Critical Care Obstetrics part 45 ppsx

Endocrine Emergencies 429 years after the diagnosis of Graves ’ disease, when the mother is either euthyroid or hypothyroid after radioactive thyroid abla- tion. Thyroid disease in pregnancy has recently been reviewed by Glinoer [41] . Neonatal thyroid status may be affected transiently by either thionamides therapy or thyroid receptor antibodies. The inci- dence of neonatal hyperthyroidism or hypothyroidism due to maternal passive transmission of thyroid receptor antibodies appears to be 1 – 3% [38] . Mitsuda et al. [42] reported overt thy- rotoxicosis in six neonates of 230 women with Graves ’ disease. In four of the mothers, TBII levels were elevated. In addition, tran- sient hypothyroidism was found in fi ve neonates with normal TBII levels and thionamides treatment. Mortimer et al. [43] reported a higher incidence of neonatal thyrotoxicosis in four infants of 44 mothers with Graves ’ disease; in all four cases, the mothers had TBII levels greater than 70%. These investigators observed that the neonatal free T4 index correlated inversely with maternal thionamides dose. In addition, women who had a free T4 index in the lower half of the reference range on thionamides were more likely to deliver a child with an elevated TSH than women with a free T4 index in the upper half of the reference range. Similarly, Momotani et al. [44] studied 43 women main- tained on thionamide therapy until delivery and 27 women in whom thionamides therapy was discontinued due to normaliza- tion of thyroid function tests prior to delivery. They found in women who took thionamides until delivery, a greater number had fetuses with increased TSH levels, lower T4 levels, and higher maternal TBII levels. It is important to note that in both of these studies there was only evidence of mild chemical, not clinical, hypothyroidism. However, taken together these data suggest that the minimal dose of thionamides therapy should be used to keep maternal thyroid function at the upper limits of normal. Because TBII antibodies are positive although at lower levels in 50 – 80% of women with Graves ’ disease [38,43,44] , their utility remains to be further demonstrated. In patients with Graves disease, the fetal heart rate may also be an indicator of fetal thyroid function and should be auscultated for a persistent fetal heart rate tachycardia at each prenatal visit. In 1 – 5% of cases, TSH receptor - stimulating antibodies may cross the placenta producing fetal/neonatal thy- rotoxicosis. Findings suggestive of fetal thyrotoxicosis could include the presence of a persistent fetal heart rate tachycardia [45] , fetal goiter, or intrauterine growth impairment. Wing et al. [28] found that only one infant of 185 women treated with propylthiouracil or methimazole had transient hypo- thyroidism at birth. Similarly, Davis et al. [27] found one neonate had transient hypothyroidism and a second was euthyroid with an asymptomatic goiter among 43 mothers receiving propylthio- uracil. Both were on high doses of propylthiouracil at the time of delivery. This is consistent with a review of the literature by Mandel et al. [46] in which the incidence of neonatal goiter in women exposed to antithyroid medications was 4%. PTU may be concentrated in the fetal compartment since umbilical blood levels were higher than maternal serum samples in fi ve maternal – fetal pairs [47] . onset of pregnancy that the free T4 index was increased in the fi rst trimester, fell in the second and third trimester, and was again increased postpartum. A fall in antimicrosomal antibodies during pregnancy and an increase postpartum was also measured in patients with Graves ’ disease or postpartum thyroiditis [34] . For further information, the reader is referred to a recent review of postpartum thyroiditis, which occurs in 5 – 7% of patients [35] . The diagnosis of Graves ’ disease is suggested by the presence of thyrotoxicosis, ophthalmopathy, a diffuse goiter, dermopathy, and thyroid receptor antibodies. The diagnosis is clinical and is supported by thyroid function tests; thyroid receptor antibody tests are often not necessary but levels of the antibodies at 36 weeks correlate with the risk of neonatal thyrotoxicosis [36] . However, pretibial dermopathy is rarely present in pregnant women, and active clinical ophthalmopathy is evident in only half of patients with Graves ’ disease [37,38] . Exophthalmos, weakness of the extraocular muscles, chemosis, and impairment of conver- gence are signs of infi ltrative ophthalmopathy and may remain despite normalization of thyroid hormone levels. In pregnancy, the signs and symptoms of hyperthyroidism are slightly more diffi cult to interpret due to the normal changes that occur during gestation. Heart rate and cardiac output increase, and heat intolerance, nausea, and weight loss are common. Thyrotoxicosis is suggested by clinical fi ndings which include a pulse rate persistently greater than 100 that fails to decrease with Valsalva in the presence of a tremor, previously mentioned signs, thyroid bruit, thyromegaly, and mild systolic hypertension. The cardiac effects of hyperthyroidism are summarized in Table 33.2 . An elevated free T4 and low serum TSH confi rms the diagnosis. Clinical signs of thyrotoxicosis without elevated total or free T4 should suggest free T3 thyrotoxicosis or defi cient TBG states [39] but these are much less common. “ Thyroid receptor antibodies ” is a generalized term that may be used to include both thyroid - stimulating immunoglobulins (TSIs) as well as thyrotropin - binding inhibitor immunoglobulins (TBIIs) and may be a useful predictor of neonatal thyroid dys- function [40] . Consequently, neonatal thyroid effects may occur Table 33.2 Cardiovascular changes in hyper - and hypothyroid states. Hyperthyroid Hypothyroid Cardiac output ↑ ↓ Heart rate ↑ ↓ Stroke volume ↑ ↓ Cardiac contractility ↑ ↓ Systemic vascular resistance ↑ ↓ Mean arterial pressure ↑ ↓ Blood volume ↑ ↓ Other Atrial fi brillation Ascites ↓ QT, ↑ PR interval Pleural effusion ST elevation ↑ QT interval ↑ conduction abnormalities Chapter 33 430 lowed by a continuous infusion at 50 – 100 µ g/kg/min. Labetalol has also been used successfully [55] . Although β - adrenergic blockade may inhibit peripheral conversion of T4 to T3, this does not alter thyroid release and does not prevent thyroid storm [56,57] . Because large increases in pulmonary diastolic pressure may be precipitated [58] and because congestive heart failure may be a common presentation of thyroid crisis in pregnant women, propranolol and other β - blocking agents should be used with caution. Corticosteroids have been advocated for inhibiting peripheral conversion of T4 and to prevent adrenal insuffi ciency, but there are few data to support their use. Fever should be treated with cooling blankets or acetaminophen to decrease cardiovascular demands. A thorough search for underlying infection is necessary because pyelonephritis, endometritis, or sepsis are common pre- cipitating factors. Because of the increased incidence of atrial arrhythmia and central nervous system emboli, thromboembolic disease should be considered in the patient with altered mental status that does not respond to the aforementioned therapy [59] . Complications of