Pheochromocytoma and Paraganglioma in Pregnancy: A New Era

Abstract

Purpose of review:

Pheochromocytoma and paraganglioma (PPGL) in pregnancy is a rare entity and management of these patients is fraught with uncertainty. Our objective is to review current literature and discuss diagnosis and management of these patients.

Recent findings:

Outcomes of PPGL in pregnancy have improved in recent years. The greatest risk for adverse maternal and fetal outcomes is the diagnosis of PPGL after delivery. Alpha- and beta-adrenergic blockade is well tolerated and is associated with less adverse outcomes. Antepartum surgery is not associated with improved maternal or fetal outcomes. Biochemical testing and cross-sectional imaging should be performed prior to conception for patients with a known germline variant associated with PPGL.

Conclusions:

Medical therapy should be initiated when PPGL is diagnosed in pregnancy. Antepartum surgery should be reserved for special circumstances. Case detection testing in high-risk patients can identify PPGL before pregnancy.

INTRODUCTION

Pheochromocytoma and paraganglioma (PPGL) in pregnancy can cause devastating consequences. Catecholamines secreted from these rare neuroendocrine tumors can lead to debilitating strokes, life-threatening cardiomyopathy, and death.(1) Women are especially vulnerable at the time of delivery when fetal movement, uterine contractions, and induction of anesthesia can precipitate an acute release of catecholamines.(2) Cardiovascular complications such as acute heart failure, cardiac arrest, and acute myocardial infarction can have permanent sequela.(1) The fetus is susceptible to surges in catecholamines as well as uncontrolled hypertension, which can disrupt placental circulation leading to hypoxia and placental abruption or fetal demise. (3, 4)

Fortunately, PPGL in pregnancy is rare, occurring in only 0.007% of all pregnancies.(5) Advances in obstetric care and improved recognition of PPGL in pregnancy have led to better outcomes for both mother and fetus. Severe maternal cardiac complications now only occur in 7% of pregnancies.(1) The bleak maternal and fetal survival rate was once 50% while a recent study reports maternal death in 1% of pregnancies and fetal loss of 9%.(1,6) Even so, some women are still advised to terminate a pregnancy due to the unpredictable nature of PPGL – especially in light of a lack of consensus about optimal treatment. We propose that PPGL in pregnancy, when recognized and treated appropriately, can typically be managed without serious complications for either the pregnant woman or fetus. Herein, we summarize existing literature on PPGL in pregnancy as well as provide recommendations for the diagnosis and management of these patients.

EVIDENCE ACQUISITION

We performed a systematic review of the literature from January 1, 2005 to November 15, 2020 using the Ovid MEDLINE and Scopus databases. We included studies of PPGL in pregnancy with more than 5 patients and original data. Of note, a study from Bancos et al.(1) includes a cumulative analysis with 8 original studies, which were identified using this systematic review.

EVIDENCE SYNTHESIS

Case detection testing in high risk individuals

Ideally, PPGL should be diagnosed and treated prior to conception, especially in patients who are at increased risk to develop these tumors. Nearly half of all patients with PPGL have an associated germline pathogenic variant that increases the susceptibility to these tumors.(7, 8) The genes include RET (multiple endocrine neoplasia type 2, MEN2), VHL (von Hippel-Lindau disease), NF1 (neurofibromatosis type 1), and SDHA, SDHB, SDHC, SDHD, SDHAF2 (succinate dehydrogenase subunits, SDHx), and more rare familial variants in MAX, and TMEM127.(7–9) PPGL associated with germline pathogenic variants present at a younger age and are often associated with multiple tumors (bilateral pheochromocytoma (PHEO), PHEO with paraganglioma (PGL), etc.).(7, 10) A recent study which included 194 patients with PPGL in pregnancy showed 66% had a germline pathogenic variant, most commonly in RET (29%) followed by SDHB (28%), VHL (19%), SDHD (8%) and NF1 (5%).(1) A quarter of these patients had a family history of PPGL at the time of their pregnancy.(1)

