Pheochromocytoma in pregnancy is associated with a dramatic increase in maternal and fetal morbidity and mortality, particularly if the diagnosis is unrecognized prior to delivery. The typical presentation of exacerbation of hypertension is frequently mistaken for pregnancy-induced hypertension or preeclampsia (1). Potential maternal complications include hemorrhage into the neoplasm, hemodynamic collapse, myocardial infarc tion, cardiac arrhythmias, congestive heart failure, and cerebral hemorrhage. These risks may increase with increasing gestational age as the enlarging uterus and actively moving fetus may compress the neoplasm.
There is minimal placental transfer of catecholamines (2,3), likely resulting from high placental concentrations of catechol-O-methyltransferase and monoamine oxidase (2,4). Adverse fetal effects are a result of catecholamine-induced uteroplacental vasoconstriction and placental insufficiency (5-7), and of maternal hypertension, hypotension, or vascular collapse.
As always, diagnosis of pheochromocytoma requires a high index of suspicion. Preconception screening of families known to have MEN-2 or familial paraganglioma is optimal. Availability of RET protooncogene testing has simplified this process in the former group. In addition, patients with MEN-2A are more likely to have paroxysmal hypertension and have higher rates of bilateral neoplasms than those with sporadic pheochromocytoma (8). Genetic testing for families with a paraganglioma history are being developed. Of interest is the inheritance pattern found in such families. Approximately half of the families involved demonstrate paternal transmission of this condition, associated with particular gene mutations (9). Individuals with neurofibromatosis (10), von Hipple-Lindau disease (11), or retinal angiomatosis should also be screened. Pheochromocytoma also should be considered in pregnant women with severe or paroxysmal hypertension, particularly when occurring in the first half of gestation or in association with episodic symptoms of palpitations, anxiety, diaphoresis, or headaches. Orthostatic hypotension is a common finding. Symptoms may present 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 (6).
Biochemical diagnosis of pheochromocytoma is unchanged from the nonpregnant state, as catecholamine metabolism is not altered by pregnancy per se (12). Urinary catecholamines may be modestly elevated in preeclampsia and other serious pregnancy complications requiring hospitalization, though they remain normal in mild preeclampsia or pregnancy-induced hypertension (13). Catecholamine levels normally rise at the onset of labor until the second day postpartum (14). If possible, methyldopa and labetolol should be discontinued prior to the biochemical investigation, as these agents may interfere with the quantification of the catecholamines and VMA (15). 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 exposure to ionizing radiation. Metaiodobenzylguanidine (MIBG) scans are contraindicated in pregnancy.
Initial medical management involves a blockade, with phentolamine, phenoxybenz-amine, prazosin, or labetolol. Phenoxybenzamine is considered the preferred agent as it provides long-acting, stable, noncompetitive blockade (6). Metyrosine has also been used to reduce catecholamine synthesis in a pregnancy complicated by malignant pheochro-mocytoma (16). P blockade is reserved for treating maternal tachycardia which persists after full a blockade and volume repletion. Placental transfer of phenoxybenzamine occurs (17), but is generally thought to be safe (18,19). P blockers may be associated with fetal bradycardia and with intrauterine growth retardation, when used early in pregnancy (12,20). These potential fetal risks are small compared to the risk of fetal wastage from unblocked high maternal levels of catecholamines.
The optimal timing of surgical excision of the neoplasm is uncertain, but may depend on the success of the medical management. Hemorrhage into the tumor, pressure from the uterus, motion of the fetus, and labor contractions are all stimuli that may lead to an acute crisis and potential maternal and fetal mortality. 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 second 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 second trimester of pregnancy (21). Other options include combined cesarean delivery and tumor resection or delivery followed by tumor resection at a later date. If possible, delivery is delayed until the fetus reaches sufficient maturity to reduce postpartum morbidity, providing successful medical management exists. As this patient was well controlled on her medical therapy, delivery was delayed until fetal lung maturity was confirmed with an amniocentesis.
Although successful vaginal delivery has been reported (22), it is thought to be associated with higher risk of maternal mortality than cesarean section. Labor may result in uncontrolled release of catecholamines secondary to pain and uterine contractions (23). Severe maternal hypertension may lead to placental ischemia and fetal hypoxia. However, intensive pain management with epidural anesthesia and avoidance of mechanical compression, employing techniques of passive descent and instrumental delivery, may make vaginal delivery a possibility for patients that are well controlled with medical therapy. As this patient was nulliparous with a frank breech presentation of the fetus, vaginal delivery was not an option nor was version of the fetus, owing to the risk of potentiating catecholamine release. Premature labor was likely in view of her uterine didelphys. Therefore, a cesarean section was scheduled upon confirmation of fetal lung maturity.
There is no available information regarding the impact of maternal use of phenoxy-benzamine on the nursing neonate. In this case, the patient pumped and discarded her breast milk until the excision of her pheochromocytomas, then initiated breastfeeding. Her daughter will be assessed with RET protooncogene testing.
Neither clinical nor histologic criteria may distinguish benign from malignant pheochromocytoma. Therefore, lifetime follow-up of all cases is required, particularly during future pregnancies.
Calcitonin levels may be elevated in individuals with pheochromocytoma, and normalize after excision of the neoplasm (24,25). Studies of calcitonin levels in pregnancy provide variable results. Some have found no significant change (26), whereas other investigators report increased concentrations longitudinally through gestation (27,28). The supposition is that the calcitonin may protect the maternal skeleton from excessive resorption (27). In this case, the elevation in calcitonin persisted postpartum and postoperative excision of the pheochromocytoma. This finding and the subsequent positive result of her RET protooncogene testing confirmed the diagnosis of MEN-2, requiring thyroidectomy for treatment of her medullary carcinoma.
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