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CALCIUM DISORDERS IN PREGNANCY Calcium metabolism is dramatically altered by pregnancy and lactation. The normal fetal skeleton accumulates approximately 30g of calcium by term, proportional to the fetal weight. The largest proportion (80%) of that accretion occurs in the third trimester, at a rate of about 250-300 mg/day (181). Total serum calcium levels fall early in pregnancy, due to hemodilution and the consequent decline in serum albumin (Figure 4). Ionized calcium levels and phosphate levels remain normal throughout pregnancy (181-5). PTH levels fall to 10-30% of the mean nonpregnant range in the first trimester but increase again to the midnormal range by term (185-7). Serum calcitonin levels increase during gestation (184,188), partly due to extrathyroidal synthesis in the placenta and breast. While PTH levels decline, total and free 1,25-dihydroxyvitamin D levels increase 2-fold in the first trimester, then remain constant until term (187,188). The maternal kidneys are the primary source for this increase in vitamin D secondary to up-regulation of the renal 1a-hydroxylase by PTHrP, with possibly small contributions from the maternal deciduas (189). PTHrP appears to increase early during pregnancy (190,191). The role of PTHrP is manifold. The amino-terminal portion stimulates renal 1a-hydroxylase and skeletal calcium resorption (189). It can also inhibit acetylcholine-induced uterine contractions in the rat and is decreased acutely in the amnion and myometrium at the onset of labor in humans (192). The carboxy-terminal portion inhibits osteoclastic bone resorption ("osteostatin"), while the mid-portion stimulates placental calcium transfer (189). The roles of estradiol, progestins, prolactin, chorionic somatomammotropin, and IGF-1 are still under investigation.
With the increase in 1,25-dihydroxyvitamin D, there is increased intestinal expression of the vitamin D-dependent calcium binding protein calbindin9K-D (189). This leads to a doubling in intestinal calcium absorption by 12 weeks of gestation (187), and appears to be the major maternal adaptation to supply the fetal calcium requirements. Prolactin and somatomammotropin may also play roles in this increased calcium absorption (189). Animal models suggest that this increased calcium intake is stored in the maternal skeleton until required in the third trimester, but this has not been assessed in humans. Urinary calcium excretion increases early in gestation secondary to an increased calcium load filtered by the kidneys and the increased glomerular filtration rate of pregnancy. The elevation of calcitonin levels may also contribute. Renal calcium excretion is low or normal in the fasted state (190). In pregnant rat models, bone turnover is increased but bone mineral content is unchanged. Bone biopsies of women who underwent an elective termination of pregnancy in the first trimester revealed increased bone resorption, with increased resorption surface, increased number of resorption cavities, and decreased osteoid (193). This is not seen at term. Most of the investigations of skeletal metabolism in pregnancy use bone markers and have a number of confounding variables including lack of prepregnancy baseline values, alterations in renal clearance, contributions from the gravid uterus, clearance by the placenta and hemodilution. Alkaline phosphatase is secreted by the placenta, and is not useful as a marker of bone formation in pregnancy. Urinary deoxypyridinoline, pyridinoline, and hydroxyproline increase in early to mid-pregnancy, suggesting bone resorption at that time (181). Bone formation markers osteocalcin and bone-specific alkaline phosphatase are decreased in early pregnancy and rise to normal or above by term (181). These findings suggest an increase in bone turnover in the first trimester but do not demonstrate a dramatic increase in the third trimester when most of the maternal-fetal calcium transfer occurs. Studies of bone mineral density in pregnancy are limited because of the concerns regarding fetal radiation exposure and the confounding effects of altered maternal body composition and weight. Conflicting results have been obtained according to the method of bone density measurement used, the site examined, and the timing during gestation and postpartum. Ultrasonography at the os calcis suggests a decline in bone mineral density through gestation (194,195). Numerous studies of osteoporotic women do not demonstrate a significant association with parity (196), suggesting that any effect on bone metabolism is transient. Transient, focal osteoporosis of the hip is a rare self-limited form of osteoporosis usually found in the third trimester or early postpartum. It generally presents as unilateral or bilateral hip pain, limp, and