We recommend case detection testing with biochemical testing and cross-sectional imaging in all women with a genetic predisposition for PPGL or with a personal history of PPGL who are contemplating conception. Additionally, women with a first or second degree family member with PPGL and no identified genetic syndrome should undergo biochemical testing prior to pregnancy. Either plasma fractionated metanephrines or 24-hour urinary fractionated metanephrines and catecholamines can be used for case detection testing. (11, 12) Plasma fractionated metanephrines are more sensitive for PPGL and easier to collect, making this an attractive option for case detection testing.(13, 14) Cross sectional imaging, preferably magnetic resonance imaging (MRI), should be combined with biochemical testing in patients with increased risk of PPGL. This will identify small PPGL, which can have normal biochemical testing, but are still clinically important to address prior to pregnancy.(10) Solitary lesions should be removed surgically, and metastatic disease should be treated with surgical resection or thermal ablation localized therapy, such as external beam radiation or artery embolization if possible. When clinically stable metastatic disease is not amenable to surgery or ablation, medical therapy with alpha- and beta-adrenergic blockade should be instituted prior to conception. This is discussed in detail later in the review. The importance of effective contraception should be emphasized until tumor sites and treatment plans have been finalized and carried out.

Metastatic PPGL

Women with metastatic PPGL can have a healthy pregnancy as long as close monitoring is in place. The largest study of patients with metastatic PPGL in pregnancy included 20 patients (24 pregnancies), and the majority (90%) were diagnosed before or during pregnancy.(1) No adverse cardiovascular maternal or fetal outcomes related to catecholamine excess occurred in these patients.(1) Eleven patients were treated with alpha-adrenergic blockade, and only one patient required hospitalization during pregnancy. (1)

Metastatic PPGL is usually characterized by indolent disease, which could explain these positive outcomes.(15) For women with a more aggressive metastatic PPGL phenotype, pregnancy may not be safe, but this is a minority of patients with metastatic PPGL. In those women with catecholamine-secreting PPGLs, we recommend starting medical therapy prior to conception in order to avoid large surges in catecholamines throughout the pregnancy.

Early recognition in pregnancy is key

Identification of germline pathogenic variants associated with PPGL has increased the early diagnosis of these tumors.(10) However, many patients with predisposing germline pathogenic variants are the first in their family to be diagnosed, often at the time they present with PPGL.(10, 16) Therefore, it should be no surprise that the majority of women with PPGL in pregnancy are diagnosed during pregnancy (54%) or after delivery (31%).(1) Diagnosing a PPGL prior to delivery is important to improve maternal and fetal outcomes.(1) PPGL left untreated or diagnosed after delivery has been associated with a 27-fold increased risk of maternal or fetal complications.(1) PPGL should preferably be diagnosed well before delivery, which allows for proper medical and/or surgical management.

Making the diagnosis during pregnancy

The diagnosis of PPGL in pregnancy can be challenging. First of all, symptoms of catecholamine excess are non-specific and can overlap with other medical conditions, including symptoms of normal pregnancy. The majority of pregnant women with PPGL (83%) have symptoms of catecholamine excess, including hypertension (77%), palpitations (58%), headache (50%), and diaphoresis (45%).(1) The spectrum of symptoms is similar to patients with PPGL who are not pregnant, although hypertension is more common in pregnancy.(10) Half of PPGL in pregnancy are diagnosed at or after the start of the third trimester, likely the result of difficulty identifying symptoms as those of PPGL.(1) One helpful clue to suggest PPGL can be the paroxysmal nature of the symptoms. Differentiating between gestational hypertension and PPGL can be difficult, but the timing of hypertension onset is helpful. Gestational hypertension presents after 20 weeks gestation and can meet criteria for pre-eclampsia if there is evidence of proteinuria, liver dysfunction, or platelet dysfunction, etc.(17) PPGL is less likely to cause end organ damage, but this can occur, further clouding the picture. Fortunately, testing for PPGL is non-invasive and relatively affordable, which means clinicians should have a low threshold to test if there are unusual features or symptoms in a patient.

