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Case Reports  |   June 2004
Neonatal Effects of Long-term Maternal Phenoxybenzamine Therapy
Author Affiliations & Notes
  • Stephanie C. Aplin, M.B., B.S. (Hons II)
    *
  • Kevin F. Yee, M.B., B.S., F.A.N.Z.C.A.
  • Michael J. Cole, F.R.A.C.P.
  • * Provisional Fellow in Anesthesia, The Children’s Hospital at Westmead, Sydney, Australia. † Consultant Anesthetist, ‡ Consultant in Perinatal Medicine, Westmead Hospital.
Article Information
Case Reports
Case Reports   |   June 2004
Neonatal Effects of Long-term Maternal Phenoxybenzamine Therapy
Anesthesiology 6 2004, Vol.100, 1608-1610. doi:
Anesthesiology 6 2004, Vol.100, 1608-1610. doi:
PHEOCHROMOCYTOMA is an uncommon cause of hypertension in pregnancy, and little is known about the effects of pheochromocytoma or its therapy on the neonate. In this report, two neonates were delivered by successive cesarean deliveries of a woman with an unresectable intracardiac pheochromocytoma on long-term phenoxybenzamine therapy. Both neonates exhibited respiratory distress and hypotension in the first 72 h of life, requiring ventilation and inotropic support.
Case Report
First Pregnancy
A 24-yr-old gravida 3 para 0 woman presented at 38 weeks’ gestation for an elective lower-segment cesarean delivery. An unresectable in-tracardiac pheochromocytoma had been diagnosed 11 months previously after she presented with paroxysmal hypertension, palpitations, headaches, and diaphoresis.
The patient was maintained on 20 mg phenoxybenzamine twice daily and had an otherwise uneventful pregnancy. Cesarean delivery was performed during epidural blockade (20 ml bupivacaine, 0.5%, plus 100 μg fentanyl), with invasive arterial blood pressure monitoring in place. Blood pressure was around 150/100 mmHg throughout. Her postoperative course was uneventful.
The 4,245-g male infant had an Apgar score of 9 at 1 min. By 5 min, he developed mottling of the extremities and respiratory distress and an Apgar score of 8. He was admitted to the neonatal intensive care unit, where his mean arterial pressure (MAP) was 31 mmHg. He was treated with continuous positive airway pressure and a dopamine infusion via  an umbilical venous catheter. At 5 h and on 10 cm H2O continuous positive airway pressure, a chest radiograph showed interstitial edema consistent with transient tachypnea of the newborn. Arterial blood gases were as follows: pH, 7.28; partial pressure of carbon dioxide (PCO2), 48 mmHg; and partial pressure of oxygen (PO2), 56 mmHg; on a fraction of inspired oxygen (FIO2) of 0.30. The infant was intubated, given 100 mg/kg surfactant, and placed on synchronized intermittent positive-pressure ventilation. His MAP remained 35–38 mmHg despite administration of dopamine at 24 μg kg−1min−1. A dobutamine infusion was commenced at 20 μg kg−1min−1, but his MAP at 10 h of life was unchanged. Hydrocortisone, 5 mg/kg and then 2.5 mg/kg every 6 hours, was added. MAP increased to greater than 50 mmHg from 25 h, and dobutamine and dopamine were weaned and ceased at 27 and 41 h, respectively. MAP remained stable thereafter at 49–52 mmHg. The infant was extubated at 48 h of life.
The mother and the infant were discharged home well on day 6. Breast-feeding was advised against on this occasion.
Second Pregnancy
Thirteen months later, the patient was admitted at 35 weeks’ gestation with recurrent postural hypotension and gestational diabetes. Phenoxybenzamine was decreased to 10 mg twice daily before cesarean delivery at 38 weeks’ gestation.
Epidural blockade was achieved with a total of 23 ml bupivacaine, 0.5%, and 100 μg fentanyl with a 16-gauge intravenous cannula and radial arterial pressure monitoring. Intravenous phentolamine boluses and oral phenoxybenzamine were required perioperatively for hypertension. The patient was stable the following day on 20 mg phenoxybenzamine twice daily.
At cesarean delivery, a 4,665-g female infant was delivered with Apgar scores of 9 and 9 at 1 and 5 min. Respiratory distress was noted at 10 min. She was admitted to the neonatal intensive care unit with a MAP of 40 mmHg and was placed on continued positive airway pressure of 11 cm H2O. She was intubated at 19 h after an increase in inspired oxygen requirement to 60% and was given 100 mg/kg surfactant. Chest radiographs showed increased reticular markings. At 40 h, MAP decreased to 32–34 mmHg, and dopamine at a rate of up to 5 μg kg−1min−1was given for a period of 9 h. She was extubated at 72 h of life.
The mother and the infant were discharged home on day 9. No neonatal hypotension was observed with breast-feeding.
Discussion
Pheochromocytoma  is a rare catecholamine-secreting tumor, accounting for 1 in 400–800 cases of hypertension. 1 More than 200 cases of coincidental pheochromocytoma in pregnancy have been reported, 2 occurring in 1 out of 54,000 pregnancies. 2 Before 1969, maternal and fetal mortality were 48% and 55%, respectively. 3,4 With antepartum diagnosis and the use of α-blocking agents, fetal mortality has decreased to as low as 14%, and maternal mortality has decreased to zero. 5 Medical management of pheochromocytoma in pregnancy has led to delivery of a healthy infant in most cases. 6–13 
The placenta is the only non-neuronal tissue to express the norepinephrine transporter, responsible for re-uptake of norepinephrine from the synaptic cleft and plasma compartments. 14,15 Little or no catecholamines cross the placental barrier, but they are taken up by the transporter and metabolized by placental catechol-O  -methyl transferase and monoamine oxidase. 14–16 
Dahia et al.  17 report the case of a woman who was diagnosed with pheochromocytoma at 24 weeks’ gestation and treated with prazosin. During cesarean delivery at 34 weeks, umbilical norepinephrine concentrations were 7% of maternal, suggesting that only a small percentage of maternal norepinephrine crosses the placenta. The neonate had no cardiovascular or respiratory problems. The noradrenaline concentration in umbilical cord blood has been measured at approximately 10% of maternal concentrations in other cases of pheochromocytoma. 18 Therefore, the direct hazardous effects of maternal catecholamines on the fetus are of little importance.