propylthiouracil and methimazole include chemical hepatitis, rash or other drug reactions (5%) and rarely agranulocytosis (0.3%) [60] . Because of the seriousness of the latter, patients with fever or sore throat should be instructed to discontinue mediation until a white cell count is checked. Agranulocytosis, as defi ned by a total leukocyte count of < 1,000/ mm 3 or granulocyte count of less than 250/mm 3 , is generally seen in older patients and within 2 months of the onset of therapy [60] . Finally lactation may be continued if the total dose of pro- pylthiouracil does not exceed 450 mg/day and if methimazole dosage does not exceed 20 mg/day [61,62] . See Table 33.3 for an overview of thyroid storm management in pregnancy. Hypothyroidism Overt hypothyroidism during pregnancy is uncommon as many women with overt hypothyroidism are anovulatory. The most common etiologies are prior surgical thyroidectomy, radioiodine, ablation, and autoimmune thyroiditis. Clinical signs and symp- toms include delayed deep tendon refl exes, fatigue, weight gain, cold intolerance, hair loss, dry skin, brawny edema, thickened tongue, hoarse voice, hypertension, and bradycardia, some of which are more diffi cult to ascertain during pregnancy. The hemodynamic changes of hypothyroidism are summarized in the table. Hyponatremia, ascites, pericardial effusions, or psychosis are not commonly present but may herald myxedema coma. Laboratory confi rmation of hypothyroidism can be established by a low free T4 in the presence of an elevated TSH. However, TSH levels may be suppressed in the fi rst trimester with less sensi- tive tests and undetectable in as many as 13% of women [63] . More sensitive TSH assays are unlikely to return undetectable. Although earlier studies of hypothyroidism suggested an increase in congenital anomalies, perinatal mortality, and infant neurologic dysfunction, more recent studies report better out- comes with adequate replacement [64] . Leung et al. [65] studied 23 women with overt hypothyroidism and 45 women with sub- In thyroid crisis or storm, an acute increase in the signs and symptoms of thyrotoxicosis may be life - threatening. The overall incidence of thyroid crisis in women who receive thionamides treatment during pregnancy, some of whom remain thyrotoxic, is about 2% [27] . A clinical diagnosis must be established and treatment initiated well before confi rmatory thyroid function tests are available. The classic signs of thyroid storm (altered mental status, temperature above 41 ° C, hypertension, and diar- rhea) are not necessarily present. Postpartum congestive heart failure, tachycardia, and severe hypertension should suggest the diagnosis and prompt an evaluation for other signs of thyrotoxi- cosis [48] . Rarely loss of consciousness following cesarean section [49] or seizures mimicking eclampsia [50] may complicate the presentation of thyrotoxicosis. The risks appear to be related to metabolic status and to the precipitating cause. Pekonen et al. [51] reported that two of seven untreated thyrotoxic women in labor developed thyroid crisis. Similar results were described in eight untreated women in labor, of whom fi ve developed heart failure, and four had stillbirths [27] . In that series, among 16 other women who had received thionamides but were still thyrotoxic at the time of delivery, two had stillbirths and one developed heart failure whereas there were no complications in 36 women who were euthyroid. In an expanded review, Sheffi eld and Cunningham [52] found that nearly 10% of thyrotoxic women developed reversible congestive heart failure. Kriplani et al. [29] also reported three patients who developed thyroid storm, including one maternal death, among 32 patients who were hyperthyroid during pregnancy. Although thyroid functions were not specifi cally detailed, thyroid storm was associated with either emergent operative delivery or infec- tion. Thionamide therapy, even of short duration, is generally effective in preventing storm. Therefore, congestive heart failure that occurs after administration of propylthiouracil should suggest another precipitating event, such as underlying infection, hypertension, or anemia. The treatment of thyroid storm is somewhat empiric and con- sists of thionamides, iodide, and β - blockers. Therapy differs from the usual management of hyperthyroidism in the dose and choice of thionamide. Although propylthiouracil and methimazole are equally effective in the treatment of hyperthyroidism in preg- nancy [28] , in the setting of thyroid storm, propylthiouracil is administrated by mouth and if necessary by nasogastric tube to inhibit peripheral conversion of T4 to T3. Despite inhibition of T4 synthesis, it may take 7 – 8 weeks of therapy to deplete thyroid colloid stores and normalize thyroid function tests [27,28] . Clinical improvement commonly precedes resolution of the tachycardia due to the long half - life of T4. Iodide inhibits thyroid release rapidly [53,54] . Iodide should be given only after propyl- thiouracil is administered and should be discontinued when there is clinical improvement to avoid the risk of congenital goiter if the pregnancy continues. Propranolol (1 mg IV every 5 minutes and repeated as necessary) may be used to control autonomic symptoms. The fast - acting/short half - life β - blocker, esmolol, is also a reasonable choice. The loading dose is 250 – 500 µ g/kg fol- Endocrine Emergencies 431 measurement should be used to guide thyroid replacement therapy because of the advantage of treating subclinical thyroid disease [26,71] . The importance between the maternal and fetal thyroid axis has recently been examined. A study using 25 216 second - trimes- ter maternal serum α - fetoprotein samples [72] selected 62 women with TSH levels greater than the 98th percentile. At 8 years of age, the children of women with elevated TSH levels had a mean IQ that was 4 points less than matched controls (p = 0.06). In 48 of the women who did not receive thyroid replacement during preg- nancy, the IQ was 7 points less than matched controls (p = 0.05) and these children scored lower on 8 of 15 neuropsychological tests. Within 11 years, 64% of the untreated women and 4% of the match - control women had confi rmed hypothyroidism. Similar differences have been found by Pop et al. [73] . A recent workshop was held to discuss the many issues surrounding hypo- thyroidism and pregnancy [74] . Although universal thyroid screening is not currently recommended [21,45] , screening of women with a history of thyroid disorders and normalization of TSH levels would appear benefi cial in these women. Pheochromocytoma Pheochromocytoma is a rare tumor of catecholamine - secreting chromaffi n cells. Recent reviews have noted 43 cases associated with pregnancy between 1988 and 1997 [75 – 77] . Compared to the period of 1980 – 1987, maternal mortality fell from 16 to 2%, fetal loss decreased from 26 to 11%, and cases diagnosed antena- tally increased from 52 to 83%. The most common signs are hypertension (90%), headache, excessive truncal sweating, and paroxysmal attacks in 40 – 50% of patients. Pallor, fl ushing, anxiety, chest pain, nausea, and vomit- ing are less common. The diagnosis should be considered in the differential with hyperthyroidism and