possible hip fracture. Bone mineral density is diminished at the femoral neck and head, with increased water content in the bone and the marrow. It generally resolves spontaneously within 2 to 6 months. There is no apparent association with the calcitropic hormones. Theories to explain this focal condition include femoral venous stasis secondary to compression by the gravid uterus, fetal pressure on the obturator nerve, marrow hypertrophy, immobilization, viral infection, trauma, and reflex sympathetic dystrophy (181). Fragility fractures in pregnancy and the puerperium may also be due to preconception osteoporosis and increased bone turnover in pregnancy and lactation. Chronic therapy with heparin, corticosteroids, and anticonvulsants may cause secondary osteoporosis. Low dietary intake of calcium and vitamin D may cause excessive skeletal calcium resorption. Adequate calcium and vitamin D intake and exercise should be instituted when needed. Specific treatment with bisphosphonates or calcitonin is contraindicated because of possible adverse effects on the developing fetus. Hypercalcemia is generally mild and asymptomatic in pregnancy and is usually found on routine screening or on investigation of hypocalcemia in the neonate (197). Hypercalcemia occurs in 0.1-0.6% of the general population. In the child-bearing years, the most common etiology is hyperparathyroidism. The diagnosis of mild hyperparathyroidism may be obscured by the pregnancy-induced fall in total calcium, the fall in intact PTH, and the rise in the 24-hour urinary excretion of calcium. In more severe forms of this condition, the risk of adverse pregnancy outcomes rises dramatically. Severe hypercalcemia may cause rapidly progressive anorexia, nausea, vomiting, weakness, fatigue, dehydration, and stupor. This requires emergency treatment as it may be fatal. Acute pancreatitis (182,197-9) may occur at rates 6 times that of the nonpregnant population, with significant risks for both mother and fetus. Patients with persistent vomiting must be hydrated rapidly to prevent worsening of the hypercalcemia from dehydration. As pregnancy tends to ameliorate hypercalcemia with the placental transfer of calcium to the fetus, maternal hypercalcemia may dramatically worsen postpartum (197-9). Infants of mothers with severe hypercalcemia are at risk for spontaneous abortion (8%), premature birth (10%), stillbirth (2%), severe hypocalcemia with or without tetany (15-25%), and neonatal death (2%) (182,197-9). PTH does not cross the placenta, and the neonatal hypocalcemia is secondary to suppression of the fetal parathyroid glands by the placental transfer of elevated calcium levels, which stops at birth. The parathyroid gland suppression and hypocalcemia is transient, lasting up to 3-5 months, and can be managed with calcium and vitamin D supplements (182,197-9). Because of the potential hazards to mother and child, all patients with known primary hyperparathyroidism should undergo surgery before conceiving. When hyperparathyroidism is diagnosed during pregnancy, parathyroidectomy is generally well-tolerated by mother and fetus. Of those pregnancies in which the hyperparathyroid mothers were treated expectantly or with oral phosphates, 40% of the neonates developed hypocalcemia. Hypercalcemia discovered late in gestation may be managed with oral phosphate (Fleet's Phospho-Soda, 15-50 cc/day in divided doses) (182,197-9). Calcium levels should be monitored every 2-4 weeks. Initial therapy for patients with severe hypercalcemia (calcium > 14 mg/dl) includes rehydration with saline. Forced diuresis with furosemide may further increase urinary calcium excretion. However, loop diuretics readily cross the placenta and cause increased fetal urine production and polyhydramnios. Glucocorticoids and calcitonin may also be used, but the safety of bisphosphonates and other agents has not been established in pregnancy. The most common cause of hypocalcemia is hypoparathyroidism secondary to surgery for thyroid or parathyroid disease. Autoimmune, infiltrative, and idiopathic causes are uncommon. Vitamin D deficiency is very rare. During pregnancy, women with hypoparathyroidism generally have fewer hypocalcemic symptoms, with decreased dependence on supplemental calcitriol to maintain a normal serum calcium (189,200,201). This likely occurs because 1,25-dihydroxyvitamin D levels are less dependent on PTH production in pregnancy, but are also regulated by PTHrP, and possibly prolactin and chorionic somatomammotropin. In late pregnancy, hypercalcemia may occur unless the calcitriol dose is decreased below the prepregnancy level (200,201) This is more pronounced during breastfeeding, likely due to the large secretion of PTHrP at that time (see below). Maternal hypocalcemia causes fetal hypocalcemia because of an inadequate transfer of calcium to the fetus. This results in fetal hyperparathyroidism with attendant skeletal demineralization, subperiostial bone resorption, osteitis fibrosa cystica and, rarely, death (202). 