Management of paroxysmal hypertension due to incidental pheochromocytoma in pregnancy.

A 25-year-old, full-term pregnant woman diagnosed with pre-eclampsia was referred to our tertiary care hospital with severe resistant hypertension. Her blood pressure remained labile despite the usual medications, which led to the suspicion of an underlying endocrinological problem. Further biochemical and radiological investigations confirmed the diagnosis of pheochromocytoma. The patient was invasively monitored and treated with alpha blockade, beta blocker, and vasodilators. The primary goals for the management of pheochromocytoma in pregnancy are early diagnosis, avoidance of a hypertensive crisis during delivery, and definitive surgical treatment. This case illustrates that one needs to be cautious when such a presentation of paroxysmal hypertension is present. With a multidisciplinary team approach, proper planning, and adequate preoperative medical management, pheochromocytoma in pregnancy can be managed successfully.

INTRODUCTION

The incidence of pheochromocytoma in pregnancy is rare, less than 0.2 per 10,000 pregnancies.[1] Pheochromocytoma should be considered when severe hypertension occurs before 20 weeks gestation with labile blood pressure (BP). It is usually associated with headaches, palpitations, and diaphoresis.[2] However, it is an uncommon cause (0.1%) of hypertension in adult patients. It is one of the few truly curable forms of hypertension. Uncontrolled catecholamine release in patients can result in malignant hypertension, cerebrovascular accidents, and myocardial infarctions. The classic triad of pheochromocytoma is headaches, palpitations, and excessive sweating, but it is not so common in the pregnant state. Antenatal diagnosis is imperative to avoid maternal and fetal morbidity and mortality. A multidisciplinary team approach is important to achieve a good maternal and fetal outcome.

CASE REPORT

A 25-year-old pregnant woman (G4, P2, L2, and A1) at 37 weeks and six days gestation, presented with severe uncontrolled hypertension for one month. She was diagnosed with severe pre-eclampsia and referred from a peripheral private hospital to our tertiary care center. Apart from elevated BP for the last one month, the rest of her antenatal period was uneventful, with no past obstetric or medical history. She was taking alpha-methyldopa 500 mg bid as per records. On admission, she had severe frontal headaches, visual disturbance, and mild pedal edema and her BP was 200 / 120 mm Hg. On the second day, her blood pressure was labile with many readings above 186 / 110 mmHg and the fluctuations in BP were more evident in the morning and evening. An immediate Cardiology referral was done. Electrocardiogram (ECG) and Echo showed mild concentric left ventricular hypertrophy, with an ejection fraction of 60%. There was Grade I hypertensive retinopathy on fundus examination. They added torsamide 10 mg od and amlodipine 5 mg bid and advised an endocrinology review. On the third day, on further questioning, she had given a history of nocturnal episodes of severe frontal headaches, dizziness, sweating, nausea, polyurea, and polydipsia. Biochemical investigations, neck and abdomen ultrasonography (USG) and magnetic resonance imaging (MRI) of the abdomen were carried out. The fetal biometry was normal. Her blood pressure continued to have wide fluctuations, with readings ranging from 212 / 96 to 78 / 46 mmHg, but the rest of her clinical history, physical, and blood examination were unremarkable. There was minimal proteinuria (270 mg/day-1) detected, therefore, it did not fit with the diagnosis of pre-eclampsia. The differential diagnosis of a pheochromocytoma was made, which needed biochemical confirmation.

The patient was kept on high dependency unit with continuous fetal and maternal monitoring. Her BP was controlled with phenoxybenzamine 30 mg tid and labetalol bid. The aim was to keep the systolic BP between 140 to 160 mmHg and diastolic BP <90 mmHg. On day four, biochemical investigations showed markedly elevated plasma norepinephrine (7,720 pmol/L) and 24-hour urine norepinephrine (730 nmol/day); vanillylmandelic acid (66 μmol/day), metanephrine (685 μmol/day), and normetanephrine (8,868 μmol/day) levels were also elevated. The abdomen ultrasound showed a right adrenal mass measuring 8 × 5 cm. The MRI demonstrated an 8.9 cm × 5.1 cm right adrenal mass, normal left adrenal gland, and no extra-adrenal tumors. The ultrasound of the neck ruled out the MEN-II syndrome. All the above investigations confirmed the diagnosis of pheochromocytoma. A multidisciplinary conference involving Endocrinology, Anesthesiology, General Surgery, and Obstetrics took place with regard to strategy planning. It was felt that adrenalectomy would be technically difficult at this time due to presence of a gravid uterus and that it would be better for elective delivery via the Caesarean section, followed by interval right adrenalectomy. However, if the patient went into spontaneous labor, one would advocate an early epidural analgesia with invasive intense monitoring, to manage any acute hypertensive crisis.

On the fifth day, she went into spontaneous labor with confirmed rupture of the membranes. The cardiotocography (CTG) was reassuring. On vaginal examination, the cervical – os was 5 cm dilated with the vertex at -1 station. An epidural was sited (0.125% bupivacaine with fentanyl throw epidural catheter) and the decision was made to allow vaginal delivery under adequate analgesia.