pre - eclampsia as higher maternal mortality is increased with hypertensive crisis when the diagnosis is not established prior to delivery. [75] . Most (90%) pheochromocytomas occur sporadically and some 10% are asso- ciated with familial disorder including multiple endocrine neo- plasia (MEN) II syndromes, von Recklinghausen ’ s disease, or von Hippel – Lindau syndrome [78] . Hypertension in the setting of caf é - au - lait spots and neurofi bromas should raise the suspicion of pheochromocytoma. Genetic screening may be warranted not only in familial syndromes [79] but also in sporadic cases [80] . MEN 2A is an autosomal dominant syndrome in which medul- lary thyroid carcinoma is associated with pheochromocytoma and hyperparathyroidism. A more extensive review of pheochro- mocytoma has been published by Prys - Roberts [78] . Advances in biochemical testing have improved the diagnosis. Table 33.4 summarizes the sensitivity and specifi city of plasma and urine tests [79] . If biochemical evaluation and the history suggest a pheochromocytoma, MRI can be safely performed in pregnancy to confi rm the presence of an adrenal mass, as 90% of pheochromocytomas arise in the adrenal glands. After delivery, clinical hypothyroidism (elevated TSH level with a normal T4 index). One stillbirth occurred in an untreated overtly hypothy- roid patient who was also eclamptic. Other than one infant with clubfeet, neonatal outcomes were satisfactory. Pre - eclampsia, pregnancy - induced hypertension, and eclampsia were common in women who were not yet euthyroid at delivery (9/30 subjects). In another study of 16 pregnancies in overtly hypothyroid women and 12 cases of subclinical hypothyroidism, complications were more common in overtly hypothyroid women including postpar- tum hemorrhage, anemia, pre - eclampsia, and placental abrup- tion [66] . Two women also had evidence of cardiac dysfunction, one of whom developed congestive heart failure. It is likely that the etiology of the increase in abruption was secondary to the higher incidence of chronic hypertension in hypothyroid patients [67] . Rarely hypothyroid patients may have prolonged bleeding times that normalize with T4 replacement [68] . As previously mentioned, thyroid replacement requirements may increase during pregnancy [64,69] . Mandel et al. [25] found it necessary to increase the mean T4 dose from 102 to 147 µ g/day in 9 of 12 patients in order to normalize TSH levels. Another group of investigators studied 35 pregnancies and noted that only 20% of women required an increase in T4 dosage [70] . TSH Table 33.3 Treatment of thyroid storm. Propylthiouracil 800 mg administered orally, then 150 – 200 mg every 4 – 6 hours Starting 1 – 2 hours after propylthiouracil administration Saturate solution of potassium iodide 2 – 5 drops orally every 8 hours, or Sodium iodide 0.5 – 1.0 g IV every 8 hours Dexametasone 2 mg IV every 6 hours for 4 doses β - blockade to decrease hypermetabolic state Propranolol 12 mg IV, repeated every 5 min, up to a total of 6 mg for extreme tachycardia or Esmolol 250 – 500 µ g/kg IV loading dose followed by 50 – 100 µ g /kg/min continuous infusion Treatment of anxiety/restlessness Hydroxyzine 50 – 100 mg orally every 6 hours or Lorazepam 1 – 2 mg orally every 6 – 8 hours or 20 – 25 µ g /kg IV every 6 hours Phenobarbital 30 – 60 mg every 8 hours as needed for extreme restlessness Search for precipitating event, in particular infection Control temperature if hyperthermic Acetaminophen 500 – 1000 mg every 4 – 6 hours, not to exceed 4000 mg/day Cooling blanket Critical tests Free T4, TSH, urine culture Evaluate for other autoimmune disorders Chest X - ray if indicated EKG (atrial fi brillation) Chapter 33 432 and the expanded extracellular fl uid volume result in an overall decrease in total serum calcium levels of 0.5 mg/dL [88] . However, ionized calcium levels are not affected. Pregnant women with primary hyperparathyroidism have biochemical parameters similar to those who are not pregnant [89] . In normal gestation, PTH levels are stable or slightly lower in the second trimester, refuting earlier studies of elevated PTH levels [90 – 92] . Thus, repeatedly elevated PTH levels in the presence of increase ionized calcium, or total calcium adjusted for albumin, must be consid- ered signifi cant. When hyperparathyroidism is diagnosed, a search for MEN is indicated [87] . Most non - parathyroid causes of hypercalcemia are associated with suppression of PTH and urinary cAMP levels. Non - parathyroid causes of hypercalcemia include malignancy (breast, melanoma, lymphoma), hypocalcuric hypercalcemia (familial, thiazides, lithium), granulomatous disease (sarcoidosis, tuberculosis), thyrotoxicosis, drug - induced causes (hypervita- minosis D or A, calcium, milk – alkali syndrome), adrenal insuf- fi ciency, and immobilization. Hypercalcemia secondary to PTH - related protein produced by breast tissue during pregnancy and lactation with normal PTH levels has also been reported [93] . A history should include the use of over - the - counter vitamin preparations and other medications. Primary hyperparathyroidism may be due to parathyroid ade- nomas (89% of cases), parathyroid hyperplasia (9%), or parathy- roid cancer (2%) [94] . The majority of patients with primary hyperparathyroidism are thought to be asymptomatic and are found to have elevated serum calcium levels on routine screening. However, on closer questioning, nearly half of these patients may complain of weakness or fatigue [95] . Approximately 20% of patients with hyperparathyroidism will have nephrolithiasis. Other common signs and symptoms include nausea or vomiting, mental disturbances, pancreatitis, and bone pain [83,96,97] . Hypercalcemic crisis is characterized by progressive hypercalce- mia with hypovolemia, renal insuffi ciency, altered mentation, and pancreatitis in the most severe cases. Rarely, seizures from hypercalcemia may mimic eclampsia [98] . The only defi nitive treatment is surgical removal of the glands. Since only 25% of asymptomatic patients will have progressive disease, which is usually in the form of a decrease in bone mass, the management of asymptomatic hyperparathyroidism is some- what controversial. In non - pregnant patients with mild to mod- erate hyperparathyroidism that was left untreated, no increase in mortality was seen. The only increase in mortality occurred in those patients with serum calcium levels in the uppermost quar- tile [99] . Treatment during pregnancy, however, may be war- ranted in view of the risk of neonatal tetany as well as the increase in perinatal complications including miscarriage and stillbirth seen in maternal hypercalcemia [100] . There is no satisfactory medical treatment for primary hyperparathyroidism in the pregnant or non - pregnant state. Mithramycin and bisphosphonates are contraindicated during pregnancy. Asymptomatic patients with mild hypercalcemia can be followed closely through pregnancy, with surgery deferred radioactive iodine - labeled metiodobenzylguanidine scintigraphy offers greater than 95% specifi city in the detection [79] of a pheochromocytome. The most frequently used treatment consists of non - specifi c α - adrenergic blockade with phenoxybenzamine given by mouth, 10 mg daily, increased by 0.5 – 1.0 