1,25-dihydroxyvitamin D is the preferred therapy because its rapid action allows precise modulation of serum calcium levels. Breast feeding causes a daily maternal calcium loss of 280-400 mg/day (196). This calcium seems to come primarily from the skeleton, with bone density losses of 1-3% per month, secondary to declining estrogen levels and high PTHrP. Ionized calcium levels increase to the high normal range (203). Phosphate levels may rise above the normal range, with increased renal reabsorption and skeletal resorption (184). PTH is reduced 50% in the first several months postpartum, and rises to above normal after weaning (187,189). Total and free levels of 1,25-dihydroxyvitamin D levels fall to normal within days postpartum (186). As 1,25-dihydroxyvitamin D levels fall to normal, intestinal calcium absorption decreases to the non-pregnant level. PTHrP levels are higher in lactating women than in nonpregnant controls, with a rise after suckling (203,204). PTHrP levels in breast milk may exceed 10,000 times that found in the serum of nonpregnant controls (205,206). PTHrP may regulate mammary development and mammary blood flow (189). It may also contribute to maternal skeletal calcium resorption, renal tubular reabsorption of calcium, and suppression of PTH. PTHrP levels correlate negatively with PTH levels and positively with the ionized calcium levels (181,203) and loss of bone mineral density in lactating women (207). The lactation influence on calcium homeostasis does not occur in women with pseudohypoparathyroidism who have resistance to the amino-terminal actions of PTH and PTHrP. Renal calcium excretion falls to 50 mg/24 hours with the decline in GFR to below prepregnant levels, and with increased tubular reabsorption of calcium. Rat models reveal increased bone turnover with a 35% loss of bone mineral in 2-3 weeks of lactation. Urinary markers of bone resorption are higher than during pregnancy, and 2- to 3-fold higher than in nonpregnant controls. Bone formation markers are also higher than in pregnancy or the nonpregnant state (189). Bone density at trabecular sites declines at a rate of 1-3% per month, for a total of 3-10% lost within 2-6 months of lactation, with smaller losses at cortical sites (196). This loss correlates with the calcium lost in breast milk (208), and is not prevented by increasing calcium supplementation (209-12). The duration of amenorrhea, which corresponds to reduced estrogen levels and increased intensity of lactation and breast milk calcium losses, correlates positively with bone loss during lactation (207,210-12). The decline in bone density is greater than that seen in women with lower estrogen levels, increased urinary calcium excretion, and suppressed 1,25-dihydroxyvitamin D and PTH, induced by GnRH agonist therapy, who lose 1-4% of their trabecular bone density in 6 months (213). Lactating women have higher estrogen levels, reduced calcium excretion, and normal 1,25-dihydroxyvitamin D levels. PTHrP may be the added mechanism contributing to their higher bone loss at both cortical and trabecular sites. Postweaning, bone density increases by 0.5-2% per month, returning to normal in 3-6 months (196,211). PTH and 1,25-dihydroxyvitamin D levels increase after weaning (214), but the exact mechanism for rapid bone accretion is unstudied. ADRENAL DISORDERS IN PREGNANCY Pregnancy modifies adrenal steroid metabolism substantially. In contract to the effects on the hypothalamic-pituitary-adrenal axis, glucocorticoid levels provide a positive feedback on the placental corticosteroid axis. Placental CRH rises several hundred-fold during pregnancy, is extensively protein bound until term, and modulates both maternal and fetal pituitary-adrenal axes and may regulate parturition (215). Both maternal and placental ACTH levels rise dramatically after 16-20 weeks' gestation (216)(Figure 5), with a final surge in ACTH and plasma cortisol during labor. Despite the increase in the placental hormones, the normal maternal circadian rhythm of ACTH secretion persists throughout pregnancy.
