fetus.13,14
Like thyroid storm, DKA is considered a medical emergency and a multidisciplinary team, including maternal fetal medicine, endocrinology neonatology and critical care, should be assembled. In addition, strong consideration should be made for admission to an intensive care unit.
Treatment includes adequate IV access and placement of an indwelling urinary catheter. Significant fluid deficits should be anticipated and corrected, insulin should be started and electrolyte abnormalities corrected. Fluid balance and vital signs need to be carefully monitored and documented.
Basic laboratory analyses, including a complete metabolic panel with magnesium and phosphorous, complete blood count with differential, urinalysis, fingerstick blood glucose, arterial blood gas, and serum ketones should be collected. Additional testing (urine culture, blood culture, chest x-ray, etc.) should be performed based on clinical suspicion and any potential underlying processes. Initially, serum ketones, electrolytes, and maternal acid/base status should be monitored every 2 hours until ketosis and acidosis are resolved. Blood sugars should be collected hourly during this time to titrate insulin.3,12,14,17,18
Once viability is confirmed, fetal monitoring should be initiated. As noted, the fetal heart tracing will likely appear concerning during the initial phase of metabolic compromise. Maternal oxygen supplementation and left lateral decubitus positioning should be used to increase blood flow to fetus and improve oxygenation. Adequate hydration and correction of acid/base derangements must be started. Delivery is generally postponed until after maternal metabolic condition is stabilized, as this will usually correct the fetal heart tracing abnormality. There are exceptions, including severely prolonged bradycardia or a persistent category III tracing.
Table 2 illustrates a general algorithm for treatment of DKA in pregnancy, including rehydration, reduction of hyperglycemia, correction of acid-base and electrolyte imbalance while searching for and treating the underlying etiology.3,12,14,17,18
The hypovolemia associated with DKA is estimated at 100 mL/kg of total body weight and is typically 4 to 10 L.19 Initially, aggressive intravenous replacement with isotonic normal saline should be started with the goal to replace ~75% of the overall deficit within the first 24 hours. Hypotonic fluids (eg, lactated ringers and 0.45% saline) should be avoided initially as they can cause a rapid decline in plasma osmolarity leading to cerebral edema. Blood glucose values should be monitored hourly and once the serum glucose reaches <250 mg/dL, IV fluids should be switched to D5-0.45% normal saline.
Intravenous insulin administration should be undertaken immediately to aid in lowering of the blood glucose levels. Subcutaneous and intramuscular are typically avoided due to the slower onset of action, which is worsened in DKA.3 The initial blood glucose target is 150 to 200 mg/dL in order to avoid rapid correction and resulting complications. It is important to remember that insulin requirements can be significant and most protocols suggest an initial bolus dose of 10 to 20 units of regular insulin, followed by an infusion rate of 5 to 10 units/h. This amount should be increased if the blood glucose values do not fall 20% to 25% over 2 hours.
It is important to continue the insulin infusion until the anion gap is closed and acidosis resolved. This can take significantly longer than correcting the hypoglycemia and typically takes 12 to 24 hours. Once it is deemed safe to transition to subcutaneous insulin, the first dose should be given before the discontinuation of the intravenous infusion to decrease the risk of recurrent ketoacidosis.
Potassium is the most common electrolyte abnormality in DKA, although levels are often normal initially. The actual deficit is estimated at 5 to 10 meq/kg. Once the serum potassium level falls below 5 mmol/L, IV replacement should begin with the goal to maintain potassium levels between 4 and 5 mmol/L. Adequate renal function should be documented before replacing potassium. Serum potassium levels should be checked every 2 to 4 hours as significant hypokalemia can precipitate a cardiac arrhythmia.
Replacement of low serum bicarbonate levels remain a source of controversy and replacement is generally agreed upon if the patients pH is <7.0. Some studies have shown that routine replacement of low serum levels of bicarbonate have not proven beneficial in DKA and may cause unnecessary maternal and fetal complications. Replacement can delay the correction of ketoacidosis in the maternal bloodstream and, if corrected to rapidly, elevate fetal PC02 impairing fetal ability to maintain adequate O2 transfer.3,18
Primary hyperparathyroidism (pHPT) is the third most common endocrine disorder (prevalence: 0.1% to 0.4% in the general population) and rare in pregnancy. In a review by Ruda et al20 solid parathyroid disorders account for 80% of cases in the general population, with the remaining cases a result of diffuse hyperplasia and adenomas.
The diagnosis requires an elevated total calcium level adjusted for serum albumin [serum calcium+0.8×(4−serum albumin)] or elevated serum ionized calcium level with an elevated parathyroid hormone level. Patients with hyperparathyroidism caused by a parathyroid adenoma or hyperplasia typically have inappropriately high PTH secretion in relation to the serum calcium concentration.
Symptoms typically include nausea, vomiting, anorexia, constipation, depression, and mental confusion. Kidney stones, pancreatitis, abdominal pain as well as EKG changes including short QT interval and arrhythmia can be seen.
In pregnancy most patients are asymptomatic and undiagnosed, as routine calcium levels are not checked. In addition, nausea and vomiting is common in pregnancy and is more commonly associated with pregnancy associated physiological changes.21
Once the diagnosis of hyperparathyroidism is ascertained, careful search for the underlying etiology should begin. Although less sensitive, imaging via ultrasound is the first line modality to screen for determination of mass as it offers less radiation compared with computed tomographic scan.
As noted above, there are many cases of asymptomatic pHPT that go undiagnosed in pregnancy. In pregnancy the most common presenting symptom is renal colic secondary to nephrolithiasis.22 pHPT is more often associated with pancreatitis in the pregnant population (7% to 13%) than in the nonpregnant state. This is thought to be secondary to elevated serum calcium levels resulting in damaged pancreatic ducts.23 Other clinical findings that can be seen in pregnancy include hypertension and preeclampsia.
pHPT does not seem to be associated with increased risk of miscarriage; however without treatment fetal complications can be seen in up to 80% of pregnancies; specifically neonatal hypocalcemia, preterm birth, intrauterine growth restriction, stillbirth, and neonatal tetany. These complications can be significantly reduced with maternal treatment and neonatal evaluation.24,25 Neonatal calcium levels should be checked after delivery to screen for hypocalcemia.
Treatment of pHPT includes conservative therapy such as increased fluids and decreased calcium intake with vitamin D supplementation. Calcitonin does not cross the placenta and thus is likely safe; however, is not generally effective. Bisphosphonates should be avoided unless absolutely necessary due to the effect on fetal bones. Surgical removal of the parathyroid glands is generally reserved for symptomatic hypercalcemia and preferred in the second trimester due to decreased maternal and fetal risks. It is the only definitive treatment.26
Pregnancy tends to offer protection from maternal hypercalcemia, due to transplacental transport to meet fetal needs, especially during the third trimester. This protection is eliminated after delivery and thus there is an increased risk of maternal hypercalcemia in the puerperal period.
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