mg/kg/daily [76,79] . Alternatively, the shorter - acting selective α 1 - blocker prazosin is less likely to cause tachycardia. The initial dosage is 1 mg three times a day, increased to 2 – 5 mg three times a day. Beta - blockers should be used in conjunction only after adrenergic blockade is initiated as unopposed α - adrenergic activity may lead to vaso- constriction and a marked increase in blood pressure. Commonly, labetalol is used as it has both α - and β - adrenergic antagonist properties. As hypertension is the most common presenting feature, pre - eclampsia will often be included in the differential diagnosis. Interestingly, magnesium sulfate given as a bolus fol- lowed by a 2 - g infusion has been used in non - pregnant patients for operative control during surgical removal of pheochromocy- toma [81,82] . The use of magnesium sulfate may therefore be advantageous. Hyperparathyroidism Primary hyperparathyroidism is more common in women than men (3 : 1 ratio). Since the average age of diagnosis is 55 years, the combination of hyperparathyroidism and pregnancy is uncommon. Approximately 145 cases of primary hyperparathy- roidism have been reported during pregnancy, which is propor- tionately less than the expected incidence of 8 new cases per 100 000 per year in women of childbearing age [83,84] . The dis- crepancy is in part due to the asymptomatic nature of most cases of hyperparathyroidism. Combining the results of two series [85,86] , the majority of patients were diagnosed postpartum fol- lowing the presentation of neonatal tetany. A recent review sum- marizes parathyroid disorders [87] . Whether in pregnancy or not, the diagnosis of hyperparathy- roidism is suggested by elevated levels of ionized calcium in the presence of inappropriately elevated parathyroid hormone (PTH). The majority of calcium is bound to albumin. The reduced serum albumin levels in pregnancy, acquisition by the fetus of 25 – 30 g of calcium, increase in glomerular fi ltration rate, Table 33.4 Biochemical tests for pheochromocytoma. Test Sensitivity (%) Specifi city (%) Plasma metanephrine 99 89 Plasama catecholamine 85 80 Urinary catecholamine 88 64 Urinary metanephrine 94 53 Urinary vanillymandelic acid 63 94 Endocrine Emergencies 433 Chronic candidiasis, alopecia, vitiligo, and multiple endocri- nopathies should suggest the autoimmune polyendocrinopathy – candidiasis – ectodermal dystrophy syndrome [87,106] . Perioral paresthesias, psychiatric disturbances, and Chvostek ’ s or Trousseau ’ s sign may be present. Trousseau ’ s sign, also known as the “ obstetrician ’ s hand ” , or carpal spasm due to ulnar and median nerve ischemia, is elicited by infl ating a sphygmomanom- eter cuff around the arm to 20 mmHg above systolic pressures The thumb adducts and the fi ngers are extended, except at the metacarpophalangeal joints, within minutes, indicating latent tetany. Cardiac changes of hypocalcemia are non - specifi c but include electrocardiogram Q – T prolongation, hypotension, and reversible congestive cardiomyopathy [104,107] . Hypopharyngeal tetany may present as stridor and seizures and may be life - threat- ening. Magnesium sulfate rarely has been implicated in hypocal- cemia and should be used cautiously when pre - eclampsia is superimposed on hypoparathyroidism [108] . Dilantin may increase vitamin D metabolism. In one case, decreased fetal heart rate variability was reported although there was no evidence of acidosis [109] . Secondary fetal or neonatal hyperparathyroidism, bone demineralization, and skeletal and skull fracture have been reported. Medical treatment of hypocalcemia can be divided into long - term and acute management. Vitamin D (50 000 – 100 000 units/ day) or 1,25 - dihydroxyvitamin D (calcitriol 0.5 – 3.0 µ g/day) and 1 – 2 g/day of elemental calcium have been used successfully in pregnancy [88] . Vitamin D 2 is the least expensive form of vitamin D, but several weeks may be needed for its full effect. Calcitriol has a faster onset of action (1 – 2 days) but requires more frequent monitoring to prevent hypercalcemia. Requirements during pregnancy may increase in the latter half of pregnancy, presum- ably due to increased vitamin D - binding protein. It is often nec- essary to reduce replacement doses in the postpartum period to avoid hypercalcemia, even in women who are breastfeeding [110] . The latter require closer monitoring of calcium levels, because it may be diffi cult to predict calcium need during lacta- tion. Of interest, in some species (cattle in particular), the onset of lactation can result in hypocalcemia and parturient paresis [111] . Acute hypocalcemia or impending signs of tetany are treated by 10% calcium gluconate (10 mL diluted in 150 mL of D5W given over 10 minutes), followed by continuous infusion of calcium (0.5 – 2.0 mg/kg/h). Serial calcium measure- ments should be measured initially every 2 – 4 hours to assess the adequacy of the administered dose and adjust the infusion rate accordingly [112] . Laboratory evaluation in addition to ionized calcium should include magnesium, phosphorus, and PTH levels. Hypoparathyroidism is diagnosed by normal serum magnesium concentration, low or inappropriately normal PTH level, and low ionized calcium. High PTH and low phosphorus levels suggest vitamin D defi ciency, whereas high PTH and high phosphorus levels are consistent with the diagnosis of pseudohypoparathyroidism or renal insuffi ciency. until after delivery [85,101,102] . Occasionally, a patient with sig- nifi cant symptoms due to hypercalcemia but who is not a surgical candidate has been controlled safely and effectively with oral phosphate therapy (1.5 g/day in divided doses) throughout gesta- tion [103] . This therapy is only indicated in patients in whom the initial serum phosphorus level is less than 3 mg/dL; phosphate administration should be adjusted to maintain serum phosphate below 4 mg/dL. Furosemide increases the excretion of calcium in the urine and can be given orally to help lower the serum calcium levels on a chronic basis. In contrast, patients with progressive symptoms, signifi cant hypercalcemia ( > 12 mg/dL), or deteriora- tion of renal function should be treated surgically by an experi- enced parathyroid surgeon [83,94] . Neck exploration should not be deferred in the symptomatic woman because of pregnancy, unless delivery is imminent [83] . Medical management for stabilization in hypercalcemic crisis includes hydration with normal saline (2 – 3 L over 3 – 6 hours), correction of electrolyte abnormalities, furosemide, which decreases distal tubular calcium reabsorption (10 – 40 mg IV every 2 – 4 hours) to maintain urine output at 200 mL/h, and calcium restriction. Hypercalcemia resistant to this regimen may be allevi- ated with more potent agents, such as calcitonin (100 – 400 units/ day). Although effective initially, tachyphylaxis to calcitonin gen- erally occurs in 4 – 6 days. Glucocorticoids can be used to decrease gastrointestinal calcium absorption. The reader is referred to a recent review [84] for greater detail. In hyperparathyroid mothers, neonatal hypocalcemia is pre- dictable and can be prevented. Transient neonatal tetany should not be associated with long - term sequelae. Management of maternal hyperparathyroidism diagnosed