The fetoplacental unit has a marked capacity for steroidogenesis. At the same time, maternal cortisol levels increase 2- to 3-fold throughout pregnancy (217,218) with an increase in the size of the maternal zona fasciculate (219). There is an estrogen-stimulated increase in circulating cortisol binding globulin levels, resulting in an increase in total cortisol levels and a decreased rate of cortisol clearance (220). With displacement of cortisol from CBG by progesterone, free cortisol levels also increase (217). Urine free cortisol levels rise 2-3 fold during gestation. Numerous changes occur in the renin-angiotensin-aldosterone system as well. Plasma renin activity increases 4-fold and plateaus at 20 weeks' gestational age, despite the increase in plasma volume with pregnancy. Angiotensin II levels increase approximately 3-fold by term, although there is resistance to its pressor effects. Plasma mineralocorticoid levels increase 5- to 7-fold during gestation (218,221), but aldosterone secretion continues to respond normally to physiologic stimuli and varies inversely to changes in volume or dietary salt (222). The increase in aldosterone correlates with the pregnancy increase in GFR and in progesterone (223), which competitively inhibits sodium retention by aldosterone at the distal renal tubules. Progesterone also demonstrates an anti-kaliuretic effect (222), with a report of amelioration of hypokalemia during pregnancy in a woman with primary aldosteronism (224). Cushing's Syndrome During Pregnancy Cushing's syndrome is uncommon, with an incidence of 2 in 1,000,000. Just over 100 cases have been reported in pregnancy to date, as fertility is generally reduced by altered gonadotropin secretion in pituitary disease, and increased adrenal androgen secretion in adrenal disease. Approximately 44% are secondary to a pituitary adenoma vs. an 80% rate expected in the nonpregnant woman. Of the remaining, 44% are adrenal adenomas, 11% adrenal carcinomas (225-31), and the remainer a mix of adrenonodular hyperplasia and ectopic ACTH (227). Recently, several cases of pregnancy-dependent Cushing's syndrome have been described, with no intrapartum adrenal steroid abnormalities noted (232,233). The increase in placental CRH rise apparently caused a pregnancy-induced exacerbation and recognition of the hypercortisolism in many cases, with occasional improvement in the symptoms postpartum (226,227). It may be difficult to diagnose Cushing's syndrome during pregnancy because the typical symptoms of weight gain, fatigue, emotional lability, glucose intolerance, hypertension, and edema are also common accompaniments of pregnancy. Pigmentation of striae and development of hirsutism or acne may suggest the hyperandrogenemia of Cushing's syndrome, and proximal myopathy may also help to distinguish Cushing's syndrome from normal pregnancy symptoms. The laboratory evaluation is confounded by the normal pregnancy rise in ACTH and cortisol levels. Normal pregnancy is also associated with "inadequate" suppression during the overnight dexamethasone suppression test (228). The elevated cortisol levels may be suppressed by the high dose dexamethasone suppression test, suggesting Cushing's disease (226). For all forms of Cushing's syndrome, ACTH levels are normal or high, likely from placental ACTH production or from the CRH-stimulated pituitary ACTH production (225-31). Thus, ACTH levels can not be used to distinguish between pituitary and adrenal etiologies. The hypercortisolism of pregnancy continues to exhibit a normal circadian rhythm. This is absent in all forms of Cushing's syndrome (234). Petrosal sinus sampling has been performed during pregnancy with no ill effects (235), and patients with Cushing's disease apparently have the typical exaggerated ACTH response to CRH (229). CT or MRI are necessary for further characterization of pituitary or adrenal lesions. Maternal complications of Cushing's syndrome include hypertension, diabetes, myopathy, postoperative wound infection and dehiscence. Fetal mortality of 25% from spontaneous abortion, stillbirth, and prematurity has been observed (225-31). Premature labor is common. The maternal hypercortisolemia may occasionally lead to fetal adrenal suppression (236), and the neonate should be tested for this and treated prophylactically until the results are known. Rates of fetal loss and premature labor decrease, though are still increased, in patients who are treated during pregnancy (225,228). Medical therapy is generally ineffective (227,228,231), though metyrapone has proved efficacious in a few patients. Adrenal surgery may be performed through a flank incision or by laparoscopy. Because of the high rate of adrenal carcinoma, early surgery may improve the poor prognosis. Transsphenoidal surgery has also been used successfully (226). The risks of surgery to both mother and fetus are outweighed by the benefits of appropriately treating the Cushing's syndrome. Primary adrenal insufficiency rarely presents in pregnancy (237). Secondary adrenal insufficiency, from pituitary neoplasms or glucocorticoid supression of the hypothalamic-pituitary-adrenal axis, is more common. Recognition of adrenal insufficiency may be difficult in the first trimester as many of the clinical features are found in normal pregnancies, including