When PPGL is suspected, we recommend testing with plasma fractionated metanephrines and 24 hour urinary fractionated metanephrines and catecholamines. Importantly, urinary epinephrine and norepinephrine levels may be elevated during delivery and for a few days following delivery as part of normal physiology.(12) Imaging can include ultrasound in the first trimester, especially if a PHEO or retroperitoneal PGL is suspected. Magnetic resonance imaging (MRI) without gadolinium can also be used, especially later in the pregnancy where visualization with ultrasound is limited. Computerized tomography (CT), metaiodobenzylguanidine (MIBG) scintigraphy, positron emission tomography (PET)-CT can be harmful to the fetus and should not be used.

Medical management

We favor the use of medical treatment over surgical management for women with PPGL during pregnancy. In our experience, medical therapy is effective and well tolerated. Bancos et al. reported on 110 pregnancies where PPGL was diagnosed antepartum, and 57% of patients were treated with alpha-adrenergic blockade.(1) Use of these medications prevented adverse maternal and fetal outcomes when used for at least 2 weeks (OR 3.6; 95%CI 1.1-13.2).(1)

Treatment goals

We recommend initiating medical therapy when the diagnosis of PPGL is made rather than waiting until 10-14 days prior to delivery. (Table 1) This approach has several advantages. First of all, it reduces the risk of hypertensive crisis and other complications associated with a large release of catecholamines such as cardiomyopathy or flash pulmonary edema. Secondly, when alpha- and beta-adrenergic blockade doses are titrated to goals early in the pregnancy, the patient is medically optimized if an emergency caesarian section or pre-term delivery is needed.

Table 1:

Medication timing and treatment goals for pheochromocytoma and paraganglioma in pregnancy

1.	Alpha-adrenergic blocker
	• Start at time of PPGL diagnosis
	• Titrate to low-normal systolic blood pressure (90-110 mmHg)
	○ Balance dosing with side effects to find a maintenance dose
	○ Emphasize increasing fluid and sodium intake
	• Intensify therapy at 36 weeks to prepare for delivery, if needed
	○ Goal systolic blood pressure 90-100 mmHg
2.	Beta-adrenergic blocker
	• Start after at least 1 week of alpha-adrenergic blockade
	• Add only if needed to control heart rate
	• Titrate to heart rate 80-90 beats per minute
3.	Calcium channel blocker
	• Start after titration of alpha-adrenergic blockade for 2-3 weeks
	• Add only if patient has persistent hypertension despite adequate alpha- and beta-adrenergic blockade

The goal of treatment is to achieve a low normal systolic blood pressure for a patient’s age, typically 90-100 mmHg. The heart rate should average less than 90 beats per minute. It is important to balance treatment goals with symptoms. For instance, it is reasonable to maintain a patient on 8 mg of doxazosin daily if the systolic blood pressure is consistently less than 110 mmHg and higher doses cause orthostatic hypotension. The alpha-adrenergic blockade can be intensified in the weeks prior to delivery by gradually increasing doses. Larger tumors will require higher doses of alpha-adrenergic blockers.(10)

Alpha-adrenergic blockade

Alpha-adrenergic blockers are category C in pregnancy. This medication class should be started as soon as the diagnosis of PPGL is confirmed. Doxazosin, a selective alpha-1 adrenergic receptor blocker, is a reasonable choice for most patients. We recommend a starting dose of 1 mg at bedtime, which can be increased to 1 mg twice daily the next day if tolerated. (Table 2) This dose can be increased by 1 mg daily to achieve target blood pressure; a more rapid titration is indicated if treating hypertensive urgency. Phenoxybenzamine is an irreversible, non-selective alpha-adrenergic blocker, making it a more potent option for higher risk patients. We will use phenoxybenzamine for patients with larger tumors or multifocal disease, particularly if fractionated metanephrine levels are high (eg, 10-fold above the upper limit of normal). PPGL in the abdomen or pelvis are associated with poor maternal and fetal outcomes, so these patients may also benefit from phenoxybenzamine use rather than doxazosin.(1) A starting dose of 10 mg once daily can be increased by 10 mg every 1 to 2 days to reach goal blood pressure.