during pregnancy should be individualized, taking into consideration the patient ’ s symptoms, the gestational age of the fetus, and the severity of the disease. Hypoparathyroidism Hypocalcemia caused by hypoparathyroidism is an extremely rare disorder in pregnancy. The most common cause of hypo- parathyroidism is non - production of PTH because of excision of the parathyroid gland, usually following thyroidectomy. Anywhere from 0.5 to 3.5% of thyroid surgeries result in hypo- parathyroidism. As mentioned earlier, although total calcium concentration decreases in pregnancy, ionized calcium does not [88,90] . In response to hypocalcemia, PTH normally increases, which in turn augments renal tubular calcium reabsorption and phosphate excretion. PTH also increases 25 - hydroxyvitamin D transformation to the active hormone 1,25 - dihydroxyvitamin D, which stimulates intestinal calcium and phosphate absorption as well as osteoclastic bone reabsorption [87] . Ineffective PTH syn- dromes may be caused by failure to respond to increased PTH (pseudohypoparathyroidism), defi cient vitamin D from malab- sorption, or increased vitamin D metabolism seen with phenytoin or other anticonvulsants [104,105] . Chapter 33 434 However, abnormal ACTH testing measures physiologic reserve and does not necessarily predict whether adrenal crisis will develop following stress. The risk of clinically apparent adrenal insuffi ciency developing in unsupplemented patients undergoing surgery is well recognized [117] . In obstetric patients, chemical adrenal suppression has been noted in women receiving two courses of betamethasone for fetal lung maturation, yet neither of these patients had clinical signs of adrenal insuffi ciency during pregnancy [118] . One suggested regimen is to use hydrocortisone 100 mg every 8 hours for 24 hours if the patient has received more than 20 mg of prednisone daily for more than 3 weeks within the previous year [114] . For chronic replacement in patients with primary adrenocorti- cal insuffi ciency, doses are similar to those in the non - pregnant patient: hydrocortisone 20 mg each morning and 10 mg each evening. Since this dosage of hydrocortisone does not replace the adrenal mineralocorticoid component, mineralocorticoid sup- plementation is usually needed. This is accomplished by the administration of 0.05 – 0.2 mg/day fl uorocortisone by mouth. Patients should also be instructed to maintain an ample intake of sodium (3 – 4 g/day). During conditions of increased sweating, exercise, nausea and vomiting, these doses may need to be increased. References 1 Gabbe SG , Mestman JH , Hibbard LT . Maternal mortality in diabetes mellitus: an 18 year Survey . Obstet Gynecol 1976 ; 48 : 549 – 551 . 2 Drury MI , Greene AT , Stronge JM . Pregnancy complicated by clini- cal diabetes mellitus: a study of 600 pregnancies . Obstet Gynecol 1977 ; 49 : 519 – 522 . 3 Kilvert JA , Nicholson HO , Wright AD . Ketoacidosis in diabetic pregnancy . Diabet Med 1993 ; 10 : 278 – 281 . 4 Montoro MN , Myers VP , Mestman JH , et al. Outcome of pregnancy in diabetic ketoacidosis . Am J Perinatol 1993 ; 10 : 17 – 20 . 5 Chauhan SP , Perry KG . Management of diabetic ketoacidosis in the obstetric patient . Obstet Gynecol Clin North Am 1995 ; 22 : 143 – 155 . 6 Bedalov A , Balasubramanyam A . Glucocorticoid induced ketoacido- sis in gestational diabetes . Diabetes Care 1997 ; 20 : 922 – 924 . 7 Bouhanick B , Biquard F , Hadjadj S , et al. Does treatment with ante- natal glucocorticoids for the risk of premature delivery contribute to ketoacidosis in pregnant women with diabetes who receive CSII? Arch Intern Med 2000 ; 160 : 242 – 243 . 8 Kitabchi A , Umpierez G , Murphy M , Barret E . Management of hyperglycemic crises in patients with diabetes . Diabetes Care 2001 ; 24 : 131 – 153 . 9 Cullen MT , Reece EA , Homko CJ , Sivan E . The changing presenta- tions of diabetic ketoacidosis during pregnancy . Am J Perinatol 1996 ; 13 : 449 – 451 . 10 Van der Meulen JA , Klip A , Grinstein S . Possible mechanisms for cerebral oedema in diabetic detoacidosis . Lancet 1987 ; ii : 306 – 308 . 11 Viallon A , Zeni F , Lafond P , et al. Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 1999 ; 27 : 2690 – 2693 . Adrenal c risis Adrenal insuffi ciency may be primary or secondary. The most common cause of primary adrenal insuffi ciency (Addison ’ s disease) is idiopathic or autoimmune adenitis. Less frequently, tuberculosis, sarcoidosis, AIDS, or bilateral hemorrhage (antiphospholipid syndrome or anticoagulation) may be the cause. Autoimmune adenitis may be associated with gonadal failure, hypothyroidism, hyperthyroidism, Hashimoto ’ s thyroid- itis, vitiligo, hypoparathyroidism, and pernicious anemia (poly- glandular failure type I or II). For further details, the reader is referred to the review of Williams and Dluhy [113] . Except for those patients on corticosteroid therapy for other medical reasons, secondary adrenal insuffi ciency is rare in pregnancy. Adrenal insuffi ciency is more commonly diagnosed during the puerperium than earlier in pregnancy, in part due to the similar symptoms of pregnancy, including nausea, fatigue, diffuse tan or bronze darkening of the elbows or creases of the hands, and bluish - black patches that may appear on the mucous membranes. Axillary and pubic hair may be reduced as adrenal androgens are diminished. The diagnosis may not be suspected until adrenal crisis develops, with potentially serious sequelae. Pregnancy may be well tolerated until stresses such as infection, trauma, surgery, labor, or dehydration from vomiting or diarrhea precipitate adrenal crisis. The clinical features of acute primary adrenocorti- cal insuffi ciency include hypotension and shock (cardiovascular collapse), weakness, apathy, nausea, vomiting, anorexia, abdomi- nal or fl ank pain, and hyperthermia. Electrolyte abnormalities include hyponatremia, hyperkalemia, mild azotemia, and metabolic acidosis. Hypoglycemia and mild hypercalcemia may also be seen. Importantly, secondary adrenal insuffi ciency may present similarly but without electrolyte changes (normal renin – aldosterone response) and should be considered in patients previously on corticosteroids. Treatment of acute adrenal insuffi ciency includes hydrocorti- sone 100 mg IV every 6 hours for 24 hours. This dose can be reduced to 50 mg every 6 hours if the patient is improving, and tapered to an oral maintenance dose in 4 – 5 days. Doses of hydro- cortisone in the range of 100 – 200 mg maximize mineralocorti- coid effects and therefore supplementary mineralocorticoid is not necessary [113] . Additional therapy includes intravenous saline and glucose and correction of precipitating factors (infection) and electrolyte abnormalities. Volume replacement is critical in improving cardiovascular status. Patients with cardiovascular collapse may not respond well to pressor agents until hydrocor- tisone is given. Patients on chronic corticosteroid therapy should receive stress doses for infections, surgery, labor, and delivery. Adrenal sup- pression is unlikely to occur when corticosteroids are used for less than 3 weeks [114] . Following withdrawal of prolonged cortico- steroids, approximately 70% of patients will have normal func- tion within a month but in some individuals up to 9 months may be necessary for restoration of normal function [115,116] . Endocrine Emergencies 435 Graves ’ disease in offspring. Therapeutic considerations . Am J Med 1984 ; 77 : 572 – 578 . 