weakness, lightheadedness, syncope, nausea, vomiting, and increased pigmentation. Addisonian hyperpigmentation may be distinguished from chloasma of pregnancy by its presence on the mucous membranes, on extensor surfaces, and over non-exposed areas. Weight loss together with these symptoms should prompt a clinical evaluation. If unrecognized, adrenal crisis may ensue at times of stress, such as a urinary tract infection or during labor (237). Fetal cortisol production may be protective, shielding the mother from severe adrenal insufficiency until postpartum (238). The fetoplacental unit largely controls its own steroid milieu, so maternal adrenal insufficiency generally causes no problems with fetal development. Maternal antiadrenal autoantibodies may cross the placenta, but usually not in sufficient quantities to cause fetal or neonatal adrenal insufficiency (239). Although Osler observed intrauterine fetal growth restriction in offspring of women with Addison's disease (240), this observation has not been supported in most subsequent case series. Adrenal insufficiency is associated with laboratory findings of hyponatremia, hyperkalemia, hypoglycemia, eosinophilia, and lymphocytosis. Plasma cortisol levels may fall in the normal "nonpregnant" range due to the increase in CBG concentrations, but will not be appropriately elevated for the stage of pregnancy. With primary adrenal insufficiency, ACTH levels will be elevated. However, ACTH will not be low with secondary forms because of the placental production of this hormone, which is nevertheless insufficient to maintain normal maternal adrenal function. Despite the normal increase in plasma cortisol during pregnancy, maternal replacement doses of corticosteroids usually are not different from those required in the non-pregnant state. Higher doses are needed at times of stress, such as during the course of "morning sickness" or during labor and delivery. Mineralocorticoid replacement requirements usually do not change during gestation, though some clinicians have decreased fludrocortisone intake in the third trimester in an attempt to treat Addisonian patients who develop preeclampsia (241). Patients who have received glucocorticoids as antiinflammatory therapy are presumed to have adrenal axis suppression for at least one year (242). These patients should be treated with "stress" doses of glucocorticoids during labor and delivery. They are at risk for postoperative wound infection and dehiscence as are patients with endogenous Cushing's syndrome, and their offspring are at risk for transient adrenal insufficiency. Although prednisone readily crosses the placenta (243), the maternal:fetal gradient is higher than with other available agents (244,245). Corticosteroid therapy during pregnancy is generally safe and suppression of neonatal adrenal function is uncommon (246). Glucocorticoid therapy during lactation is also safe, as minimal amounts of these medications are passed into breast milk. Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia is a family of monogenic inherited enzymatic defects of adrenal steroid biosynthesis, with manifestations secondary to an accumulation of precursors proximal to the enzymatic deficiency. The most common form of CAH in the population is 21-hydroxylase deficiency, seen in more than 90% of the CAH cases in pregnancy (247,248). Classic, severe 21-hydroxylase deficiency is associated with ambiguous genitalia, an inadequate vaginal introitis, and progressive postnatal virilization including precocious adrenarche, advanced somatic development, central precocious puberty, menstrual irregularity, a reduced fertility rate, and possibly salt wasting (248-50). The spontaneous abortion rate is twice that in the normal population (251), and congenital anomalies are more frequent. Cephalopelvic disproportion from an android pelvis may occur, sometimes complicated by the previous reconstructive surgery (252,253). Conception requires adequate glucocorticoid therapy, which then continues at stable rates during gestation, except at labor and delivery. Nonclassic (late-onset) 21-hydroxylase deficiency patients present with pubertal and postpubertal hirsutism and menstrual irregularity and may have improved fertility with glucocorticoid therapy (251). Often, however, ovulation induction is required to enable these patients to conceive children. Fetal risk depends on the carrier status of the father. Unfortunately, ACTH stimulation testing to measure 17-OH progesterone demonstrates overlap between heterozygotes for CAH and the normal population (254). Virilization is not seen in the female fetus with nonclassic 21-hydroxylase deficiency (255), but occurs in a fetus with classic 21-hydroxylase deficiency unless fetal adrenal androgen production is adequately suppressed. Dexamethasone most readily