Table 2:

Medication dosing, titration, and side effect for pheochromocytoma and paraganglioma in pregnancy

Medication	Dosing and titration	Side Effects	Considerations
Alpha-adrenergic blockade
Phenoxybenzamine	Starting dose: 10 mg once daily Titration: Increase by 10 mg every 1 to 2 days based on blood pressure measurements. Increase dosage by 20-40 mg daily if hypertensive urgency. Dosing: usually twice daily	Postural hypotension, tachycardia, miosis, nasal congestion, diarrhea, and fatigue	- Expensive, may require specialty pharmacy - Irreversible blockade – preferable for large tumors with marked catecholamine excess - The choice of medication, dosing and incremental adjustment/titration of phenoxybenzamine and doxazosin during pregnancy depends on the duration of proposed treatment, level of catecholamine excess, anticipated compliance, and cost
Doxazosin	Starting dose: 1 mg at bedtime Titration: Increase by 1mg daily based on blood pressure measurements. Increase by 2-4 mg per day if hypertensive urgency. Dosing: twice or 3 times daily	First-dose effect, orthostasis, peripheral edema, fatigue, and somnolence
Phentolamine	Starting dose: 1 mg bolus test dose Titration: Repeat 5 mg bolus as indicated to achieve blood pressure control; Continuous infusion with the rate titrated for blood pressure control, starting at 1 mg/hr and increasing at interval of 1 mg/hr every 15 minutes, maximum dose is 40 mg/hr Dosing: Bolus or continuous infusion	Nasal congestion, pain, hypotension, stroke	- Emergency use only
Beta-adrenergic blockade
Metoprolol succinate extended release	Starting dose: 25 mg daily Titration: Increase by 25 mg every 1 to 2 days as needed to achieve target average heart rate of 90 beats per minute Dosing: once to twice daily	Bradycardia, hypotension, fatigue, dizziness, dyspnea	- Neonatal observation for 48-72 hours for hypoglycemia, bradycardia, hypotension - Use only if needed to treat tachycardia with target heart rate of 90 beats per minute
Propranolol	Use not recommended	Use not recommended	- May impair relaxation of myometrium layer of uterus - Risk of neonatal hypoglycemia, bradycardia, hypotension
Atenolol	Use not recommended	Use not recommended	- Associated with restricted uterine growth and low birth weight
Esmolol	Starting dose: 0.5 mg/kg over 1 min, then 0.05 mg/kg/min for next 4 minutes Titration: Continue at 0.05 mg/kg per minute or increase by 0.05 mg/kg per minute at intervals of 4-5 minutes to target heart rate of 90 beats per minute, up to maximum of 0.2 mg/kg per minute Dosing: Continuous	Hypotension, nausea, injection site reaction	- Emergency use only
Calcium channel blockade
Nifedipine extended release	Starting dose: 30 mg daily Titration: Increase by 30 mg to target systolic blood pressure, up to maximum of 120 mg daily Dosing: once daily Emergency dosing (when no intravenous access): 10 mg, repeat 10-20 mg in 20 minutes	Edema, headache, dizziness, dyspepsia, flushing	- Add only if needed to control systolic blood pressure - Risk of hypotension when used as an emergency medication, do not give sublingually
Amlodipine	Starting dose: 2.5 mg daily Titration: Increase by 2.5 mg daily to target systolic blood pressure, up to a maximum of 10 mg daily Dosing: once daily	Edema, dizziness, headache, flushing, nausea, dyspepsia	- Use in special circumstances, such as concern for wearing off effect or poor compliance with nifedipine
Nicardipine	Starting dose: Continuous infusion at 5.0 mg/hr Titration: Increase by 2.5 mg/hr every 15 minutes to target goal blood pressure, up to a maximum of 15.0 mg/hr Dosing: continuous	Phlebitis at infusion site, headache, edema, hypotension, nausea, vomiting

Patients with functioning metastatic PPGL should be on low-dose alpha-adrenergic blockade prior to conception. As fractionated metanephrine levels tend to be lower and the disease is more indolent, doxazosin is a reasonable choice in this scenario. The dosage of doxazosin should be titrated to keep the systolic blood pressure between 90-100 mmHg. Again, the alpha-adrenergic blockade can be intensified in the weeks prior to delivery.