33 Amino N , Tanizawa O , Mori H , et al. Aggravation of thyrotoxicosis in early pregnancy and after delivery in Grave ’ s disease . J Clin Endocrinol Metab 1982 ; 55 : 108 – 112 . 34 Amino N , Kuro R , Tanizawa O , et al. Changes of serum anti - thyroid antibodies during and after pregnancy in autoimmune thyroid dis- eases . Clin Exp Immunol 1978 ; 31 : 30 – 37 . 35 Muller A , Drexhage H Berghout A . Postpartum thyroiditis and auto- immune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care . Endocrine Rev 2001 ; 22 : 605 – 630 . 36 Zimmerman D . Fetal and neonatal hyperthyroidism . Thyroid 1999 ; 9 : 727 – 733 37 Epstein RH . Pathogenesis of Graves ’ ophthalmopathy . N Engl J Med 1993 ; 329 : 1468 . 38 Weetman AP . Graves ’ disease . N Engl J Med 2000 ; 343 : 1236 – 1248 . 39 Bitton RN , Wexler C . Free triiodothyronine toxicosis: a distinct entity . Am J Med 1990 ; 88 : 531 – 533 . 40 Peleg D , Cada S , Peleg A , Ben - Ami M . The relationship between maternal serum thyroid stimulating immunoglobulin and fetal and neonatal thyroitoxicosis . Obstet Gynecol 2002 ; 99 : 1040 – 1043 . 41 Glinoer D . Thyroid disease in pregnancy . In: Braverman LE , Utiger RD , eds. Werner and Ingbar ’ s The Thyroid , 9th edn. Philadelphia : JB Lippincott , 2004 : 1086 . 42 Mitsuda N , Tamaki H , Amino N , et al. Risk factors for developmen- tal disorders in infants born to women with Graves disease . Obstet Gynecol 1992 ; 80 : 359 – 364 . 43 Mortimer TH , Tyuack SA , Galligan JP , et al. Graves ’ s disease in pregnancy: TSH receptor binding inhibiting immunoglobulins and maternal and neonatal thyroid function . Clin Endocrinol 1990 ; 32 : 141 – 152 . 44 Momotani N , Noh J , Oyanagi , Ishikawa N , Ito K . Antithyroid drug therapy for Grave ’ s disease during pregnancy. Optimal regimen for fetal thyroid status . N Engl J Med 1986 ; 315 : 24 – 28 . 45 American College of Obstetricians and Gynecologists . Practice Bulletin No. 32. Thyroid Disease in Pregnancy . Washington, DC : American College of Obstetricians and Gynecologists , 2001 . 46 Mandel SJ , Brent GA , Larsen PR . Review of antithyroid drug use during pregnancy and a report of aplasia cutis . Thyroid 1994 ; 4 : 129 – 133 . 47 Gardner DF , Cruishank DP , Hays PM , et al. Pharmacology of pro- pylthiouracil (PTU) in pregnant hyperthyroid women: correlation of maternal PTU concentrations with cord serum thyroid function test . J Clin Endocrinol Metab 1986 ; 62 : 217 – 220 . 48 Easterling TR , Schmucker BC , Carlson KL , et al. Maternal hemody- namics in pregnancies complicated by hyperthyroidism . Obstet Gynecol 1991 ; 78 : 348 – 352 . 49 Pugh S , Lalwani K , Awal A . Thyroid storm as a cause of loss of consciousness following anaesthesia for emergency caesarean section . Anaesthesia 1994 ; 49 : 35 – 37 . 50 Mayer DC , Thorp J , Baucom D , et al. Hyperthyroidism and seizures during pregnancy . Am J Perinatol 1995 ; 12 : 192 – 194 . 51 Pekonen F , Lamberg BA , Ikonen E . Thyrotoxicosis and pregnancy: an analysis of 43 pregnancies in 42 thyrotoxic mothers . Ann Chir Gynaecol 1978 ; 67 : 1 – 7 . 5 2 S h e f fi eld J , Cunningham FG . Thyrotoxicosis and heart failure that complicate pregnancy . Am J Obstet Gynecol 2004 ; 190 ( 1 ): 211 – 217 . 12 Miodovnik M , Lavin J , Harrington D , et al. Effect of maternal keto- acidemia on the pregnant ewe and the fetus . Am J Obstet Gynecol 1982 ; 144 : 585 – 593 . 13 Nylund L , Lunell N , Lewander R , et al. Uteroplacental blood fl ow in diabetic pregnancy: measurements with indium 113m and a com- puter - linked gamma camera . Am J Obstet Gynecol 1982 ; 144 : 298 – 302 . 14 Hughes AB . Fetal heart rate changes during diabetic ketosis . Acta Obstet Gynecol Scand 1987 ; 66 : 71 – 73 . 15 Takahashi Y , Kawabata I , Shinohara A , Tamaya T . Transient fetal blood fl ow redistribution induced by maternal diabetic ketoacidosis diagnosed by Doppler ultrasonography . Prenat Diagn 2000 ; 20 : 524 – 525 . 16 Burrow GN , Fisher DA , Larsen PR . Maternal and fetal thyroid func- tion . N Engl J Med 1994 ; 331 : 1072 – 1078 . 17 Glinoer D , Delange F . The potential repercussions of maternal, fetal and neonatal hypothyroxinemia on the progeny . Thyroid 2000 ; 10 : 871 – 887 . 18 Ain KB , Mori Y , Refetoff S . Reduced clearance rate of thyroxine - binding globulin (TBG) with increased sialylation: a mechanism for estrogen - induced elevation of serum TBG concentrations . J Clin Endocrinol Metab 1987 ; 65 : 689 – 696 . 19 Berghout A , Endert E , Ross A , et al. Thyroid function and thyroid size in normal pregnant women living in an iodine replete area . Clin Endocrinol (Oxf) 1994 ; 41 : 375 – 379 . 20 Wartofsky L , Dickey RA . The evidence for a narrower thyrotropin reference range is compelling . J Clin Endocrinol Metab 2005 ; 90 : 5483 – 5488 . 21 Surks MI , Ortiz E , Daniels GH , et al. Subclinical thyroid disease: scientifi c review and guidelines for diagnosis and management . JAMA 2004 ; 291 : 228 – 238 . 22 Hak AE , Pols HAP , Visser TJ , et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarc- tion in elderly women: the Rotterdam study . Ann Intern Med 2000 ; 132 : 270 – 278 . 23 Imaizumi M , Akahoshi M , Ichimaru S , et al. Risk for ischemic heart disease and all - cause mortality in subclinical hypothyroidism . J Clin Endocrinol Metab 2004 ; 89 : 3365 – 3370 . 24 Redondi N , Newman AB , Vittinghoff E , et al. Subclinical hypothy- roidism and the risk of heart failure, other cardiovascular events, and death . Arch Intern Med 2005 ; 165 : 2460 – 2466 . 25 Mandel SJ , Larsen RP , Seely EW , et al. Increased need for thyroxine during pregnancy in women with primary hypothyroidism . N Engl J Med 1990 ; 323 : 91 – 96 . 26 Toft AD . Thyroxine therapy . N Engl J Med 1994 ; 331 : 174 – 180 . 27 Davis LE , Lucas MJ , Hankins GD , et al. Thyrotoxicosis complicating pregnancy . Am J Obstet Gynecol 1989 ; 160 : 63 – 70 . 28 Wing DA , Miller LK , Koonings PP , et al. A comparison of propyl- thiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy . Am J Obstet Gynecol 1994 ; 170 : 90 – 95 . 29 Kriplani A , Buckshee K , Bhargava VL , et al. Maternal and perinatal outcome in thyrotoxicosis complicating pregnancy . Eur J Obstet Gynecol Reprod Biol 1994 ; 54 : 159 – 163 . 30 Neale D , Burrow G . Thyroid disease in pregnancy . Obstet Gynecol Clin 2004 ; 31 : 893 – 905 . 31 Nader S . Thyroid disease and other endocrine disorder in preg- nancy . Obstet Gynecol Clin North Am 2004 ; 31 : 257 – 285 . 32 Volpe R , Ehrlich R , Steriner G , et al. Graves ’ disease in pregnancy years after hypothyroidism with recurrent passive - transfer neonatal Chapter 33 436 76 Hermayer K , Szpiech M . Diagnosis and management of pheochro- mocytoma during pregnancy: a case report . Am J Med Sci 1999 ; 318 : 186 – 189 . 77 Almog B , Kupferminc M , Many A , Lessing J . Pheochromocytoma in pregnancy: a case report and review of the literature . Acta Obstet Gynecol Scand 2000 ; 79 : 709 – 711 . 78 Prys - Roberts C . Phaeochromocytoma: recent progress in its man- agement . Br J Anaesth 2000 ; 85 : 44 – 57 . 