The patient was monitored with invasive arterial blood pressure, five leads ECG, SPO2, input / output monitoring with strict vigilance of the maternal and fetal condition. The labor was augmented with intravenous oxytocin 2U in 500 ml solution of Ringer's lactate. A nitroglycerin (NTG) basal infusion was started and titrated to control BP during labor to keep the blood pressure below 160 / 90 mmHg. An injection of Phentolamine drip and beta blocker esmolol was kept ready, to control the wide fluctuation of blood pressure. She delivered a live, healthy, male infant weighing 2.5 Kg. She was kept in the ICU for 72 hours with epidural patient-controlled analgesia. Thereafter, treatment was managed on the ward with proper monitoring. The patient was not keen for a resection of the adrenal tumor immediately after delivery. She was discharged with medical management, with a further plan for surgery in due course.

DISCUSSION

Although it is difficult to distinguish between pre-eclampsia and pheochromocytoma in pregnancy, it is important to maintain a high index of suspicion in patients with paroxysmal or sustained episodes of hypertension with severe headaches, sweating, and palpitations. Symptoms may occur for the first time in pregnancy or worsen due to the pregnant state, because of the increased vascularity of the tumor, and the mechanical factors or fetal movements that can stimulate catecholamine secretion.[3] An important distinction between the two is that pre-eclampsia is associated with proteinuria (≥300 mg.day-1) and hypertension occurring after the twentieth week of gestation. Although pheochromocytoma is rarely associated with proteinuria, it may cause hypertension throughout the entire pregnancy.[4] In retrospect, this patient's initial signs and symptoms were classic. Had she not been pregnant, the symptom triad of headaches, sweating, and palpitations in a young patient with hypertension would have demanded an immediate evaluation for pheochromocytoma. The most sensitive and specific diagnostic finding in pheochromocytoma is an elevation of urinary and plasma catecholamines and their metabolites.[5] Unrecognized pheochromocytoma in pregnancy can result in a potentially fatal hypertensive crisis, precipitated by the mechanical effects of an enlarging uterus, uterine contractions or fetal movements, and anesthesia or vaginal delivery.[6] The primary goal in the management of pheochromocytoma is to avoid a hypertensive crisis, which can lead to hemorrhage and infarction in the vital organs, congestive heart failure, cardiac dysrhythmias, and even death. In pregnancy, such a crisis can lead to uteroplacental insufficiency with resultant intrauterine growth restriction, fetal hypoxia, and death.[7] Fetal mortality is 11 to 15% when pheochromocytoma is diagnosed before delivery, but approaches 55%, if the diagnosis is delayed or missed. In a review of 42 cases, Harper et al. found an overall maternal mortality of 17% and a fetal loss of 26%. With antepartum diagnosis, maternal mortality was reduced to nearly 0% and fetal loss to 15%. High rates of both maternal and fetal morbidity and mortality are to be expected, if the diagnosis of pheochromocytoma is missed during pregnancy.[67]

However, early induction of labor and delivery at 37 weeks’ gestation under epidural labor analgesia, were well-tolerated in our patient. Had her diagnosis been suspected earlier, adequate alpha-adrenergic blockade would have been established earlier.[89] Ideally, patients should have one-to-two weeks of alpha-adrenergic blockade, after which a beta blocker is added to control tachycardia and tachyarrhythmias. Labetalol does not have adequate alpha-adrenergic blocking properties to justify its use when a catecholamine-secreting tumor is suspected.[10]

Surgical excision of the tumor is the definitive treatment. Surgical management in early pregnancy is controversial. Keely cites a 44% risk of fetal death if surgery is performed before 24 weeks’ gestation.[10] Any decision to delay surgery might increase the risk of hemorrhage into the tumor, and patient informed consent is essential.

Long-term treatment with adrenergic receptor blocking agents has no adverse effects on the fetus, although the use of beta blockers could cause fetal growth restriction. Prazosin, although less potent, causes less reflex tachycardia and make the use of beta blockers unnecessary.[9] Experts concur, therefore, that a pheochromocytoma diagnosed in later pregnancy is best treated medically until the fetus is viable, unless maternal or fetal deterioration is noted.[810] Phenoxybenzamine is the preferred long-acting alpha-blocker. Intravenous propranolol or esmolol might be required to treat tachyarrhythmias.[11]

An acute surge in BP was managed with NTG infusion, Phentolamine infusion, and beta blocker esmolol, to control the wide fluctuation of blood pressure. Literature shows that oxytocin use to augment the labor in pheochromocytoma can be simultaneously and safely used with antihypertensive drugs alpha blocker, vasodilators (NTG), and beta-blocker.[12]

Elective caesarean section is the preferred mode of delivery when the tumor is still present.[1314] It is believed that vaginal delivery stimulates the massive release of catecholamines from the tumor.[815] If vaginal delivery is attempted; adequate analgesia and proper treatment is required to manage the extreme hemodynamic fluctuations.

To conclude, the only way to diagnose a pheochromocytoma is to first think of it. The challenge is to differentiate pre-eclampsia from the hypertensive crisis of an unrecognized pheochromocytoma. If the tumor is diagnosed later in pregnancy adequate medical management with a multidisplinary approach should be performed. If unfortunately, the patient undergoes active labor, optimal maternal and fetal outcome can be assured with intensive monitoring and adequate analgesia.