Ms. NL, a 33-year-old pregnant woman with a history of “endometriosis,” and an obstetrical history of G5P2M2, started experiencing transient episodes of anxiety, headache, chest tightness and flushing at 36 weeks of her current gestation. The symptoms were unrelated to activity and were lasting for 15 minutes to a couple of hours. Her current pregnancy had been uneventful until now, and she’d delivered by C-section during her previous two full-term pregnancies. An abdominal ultrasound done at a local hospital was reported unremarkable save for gestation. She was transferred for further assessment and management. Because of previous C-sections, a C-section was already planned at 38-weeks by her obstetrician.
She was on no medications except for prenatal vitamins. She didn’t smoke and denied alcohol use. She had no history of hypertension.
Physical examination was unremarkable save for gravid uterus. Heart sounds were normal. Most of the time, her blood pressure ranged between 100-110/70 mm Hg but there were occasional episodes when her blood pressure would spike to 190/110 mm Hg with a heart rate of 70 to 90 beats per minute. There was no peripheral edema.
Her hemoglobin was 118 g/L. Serum creatinine, serum potassium, BUN and thyroid stimulating hormone were all normal, as were urinalysis and electrocardiogram.
She was admitted for ongoing monitoring and a few days later she started to experience occasional uterine contractions.
What is the diagnosis? How will you manage her current pregnancy?
Pheochromocytoma in pregnancy
Hypertension during pregnancy, in Ms NL may be secondary to pre-existing hypertension, new-onset hypertension during pregnancy, gestation hypertension or preeclampsia/eclampsia, or — rarely — could be secondary to an adrenal pathology. The symptoms of episodic severe hypertension associated with headaches, palpitations, flushing and chest tightness raised the possibility of a catecholamine-induced pathology, such as pheochromocytoma, and plasma free catecholamines and urinary catecholamines were requested.
The plasma free catecholamines levels came back a week later and showed an elevated norepinephrine level of 4.0 nmol/L (normal range 0.8-3.4) and normal epinephrine level of 0.4 nmol/L (normal range < 0.8). The 24-hr urine results revealed markedly elevated epinephrine of 1,894 [normal range < 120 nmol/d], norepinephrine of 1,401 [normal range < 500 nmol/d], dopamine of 4,023 [normal range < 3,200 nmol/d] and vanillyl mandelic acid (VMA) of 204 [normal range 6-36 µmol/d], confirming catecholamine excess either from adrenal chromaffin cells (pheochromocytoma) or extra-adrenal paraganglia (paraganglioma).
She was started on doxazosin 1 mg twice a day with a plan to increase as tolerated to 10 mg a day and was transferred to a high-risk pregnancy management centre, where after increasing the dose of doxazosin, she underwent a C-section under the supervision of a multidisciplinary team comprised of an obstetrician, intensivist, endocrinologist and anesthesiologists. An abdominal ultrasound showed a 7-8 cm mass in her left adrenal gland (missed on the initial abdominal ultrasound) that was also confirmed by an MRI, consistent with pheochromocytoma. A laparoscopic adrenalectomy is being arranged.
Pheochromocytoma is a rare [< 0.2 per 10,000 pregnancies] but an important cause of hypertension in pregnancy because of its high morbidity and mortality [up to 58%] in both the mother and the fetus. Most adrenal tumours produce either epinephrine and norepinephrine together or predominantly epinephrine, whereas most extra-adrenal tumours produce predominantly norepinephrine. Norepinephrine increases peripheral vascular resistance resulting in an increase in systolic and diastolic BP. Epinephrine increases cardiac output and systolic BP. Epinephrine producing tumours often produce episodic symptoms whereas norepinephrine symptoms are often associated with continuous (non-episodic) symptoms.
Several mechanisms can unmask pheochromocytoma during pregnancy and include an increase in intra-abdominal pressure, fetal movement, uterine contractions, process of delivery, surgical intervention and even general anesthesia.
The 24-hr urine collection for catecholamines is recommended in pregnant patients and these levels aren’t affected by pregnancy. The plasma catecholamines have a specificity of 85-89% with a false positive rate of 11-15%.
The primary goal of therapy is to prevent a hypertensive crisis that may result in fetal or maternal demise. Therapy with α-blockade is a must and should be started as soon as the diagnosis is established and ideally should be given for 10-14 days before delivery or surgery. The drug of choice is phenoxybenzamine, but this is often difficult to get. Doxazosin (selective α1 blocker) has been used lately with success. However, as doxazosin is a competitive antagonist, it can be displaced by high-levels of endogenous catecholamines. Unopposed β-blockade should be avoided, as this precipitates a hypertensive crisis and should only be used after adequate α-blockade to control tachycardia. Methyldopa, an agent commonly used to treat hypertension during pregnancy, should be avoided as it may worsen symptoms of pheochromocytoma.
Surgery is the definitive treatment for pheochromocytoma. In early pregnancy tumour removal is recommended after optimal medical management, but after 24-weeks of gestation surgical removal is recommended after an elective cesarean section. Vaginal delivery has higher mortality (31%) compared to C-section (19%).
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