79 Pacak K , Linehan WM , Eisenhofer G , et al. Recent advances in genetics, diagnosis, localization and treatment of pheochromocy- toma . Ann Intern Med 2001 ; 134 : 315 – 329 . 80 Neumann H , Bausch B , McWhinney SR , et al. Germ - line mutations in nonsyndromic pheochromocytoma . N Engl J Med 2002 ; 346 : 1459 – 1466 . 81 James MF , Use of magnesium sulphate in the anaesthetic manage- ment of phaeochromocytoma: a review of anaesthetics . Br J Anaesth 1989 ; 62 : 616 – 623 . 82 James M . Phaeochromocytoma: recent progress in its management . Br J Anaesth 2001 ; 86 ; 594 – 595 . 83 Carella MJ , Gossain V . Hyperparathyroidism and pregnancy . J Gen Intern Med 1992 ; 7 : 448 – 453 . 84 Schnatz P , Curry S . Primary hyperparathyroidism in pregnancy: evidence based management . Obstet Gynecol Surv 2002 ; 57 : 365 – 376 . 85 Gelister JS , Sanderson JD , Chapple CR , et al. Management of hyper- parathyroidism in pregnancy . Br J Surg 1989 ; 76 : 1207 – 1208 . 86 Kort KC , Schiller HJ , Numann PJ . Hyperparathyroidism and preg- nancy . Am J Surg 1999 ; 177 : 66 – 68 . 87 Marx SJ . Hyperparathyroid and hypoparathyroid disorders . N Engl J Med 2000 ; 343 : 1863 – 1875 . 88 Pitkin RM . Calcium metabolism in pregnancy and the perinatal period. A review . Am J Obstet Gynecol 1985 ; 151 : 99 – 109 . 89 Ammann P , Irion O , Gast J , et al. Alterations of calcium and phos- phate metabolism in primary hyperparathyroidism during preg- nancy . Acta Obstet Gynecol Scand 1993 ; 72 : 488 – 492 . 90 Seki K , Makimura N , Mitsui C , et al. Calcium - regulating hormones and osteocalcin levels during pregnancy: a longitudinal study . Am J Obstet Gynecol 1991 ; 164 : 1248 – 1252 . 91 Kohlmeier L , Marcus R . Calcium disorder of pregnancy . Endocrinol Metab Clin North Am 1995 ; 24 : 15 – 39 . 92 Seely EW , Brown EM , DeMaggio DM , et al. A prospective study of calciotropic hormones in pregnancy and postpartum reciprocal changes in serum intact parathyroid hormone and 1,25 - dihydroxyvitamin D . Am J Obstet Gynecol 1997 ; 176 : 214 – 217 . 93 Lepre F , Grill V , Ho PW , et al. Hypercalcemia in pregnancy and laction associated with parathyroid hormone - related protein . N Engl J Med 1993 ; 328 : 666 – 667 . 94 Kelly TR . Primary hyperparathyroidism during pregnancy . Surgery 1991 ; 110 : 1028 – 1033 . 95 Bilezibian JP , Silverbert SJ , Gartenberg F , et al. Clinical presentation of primary hyperparathyroidism . In: Bilezibian JP , Levine MA , Marcu R , eds. The Parathyroids: Basic and Clinical Concepts , 2nd edn. San Diego, CA : Academic Press , 2001 . 96 Kristoffersson A , Dahlgren S , Lithner F , et al. Primary hyperpara- thyroidism in pregnancy . Surgery 1985 ; 97 : 326 – 330 . 97 Murray J , Newman W , Dacus J . Hyperparathyroidism in pregnancy: diagnostic dilemma? Obstet Gynecol Surv 1999 ; 541 : 183 . 98 Whalley PJ . Hyperparathyroidism and pregnancy . Am J Obstet Gynecol 1963 ; 86 : 517 . 53 Wartofsky L , Ransil B , Ingbar S . Inhibition by iodine of the release of thyroxine from the thyroid gland of patients with thyrotoxicosis . J Clin Invest 1970 ; 49 : 78 – 86 . 54 Tan TT , Morat P , Ng ML , et al. Effects of Lugol ’ s solution on thyroid function in normals and patients with untreated thyrotoxicosis . Clin Endocrinol 1989 ; 30 : 645 – 649 . 55 Bowman ML , Bergmann M , Smith JF . Intrapartum labetalol for the treatment of maternal and fetal thyrotoxicosis . Thyroid 1998 ; 8 : 795 – 796 . 56 Eriksson M , Rubenfeld S , Garber AJ , et al. Propranolol does not prevent thyroid storm . N Engl J Med 1977 ; 296 : 263 – 264 . 57 Ashikaga H . Propranolol administration in a patient with thyroid storm . Ann Intern Med 2000 ; 132 : 681 – 682 . 58 Ikram H . The nature and prognosis of thyrotoxic heart disease . Q J Med 1985 ; 54 : 19 – 28 . 59 Woeber K . Update on the management of hyperthyroidism and hypothyroidism . Arch Intern Med 2000 ; 160 : 1067 – 1071 . 60 Cooper DS , Goldminz D , Levin A , et al. Agranulocytosis associated with antithyroid drugs . Ann Intern Med 1983 ; 98 : 26 – 29 . 61 Azizi F , Khoshniat M , Bahrainian M , et al. Thyroid function and intellectual development of infants nursed by mothers taking methimazole . J Clin Endocrinol Metab 2000 ; 85 : 3233 – 3238 . 62 Mandel SJ , Cooper DS . The use of antithyroid drugs in pregnancy and lactation . J Clin Endocrinol Metab 2001 ; 86 : 2354 – 2359 . 63 Glinoer D , de Nayer P , Bourdoux P , et al. Regulation of maternal thyroid during pregnancy . J Clin Endocrinol Metab 1990 ; 71 : 276 – 278 . 64 Abalovich M , Gutierrez S , Alcaraz G , et al. Overt and subclinical hypothyroidism complicating pregnancy . Thyroid 2002 ; 12 : 63 – 68 . 65 Leung AS , Millar LK , Koonings PP , et al. Perinatal outcome in hypothyroid pregnancies . Obstet Gynecol 1993 ; 81 : 349 – 353 . 66 Davis LE , Leveno KJ , Cunningham FG . Hypothyroidism complicat- ing pregnancy . Obstet Gynecol 1988 ; 72 : 108 – 112 . 67 Bing RF , Briggs RSJ , Burden AC , et al. Reversible hypertension and hypothyroidism . Clin Endocrinol (Oxf) 1980 ; 12 : 339 – 342 . 68 Myrup B , Bregengard C , Faber J . Primary haemostasis in thyroid disease . J Intern Med 1995 ; 238 : 59 – 63 . 69 Chopra I , Baber K . Treatment of primary hypothyroidism during pregnancy: is there an increase in thyroxine dose requirement in pregnancy? Metabolism 2003 ; 52 : 122 – 128 . 70 Girling JC , de Swiet M . Thyroxine dosage during pregnancy in women with primary hypothyroidism . Br J Obstet Gynaecol 1992 ; 99 : 368 – 370 . 71 Monzani F , di Bello V , Caraccion N , et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo - controlled study . J Clin Endocrinol Metab 2001 ; 86 : 1110 – 1115 . 72 Haddow J , Palomaki G , Allan W , et al. Maternal thyroid defi ciency during pregnancy and subsequent neurophyschological develop- ment of the child . N Engl J Med 1999 ; 341 : 549 – 555 . 73 Pop VJ , Brouwers EP , Vader HL , et al. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3 year follow up study . Clin Endocrinol 2003 ; 59 : 282 – 288 . 74 LaFranchi SH , Haddow JE , Hollowell JG . Is thyroid inadequacy during gestation a risk factor for adverse pregnancy and develop- mental outcomes? Thyroid 2005 ; 15 ( 1 ): 60 – 71 . 75 Ahlawat S , Jain S , Kumari S , et al. Pheochromocytoma associates with pregnancy: case report and review of the literature . Obstet Gynecol Surv 1999 ; 54 : 728 – 737 . Endocrine Emergencies 437 109 Hagay S , Mazor M , Leiberman J , et al. The effect of maternal hypo- calcemia on fetal heart rate baseline variability . Acta Obstet Gynecol Scand 1986 ; 65 : 513 – 515 . 110 Caplan RH , Beguin EA . Hypercalcemia in a calcitriol - treated hypoparathyroid women during lactation . Obstet Gynecol 1990 ; 76 : 485 – 489 . 111 Goff JP , Reinhardt TA , Horst RL . Recurring hypocalcemia of bovine parturient paresis is associated with failure to produce 1,25 - dihydroxyvitamin D . Endocrinology 1989 ; 125 : 49 – 53 . 112 Reber PM , Heath H . Hypocalcemic emergencies . Med Clin North Am 1995 ; 79 ( 1 ): 93 – 106 . 113 Williams G , Dluhy R . Primary adrenocortical defi ciency (Addison ’ s disease ). In: Braunwald E , Fauci AS , Isselbacher KJ , et al., eds. Harrison ’ s Principles of Internal Medicine , 15th edn. New York : McGraw - Hill , 2001 . 114 Jabbour S . Steroids and the surgical patient . Med Clin North Am 2001 ; 85 : 1311 – 1317 . 