Beta-adrenergic blockade

Beta-adrenergic blocking medications are category C in pregnancy. These medications should not be started until a patient has been on alpha-adrenergic blockade for at least 7 days. We recommend the use of cardioselective (β₁ beta-adrenergic blockers as there are β₂ receptors on the myometrial layer of the uterus. Blockade of the β₂ receptors could reduce relaxation of the myometrium.

We typically use extended release metoprolol succinate, starting at a dose of 25 mg once daily, and increasing by 25 mg every 1 to 2 days to target the goal heart rate. (Table 2) Atenolol has been associated with low birth weight and should be avoided.(18) Propranolol is not advised as it is both a non-selective beta-adrenergic blocker but has also been associated with neonatal hypoglycemia, hypotension, and bradycardia following delivery.(19) These neonatal effects can be observed with other beta-adrenergic blockers, so neonatal monitoring is advised for 48-72 hours after delivery.

Labetalol has the illusion of being the ideal choice in these patients since it can be safely used in pregnancy and provides combined alpha- and beta-adrenergic blockade. However, labetolol predominately provides beta-adrenergic blockade and the ratio of alpha- and beta-adrenergic blockade is fixed, making it difficult to titrate to treatment goals.(20) Sufficient alpha blockade is challenging to achieve with labetalol, so we do not use it in our patients with PPGL in pregnancy.

Calcium channel blockade

Calcium channel blockers are category C in pregnancy. We reserve the use of calcium channel blockade for patients who have persistent hypertension despite adequate alpha- and beta-adrenergic blockade. This can also be used as an adjunct for patients who are not able to tolerate higher doses of alpha-adrenergic blockade. The use of calcium channel blockers may reduce hypertensive crisis and mortality as this has been observed in non-pregnant patients with PPGL.(21) Calcium channel blockers do not blunt all hemodynamic changes since they cannot directly block catecholamine activity.(21)

Only dihydropyridine calcium channel blockers should be used as these have the greatest vasodilatory and anti-hypertensive effects. The safety of nifedipine has been studied more extensively in pregnant patients compared to other calcium channel blockers.(17, 18, 22) It is the preferred calcium channel blocker for the treatment of chronic hypertension in pregnancy and pre-eclampsia.(17, 18, 22) The extended release formulation should be used to avoid frequent dosing and fluctuations in hypertension control. Amlodipine has a longer half-life than nifedipine, therefore it can be used if there is concern for wearing off effect or poor adherence.(23) The risk of severe hypertension and placental abruption may be higher for amlodipine compared to nifedipine, and we use amlodipine cautiously in these patients.(18)

Other medications

Metyrosine inhibits the rate-limiting step in catecholamine synthesis. It is category C in pregnancy, but generally is not recommended. We do not have any clinical experience using metyrosine in pregnant patients. Methyldopa has been used for years to treat pre-eclampsia and appears to be a consideration for PPGL in pregnancy. Methyldopa inhibits the decarboxylation of levodopa, which intuitively could reduce norepinephrine and epinephrine levels. However, a study did not show much benefit in terms of reduction in urine catecholamines or improvement in PPGL-related symptoms.(24) Some case reports suggest hypertension may worsen with the addition of methyldopa in pregnant patients with PPGL.(25, 26)

Magnesium sulfate has been used to treat pre-eclampsia and has a good safety profile in pregnancy. It causes direct vasodilation, but also blocks peripheral catecholamine receptors and reduces release of catecholamines from PPGL tumors.(27) It has been proposed as an adjunct to medications used intra-operatively during PPGL resection or in the management of PPGL crisis.(27, 28) Unfortunately, a study of intra-operative catecholamine levels showed that magnesium controls systolic blood pressure well until tumors are manipulated. Additional medications are usually required to control hypertension.(27) We do not routinely use magnesium sulfate in our pregnant patients with PPGL. The use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers is contraindicated in pregnancy.