crosses the placenta as it is not bound to CBG and is not metabolized by placental 11 b-hydroxysteroid dehydrogenase. It is commonly used at doses of 20 mg/kg maternal body weight per day to a maximum of 1.5 mg daily in 3 divided doses beginning before the 9th week of gestation (248,249). Maternal plasma and/or urinary estriol levels reflect fetal adrenal synthesis and are monitored to assess efficacy. Maternal cortisol and DHEA-S will determine maternal adrenal suppression. There is little effect on maternal 17-OH progesterone with therapy. As only 25% of female fetuses are affected in a family with CAH, it is important to discontinue therapy as soon as possible in the male fetus and unaffected female fetus. Chorionic villus sampling at 9-11 weeks' gestation may be used for gender determination and direct DNA analysis for the 21-hydroxylase gene CYP21.(247,249,256) The test itself is associated with a 1-4% risk of miscarriage and 2% risk of limb defects. An alternative is karyotyping and DNA analysis or measuring androstenedione and 17-OH progesterone levels in amniotic fluid at 16-18 weeks of gestation after dexamethasone has been withheld for 5 days.(256) Side effects of dexamethasone therapy are potentially significant, including excessive weight gain, severe striae with scarring, edema, irritability, gestational diabetes mellitus, hypertension, and gastrointestinal intolerance (249,257). In affected pregnancies, dexamethasone may be lowered to 0.75 to 1.0 mg/day in the second half of pregnancy to decrease maternal side effects while avoiding fetal virilization (257). Treatment by the 9th week of gestation is very effective in reducing the risk of virilization in the affected female fetus (249). Primary Hyperaldosteronism During Pregnancy Primary hyperaldosteronism rarely has been reported in pregnancy (258-61), and is most often caused by an adrenal adenoma. The elevated aldosterone levels found in patients are similar to those in normal pregnant women, but the plasma renin activity is suppressed (258-61). Salt loading tests may be used to diagnose hyperaldosteronism. If baseline and suppression testing are equivocal, or radiologic scanning does not suggest unilateral disease, patients may be treated medically until delivery to allow more definitive investigations (260). Spironolactone, the usual nonpregnant therapy, is contraindicated in pregnancy as it crosses the placenta and is a potent antiandrogen which can cause ambiguous genitalia in a male fetus (261). Surgical therapy may be delayed until postpartum if hypertension can be controlled with agents safe in pregnancy, such as methyldopa, labetolol, and amiloride. As noted above, the hypokalemia may ameliorate in pregnancy because of the antikaliuretic effect of progesterone. Both hypertension and hypokalemia may exacerbate postpartum due to removal of the progesterone effect (262,263). Exacerbation of hypertension is a typical presentation of pheochromocytoma in nonpregnant patients, but during pregnancy is frequently mistaken for pregnancy-induced hypertension or preeclampsia (264). As the uterus enlarges and an actively moving fetus compresses the neoplasm, maternal complications such as severe hypertension, hemorrhage into the neoplasm, hemodynamic collapse, myocardial infarction, cardiac arrhythmias, congestive heart failure, and cerebral hemorrhage may occur. Extra-adrenal tumors which occur in 10%, such as in the organ of Zuckerkandl at the aortic bifucation, are particularly prone to hypertensive episodes with changes in position, uterine contractions, fetal movement, and Valsalva maneuvers (265). Unrecognized pheochromocytoma is associated with a maternal mortality rate of 50% at induction of anesthesia or during labor (266,267). There is minimal placental transfer of catecholamines (268,269), likely due to high placental concentrations of catechol-O-methyltransferase and monoamine oxidase (268,270). Adverse fetal effects such as hypoxia are a result of catecholamine-induced uteroplacental vasoconstriction and placental insufficiency (271-3), and of maternal hypertension, hypotension, or vascular collapse. As always, diagnosis of pheochromocytoma requires an index of suspicion. Preconception screening of families known to have MEN 2 with RET proto-oncogene is essential. Patients with MEN 2A are more likely to have paroxysmal hypertension and have higher rates of bilateral neoplasms than those with sporadic pheochromocytoma (274). Examination for associated evidence for MEN2 may be difficult in pregnancy, with the expected pregnancy alterations in calcium, PTH, and calcitonin. Clinical thyroid examination should be done, with fine needle aspiration of any nodules so that overt medullary carcinoma can be treated immediately. Individuals with neurofibromatosis (275), von Hipple-Lindau