115 Graber A , Ney R , Nicholson W , et al. Natural history of pituitary - adrenal function recovery after long - term suppression with cortico- steroids . J Clin Endocrinol 1965 ; 25 : 11 . 116 Aceto T , Beckhorn G , Jorgensen J , et al. Iatrogenic ACTH - cortisol insuffi ciency . Pediatr Clin North Am 1966 ; 13 : 543 . 117 Kehlet J , Binder C . Adrenocortical function and clinical course during and after surgery in unsupplemented glucocorticoid - treated patients . Br J Anaesth 1973 ; 45 : 1043 – 1048 . 118 Helal K , Gordon MC , Lightner CR , et al. Adrenal suppression induced by betamethasone in women at risk for premature delivery . Obstet Gynecol 2000 ; 96 : 287 – 290 . 99 Silverberg SJ , Shane E , Jacobs TP , Siris E , Bilezikian JP . A 10 year review prospective study of primary hyperparathyroidism with or without parathyroid surgery . N Engl J Med 1993 ; 341 : 1249 – 1255 . 100 Shangold MN , Dor N , Welt S , et al. Hyperparathyroidism and preg- nancy: a review . Obstet Gynecol Surv 1982 ; 37 : 217 – 228 . 101 Croom RD , Thomas CG . Primary hyperparathyroidism during pregnancy . Surgery 1984 ; 96 : 1109 – 1118 . 102 Hill NC , Lloyd - Davies SV , Bishop A , et al. Primary hyperparathy- roidism and pregnancy . Int J Gynaecol Obstet 1989 ; 29 : 253 – 255 . 103 Montoro MN , Collear JV , Mestman JH . Management of hyperpara- thyroidism in pregnancy with oral phosphate therapy . Obstet Gynecol 1980 ; 55 : 431 – 434 . 104 Zalonga GP , Eil C . Diseases of the parathyroid glands and nephro- lithiasis during pregnancy . In: Brody SA , Ueland K , Kase N , eds. Endocrine Disorders in Pregnancy . Norwalk, CT : Appleton and Lange , 1989 : 231 . 105 Potts JT . Disease of the parathyroid gland and other hyper and hypocalcemic disorders . In: Braunwald E , Fauci AS , Isselbacher KJ , et al., eds. Harrison ’ s Principles of Internal Medicine , 15th edn. New York : McGraw - Hill , 2001 . 106 Ahonen P , Myllarniemi S , Sipila I , et al. Clinical variation of autoimmune poly - endocrinopathy - candidiasis - ectodermal dystro- phy (APECED) in a series of 68 patients . N Engl J Med 1990 ; 322 : 1829 – 1836 . 107 Csanady M , Forster T , Juesz J . Reversible impairment of myocardial function in hypoparathyroidism causing hypocalcaemia . Br Heart J 1990 ; 63 : 58 – 60 . 108 Eisenbud E , LoBue C . Hypocalcemia after therapeutic use of mag- nesium sulfate . Arch Intern Med 1976 ; 136 : 688 – 691 . 438 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy. © 2010 Blackwell Publishing Ltd. 34 Complications of Pre - eclampsia Gary A. Dildy III 1 & Michael A. Belfort 2 1 Maternal - Fetal Medicine, Mountain Star Division, Hospital Corporation of America, Salt Lake City, UT and Department of Obstetrics and Gynecology, LSU Health Sciences Center, School of Medicine in New Orleans, New Orleans, LA, USA 2 Department of Obstetrics and Gynecology, Division of Maternal - Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT and HCA Healthcare, Nashville, TN, USA Introduction Hypertensive disorders complicate 6 – 8% of pregnancies and remain signifi cant contributors to maternal and perinatal mor- bidity and mortality [1] . Classifi cation systems of hypertensive diseases during pregnancy tend to be confusing. A National Institutes of Health (NIH) sponsored working group proposed a modifi ed classifi cation system (Table 34.1 ) for the purpose of providing clinical guidance in managing hypertensive patients during pregnancy. Chronic hypertension is defi ned as hyperten- sion that is present before pregnancy or diagnosed before the 20th week of gestation. Pre - eclampsia is defi ned as the appearance of hypertension plus proteinuria, usually occurring after 20 weeks of gestation. Chronic hypertension may be complicated by super- imposed pre - eclampsia or eclampsia. In this classifi cation system, gestational hypertension is reassigned retrospectively following the puerperium as transient hypertension of pregnancy or chronic hypertension. In the United States, pre - eclampsia is one of the top three causes of maternal mortality in advanced gestations [2 – 5] . Substandard care is often an underlying factor leading to mater- nal mortality and severe morbidity [6 – 9] . Pathologic changes commonly affect the maternal cardiovas- cular, renal, hematologic, neurologic, and hepatic systems (Table 34.2 ). Equally important are the adverse effects on the uteropla- cental unit, resulting in fetal and neonatal complications [10 – 12] ). Our goal is to help guide the clinician in managing potentially severe complications of pre - eclampsia. Therapy for pregnant women with chronic hypertension will not be addressed in this chapter [13,14] . Etiology of p re - eclampsia Pre - eclampsia has been a recognized pathologic entity since the time of the ancient Greeks [15,16] . The inciting factor remains unknown, however, and an empty shield located on a portico at the Chicago Lying - In Hospital awaits inscription of the name of the person who discovers the etiology of the disease [17] . A sig- nifi cant amount of investigation has been undertaken during recent decades to elucidate the cause and improve the treatment of this disease. During the past 40 years of medical research, the number of published articles has grown in a geometric manner. Numerous risk factors are associated with the development of pre - eclampsia (Table 34.3 ), allowing for antenatal recognition of potential problems in some cases. Multiple interrelated patho- physiologic processes have been proposed as etiologic in the development of this disease [18 – 20] , including prostaglandin imbalance [21 – 25] , immunologic mechanisms [26 – 30] , hyperdy- namic increase in cardiac output [31] , and subclinical blood coagulation changes [32] . Endothelial involvement and the role of tumor necrosis factor, β - carotene, and reduced antithrombin III have also been investigated, but remain incompletely under- stood [33 – 38] . Increased vascular reactivity to vasoactive agents was demon- strated by Dieckmann and Michel in 1937 [39] . In 1961, Abdul - Karim and Assali [40] found that normal pregnant women were less responsive to angiotensin II than non - pregnant women. Gant et al. [41] published data that demonstrated an early loss of refractoriness to angiotensin II in those patients who later were to develop pre - eclampsia. Although clinical improvement may follow hospitalization and bed rest, vascular sensitivity to angio- tensin II does not decrease until after delivery of the fetus [42] . A molecular variant of the angiotensinogen gene (T235), found to be associated with essential hypertension, also has been associ- ated with pre - eclampsia [43] . It is postulated that increased con- centrations of plasma or tissue angiotensinogen could lead to increased baseline or reactive production of angiotensin II, . Salt Lake City, UT and Department of Obstetrics and Gynecology, LSU Health Sciences Center, School of Medicine in New Orleans, New Orleans, LA, USA 2 Department of Obstetrics and Gynecology,. after therapeutic use of mag- nesium sulfate . Arch Intern Med 1976 ; 136 : 688 – 691 . 438 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy again increased postpartum. A fall in antimicrosomal antibodies during pregnancy and an increase postpartum was also measured in patients with Graves ’ disease or postpartum thyroiditis [34]