Emergency medications

Intravenous medications should be reserved for use only in emergency situations, such as hypertensive crisis. Hypotension should be avoided. Fetal monitoring, especially fetal heart rate tracking, should be in place prior to giving any rescue medications.

Phentolamine is an alpha-adrenergic blocker which is available as an intravenous lypophilized formulation in vials containing 5 mg.(29) An initial test dose of 1 mg is administered and, if necessary, this is followed by repeat 5 mg boluses or a continuous infusion.(29) The response to phentolamine is maximal in 2 to 3 minutes after a bolus injection and lasts 10 to 15 minutes.(29) A solution of 100 mg of phentolamine in 500 ml of 5% dextrose and water can be infused at a rate titrated for blood pressure control. Phentolamine use has been associated with severe maternal hypotension and maternal and fetal death, so it should only be used in emergencies, such as hypertensive crisis.(30)

Intravenous nicardipine can be added if hypertension control is not achieved with phentolamine. A starting infusion of 5.0 mg/hr can be titrated to the target the goal blood pressure.(31) The onset of action is 1 minute with the dose lasting for up to 3 hours.(31) Patients who are currently using oral nifedipine or nicardipine will require larger doses of intravenous nicardipine. Oral, immediate release nifedipine can be used emergently while intravenous access is being obtained, but should not be given sublingually due to risk of hypotension.(32)

Esmolol is an intravenous beta-adrenergic blocker, which should only be administered in conjunction with an alpha-adrenergic blockade to help with heart rate control. A bolus of 0.5 mg/kg can be given over the first minute followed by a continuous infusion of 0.05 mg/kg per minute for the next 4 minutes.(33) Onset of action is almost immediate with peak effect in 5 minutes.(33) With a loading dose followed by a continuous infusion, steady state can be reached in 5 minutes.(33) No human studies have been performed to determine the safety of esmolol in pregnancy, so this should only be used when maternal benefit outweighs the risk to the fetus.

Intravenous hydralazine is recommended for acute hypertension in pregnancy but can precipitate acute coronary syndrome in patients with PPGL.(32, 34) We do not recommend using hydralazine. Sodium nitroprusside has been associated with stillbirths and fetal cyanide toxicity and should not be used. (35)

Monitoring and counseling for patients

Patients should be taught to monitor their blood pressure and heart rate at home. We advise our patients to obtain blood pressure and heart rate in the supine, sitting, and standing positions every morning and evening. Frequent daily dose adjustment is required during initiation of therapy as well as intensification prior to delivery. Monitoring will also help ensure blood pressure remains within goal to help minimize the negative effects of hypertension on the fetus.

Side effects of individual medications are discussed in Table 2. To minimize side effects, patients should be counseled to increase fluid and sodium intake. This helps prevent severe orthostasis as alpha-adrenergic blockers take effect. Patients who are not able to tolerate a high sodium diet (such as those with hyperemesis in pregnancy) can be prescribed sodium chloride tablets starting at 1 gram, three times daily. These tablets are category C in pregnancy and should be prescribed only when necessary. Intravenous fluids can be used for patients who are not able to tolerate increased oral intake.

Surgical management

Surgery for PPGL in pregnancy is typically not required as medical management is generally well tolerated and effective. Previously, studies have suggested antepartum surgery is the only approach, but a recent study which included 230 pregnancies, showed antepartum surgery was not associated with better maternal or fetal outcomes.(1, 36, 37) However, surgery should be considered for patients who remain hypertensive despite maximally tolerated alpha-adrenergic blockade or patients who are unable to adhere to medical therapy. If needed, surgery should be performed in the second trimester after alpha- and beta-adrenergic blockade are titrated as tolerated. Surgery should not be performed in the third trimester as the fetus is larger, limiting visibility in the abdomen and pelvis. Extensive surgery should be avoided, such as an open surgery for a large abdominal PGL or sternotomy for removal of a cardiac PGL.