disease (276), or retinal angiomatosis should also be screened for pheochromocytomas prior to pregnancy. The diagnosis should be considered in pregnant women with severe or paroxysmal hypertension, particularly in the first half of pregnancy or in association with orthostatic hypotension or episodic symptoms of anxiety, headaches, palpitations, or diaphoresis. Symptoms may occur or worsen during pregnancy because of the increased vascularity of the tumor and mechanical factors such as pressure from the expanding uterus or fetal movement (272). Laboratory diagnosis of pheochromocytoma is unchanged from the nonpregnant state as calecholamine metabolism is not altered by pregnancy per se (277). If possible, methyldopa and labetolol should be discontinued prior to the investigation as these agents may interfere with the quantification of the catecholamines and VMA (278). Provocative testing should be avoided because of the increased risk of maternal and fetal mortality. Tumor localization with MRI, with high intensity signals noted on T2-weighted images, provides the best sensitivity without fetal exposure to ionizing radiation. Metaiodobenzylguanidine scans are contraindicated in pregnancy, but may be necessary if other tumor localization methods fail. Differentiation from preeclampsia is generally simple. The edema, proteinuria, and hyperuricemia found in preeclampsia are absent in pheochromocytoma. Plasma and urinary catecholamines may be modestly elevated in preeclampsia and other serious pregnancy complications requiring hospitalization, though they remain normal in mild preeclampsia and pregnancy-induced hypertension (279). Catecholamine levels are 2- to 4-times normal after an eclamptic seizure (280). Initial medical management involves a-blockade with phenoxybenzamine, phentolamine, prazocin, or labetolol. All of these agents are well-tolerated by the fetus, but phenoxybenzamine is considered the preferred agent as it provides long-acting, stable, non-competitive blockade (272). Placental transfer of phenoxybenzamine occurs (281), but is generally safe (282,283). If hypertension remains inadequately controlled, metyrosine has also been used successfully to reduce catecholamine synthesis in a pregnancy complicated by malignant pheochromocytoma (284), but may potentially adversely affect the fetus. Beta blockade is reserved for treating maternal tachycardia or arrhythmias which persists after full a-blockade and volume repletion. Beta blockers may be associated with fetal bradycardia and with intrauterine fetal growth restriction, when used early in pregnancy (277,285). All of these potential fetal risks are small compared to the risk of fetal wastage from unblocked high maternal levels of catecholamines. Hypertensive emergencies should be treated with phentolamine or nitroprusside, although the latter should be limited because of fetal cyanide toxicity. The timing of surgical excision of the neoplasm is controversial and may depend on the success of the medical management and the location of the tumor. As noted above, pressure from the uterus, motion of the fetus, and labor contractions are all stimuli that may cause an acute crisis, particularly in patients with a tumor at the organ of Zuckerkandl. In the first half of pregnancy, surgical excision may proceed once adequate a-blockade is established, although there is a higher risk of miscarriage with first trimester surgery. In the early 2nd trimester, abortion is less likely and the size of the uterus will not make excision difficult. If the pheochromocytoma is not recognized until the second half of gestation, increasing uterine size makes surgical exploration difficult. Successful laparoscopic excision of a pheochromocytoma has been described in the 2nd trimester of pregnancy (286). Other options include combined cesarean delivery and tumor resection or delivery followed by tumor resection at a later date. Delivery is generally delayed until the fetus reaches sufficient maturity to reduce postpartum morbidity, providing successful medical management exists. Although successful vaginal delivery has been reported (287), it has been associated with higher rates of maternal mortality than cesarean section. Labor may result in uncontrolled release of catecholamines secondary to pain and uterine contractions (288). Severe maternal hypertension may lead to placental ischemia and fetal hypoxia. However in the well-blocked patient, vaginal delivery may be possible with intensive pain management with epidural anesthesia and avoidance of mechanical compression, employing techniques of passive descent and instrumental delivery. There is no available information regarding the impact of maternal use of phenoxybenzamine on the nursing neonate. |
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