The fetus has a high basal rate of catecholamine production and low circulating catecholamine concentrations. 15 Intrauterine catecholamine clearance by the fetus is higher than under any other physiologic conditions, at 100–200 ml kg−1min−1, 14,15 compared with a clearance rate of 30–50 ml kg−1min−1in adults. 15 The placenta accounts for nearly 50% of total fetal norepinephrine clearance. 15 
Circulating catecholamine concentrations increase exponentially at birth to support adaptation to extrauterine life. 14,15,19 Umbilical cord blood catecholamine concentrations in normal term neonates have been measured at almost 23 nmol/ml, similar to levels seen in pheochromocytoma. Any blockade of catecholamine receptors may impair the neonate’s ability to cope with hypoxia and other stressors. 19 
Catecholamines at birth stimulate inotropy and chronotropy, redistribute blood flow to vital organs, stimulate clearance of alveolar and interstitial lung fluid and surfactant production, promote glycogenolysis and lipolysis, activate nonshivering thermogenesis, and stimulate nervous system functions such as arousal, muscular tone, and development of chemoreceptor activity. 20 Failure of catecholamine activation has been associated with neonatal hypoglycemia and idiopathic apnea of prematurity. 20 
The secretion of surfactant and secretion of lung fluid is mediated by β2adrenergic receptors. Rats given a β2antagonist in the immediate neonatal period cannot survive hypoxia. However, specific β1antagonist do not cause an increase in hypoxia-related mortality, suggesting that β receptors are not critical to cardiac function in the hypoxic neonate. In the neonatal rat, phenoxybenzamine causes a loss of tolerance to hypoxia, leading to cardiac failure, and cardiac α receptors are present in greater concentration than are β receptors. This suggests that intact α receptors may be important in the maintenance of cardiac function in the first week of life. 19 
α-Blocking agents have been used successfully in pheochromocytoma in pregnancy since the 1950s. 3 Phenoxybenzamine, an irreversible α-adrenoceptor antagonist with a half-life of approximately 24 h, is the most common agent used. 1 There are many reports of good neonatal outcomes in the presence of maternal phenoxybenzamine. 21 Indeed, until 1989, there were no reports of adverse fetal effects. 5 In two reported cases, phenoxybenzamine has been shown to cross the placenta.
Kothari et al.  2 reported a case of a woman who was diagnosed with bilateral pheochromocytomas at 26 weeks’ gestation and treated with 60 mg phenoxybenzamine four times daily, propranolol, and nifedipine. She underwent cesarean delivery at 29 weeks. Apgar scores were 5 and 8 at 1 and 5 min, respectively, and the neonate was intubated and ventilated. No mention was made of neonatal hypotension, and the neonate was discharged at 7 weeks. The fetal:maternal plasma phenoxybenzamine ratio was 1.13:1, indicating that phenoxybenzamine crosses the placenta and accumulates in the fetus.
Santeiro et al.  22 reported a case of a woman who was diagnosed with pheochromocytoma at 33 weeks’ gestation and managed with phenoxybenzamine and labetalol for 26 days before cesarean delivery. Apgar scores were 2 and 8 at 1 and 5 min, respectively, and the neonate was intubated briefly for poor respiratory effort. He also had mild hypotension for the first 3 days of life. The fetal: maternal plasma accumulation ratio of phenoxybenzamine was 1.6:1. The authors suggest that neonates of mothers receiving phenoxybenzamine should be monitored for the first few days of life for hypotension and respiratory depression.
Both neonates in this case exhibited hypotension and respiratory distress in the first 3 days of life. The fetus is largely isolated from high maternal catecholamine concentrations by the placenta but is exposed to phenoxybenzamine. Intact catecholamine function is important in adaptation to the extrauterine environment.
We postulate that α blockade by maternal phenoxybenzamine caused hypotension in these neonates. In the first neonate, dopamine and dobutamine did not seem to improve blood pressure. Glucocorticoids regulate the expression of cardiovascular adrenergic receptors and are used to counteract the down-regulation of these receptors in critically ill neonates. 23 They may have improved the hypotension in the first neonate, who was exposed to a greater dose of phenoxybenzamine and had a more prolonged and more resistant period of hypotension.
Because the neonatal heart has a large proportion of α -receptors, there may have been an element of cardiac failure contributing to the respiratory distress seen. However, the relation between phenoxybenzamine and respiratory distress is not clear.
There have been many reported cases of healthy neonates delivered to mothers receiving phenoxybenzamine. Because pheochromocytoma is usually resected if diagnosed in the first 20 weeks of gestation, these neonates were exposed to phenoxybenzamine for shorter periods of time than in this case.
There is no data on the transmission of phenoxybenzamine via  breast milk or its effects on the breast-fed neonate. 24 However, the milk-to-maternal drug plasma concentration for most drugs is 0.5–1.0, indicating that less than 1% of a maternal dose is available to the infant. 25 No hypotension was seen in the breast-fed infant in this case. We suggest that initiation of breast-feeding in a monitored environment is appropriate.
In conclusion, neonates born to mothers receiving phenoxybenzamine should be monitored closely in an intensive care unit, with particular observation for hypotension and respiratory distress.
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