Delivery considerations

Caesarian section (C-section) has traditionally been preferred for patients with PPGL in pregnancy. A recent study of 232 patients with PPGL in pregnancy showed vaginal delivery was not associated with poor maternal or fetal outcomes when compared to C-section delivery.(1) Of note, C-section delivery occurred about twice as often as vaginal delivery, and metanephrines were more elevated in the C-section group, suggesting higher risk patients may have undergone C-section.(1) We have generally recommended C-section for our patients due to concern that physiologic changes during vaginal delivery increase risk of catecholamine release. Intuitively, vaginal delivery with uterine contractions and fetal descent could increase pressure on the PPGL tumors in the abdomen and pelvis leading to a massive release of catecholamines. However, this study suggests a subset of women with PPGL may have a safe vaginal delivery, such as those with small tumors, low catecholamine burden, or tumors outside of the abdomen/pelvis. Multiparous women deliver more quickly, so vaginal delivery could also be considered in this setting.

Elective termination

The majority of PPGL in pregnancy can be managed safely with medical or surgical therapy. Elective termination should be considered when the life of a pregnant woman is at risk. Pelvic or urinary bladder PGL are located in a precarious position as the fetus continues to grow and elective termination may be necessary. Persistent hypertension despite alpha- and beta-adrenergic blockade is an indication for surgery during pregnancy, but the location or size of the tumor may make surgery high risk. Additionally, some women may be intolerant to alpha-adrenergic blockade. A multi-disciplinary team is needed to assess the risk to the woman and fetus and to provide support to a patient as these decisions are made.

Post-delivery recommendations

PPGL should be surgically removed after delivery, allowing time for the woman to recover from delivery and for the uterus to involute. If surgery must be delayed, the importance of contraception should be emphasized. Patients who do not have a known predisposing germline pathogenic variant for PPGL or have not been previously tested, should be offered genetic testing. These women are presenting at a younger age and thus the likelihood that they have a genetic susceptibility to PPGL is very high. Plasma fractionated metanephrines and imaging should be repeated prior to any subsequent pregnancies to identify new tumors, recurrence, or metastatic disease.

Medical Advances and PPGL in Pregnancy

Obstetric care has improved over the last 50 years, leading to better recognition of PPGL in pregnancy. Other advances have the potential to improve outcomes for these patients. Robotic-assisted minimally invasive surgery has been used in at least 2 patients with PPGL in pregnancy with good results.(38, 39) This approach improves dexterity in small spaces, which can be helpful for removal of large paragangliomas in the retroperitoneum or surgery in an obese patient.(39)

Gene panel testing and whole genome sequencing can identify patients at higher risk for PPGL and hopefully increase case detection testing prior to pregnancy. Importantly, not all germline variants are pathogenic, and the PPGL phenotype can vary greatly, especially in SDHx. Prediction software and further clinical understanding will help improve the quality of genetic counseling patients receive prior to conception. For patients who have a germline pathogenic variant, pre-implantation diagnosis can be used during in vitro fertilization-embryo transfer to ensure a pathogenic variant is not present in an embryo.(40)

Conclusions

PPGL in pregnancy can be dangerous, especially when the diagnosis is made after delivery. Early recognition of these tumors is associated with better maternal and fetal outcomes. Medical therapy is generally effective and well tolerated, and surgical therapy during pregnancy can be reserved for more complex cases. Women with metastatic PPGL can safely conceive with good outcomes, likely due to low catecholamine burden and indolent disease. Most importantly, women with pre-disposing germline pathogenic variants for PPGL should undergo biochemical testing and cross sectional imaging prior to conception. Women with PPGL in pregnancy should be offered germline genetic testing if they have not been tested and also undergo case detection testing for PPGL prior to subsequent pregnancies.