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The Journal of Obstetrics and Gynaecology
Adrenal disorders in pregnancy, labour and postpartum - an overview
Madhavi Manoharan, Prabha Sinha & Shabnum Sibtain
To cite this article: Madhavi Manoharan, Prabha Sinha & Shabnum Sibtain (2019): Adrenal disorders in pregnancy, labour and postpartum - an overview, Journal of Obstetrics and Gynaecology, DOI: 10.1080/01443615.2019.1648395
To link to this article: https://doi.org/10.1080/01443615.2019.1648395
Published online: 30 Aug 2019.
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Adrenal disorders in pregnancy, labour and postpartum - an overview
Madhavi Manoharanª, Prabha Sinhab and Shabnum Sibtain“
ªWomen’s Clinical Management Group, Sidra Medicine, Doha, Qatar; bDepartment of Obstetrics and Gynaecology, Oman Medical College, Muscat, Oman; ‘Department of Obstetrics and Gynaecology, Azra Naheed Medical College, Lahore, Pakistan
ABSTRACT
Adrenal disorders may manifest during pregnancy for the first time, or present from before pregnancy as either undiagnosed or diagnosed and treated. They may present as hormonal hypofunction or hyperfunction, or with mass effects or other non-endocrine effects. Adrenal disorders such as Cushing’s syndrome, Addison’s disease, pheochromocytoma, primary hyper-aldosteronism and adreno-cortical carcinoma are rare in pregnancy. Pregnancy presents special problems in the evaluation of the hypo- thalamic-pituitary-adrenal and renin-angiotensin-aldosterone axis as these undergoe major changes during pregnancy. Diagnosis is challenging as symptoms associated with pregnancy are also seen in adrenal diseases. A timely diagnosis and treatment is critical as these disorders can cause maternal and foetal morbidity and mortality. A high index of suspicion must be maintained as they can go unrecog- nised and untreated. An early diagnosis and treatment often improves outcomes. The aim of this article is to review the patho-physiology, clinical manifestation, diagnosis and management of various adrenal disorders during pregnancy.
KEYWORDS
Pregnancy; adrenal disease; Addison’s disease; pheochromocytoma
Introduction
Disease of the adrenal gland is rare in pregnancy. It can manifest as over- or under activity of the cortex or medulla. Adrenal disease such as Cushing syndrome, Addison disease, pheochromocytoma and primary hyperaldosteronism is asso- ciated with impaired fertility. During pregnancy, they are associated with significant impact on maternal and foetal health. Given the rarity of these conditions in the general population, and therefore even lower prevalence in the preg- nant population, limited and contradictory data exist on maternal and neonatal outcomes in pregnancies. Management is based on observational findings from case reports, and more recently several larger population-based studies. This review aims to describe the patho-physiology, clinical manifestation, with updates on diagnostic modalities and treatment options of common adrenal disorders in pregnancy.
Materials and methods
We searched the Medline, PubMed, Ovid and Cochrane Library using the following keywords: ‘Adrenal disorders in pregnancy’, Cushing’s syndrome in pregnancy’, ‘Primary Hyperaldosteronism in pregnancy’, ‘Adrenal carcinoma in pregnancy’, Addison’s disease in pregnancy’. All studies from January 1st 1990 till January 31st 2019, which described case reports, case series and review of literature were included. Only publications in English language were chosen. Articles
were screened by titles and abstracts and then full text papers were obtained.
Discussion
Pregnancy modifies the hypothalamic-pituitary-adrenal (HPA) axis with increase in placental corticotropin-releasing hor- mone (CRH), and adreno-corticotrophic hormone (ACTH) pro- duction. During the first trimester, a substantial increase in CRH and ACTH is observed. This is balanced by an increased production of CRH-binding protein in pregnancy. Maternal circadian rhythm of ACTH secretion is maintained thought out the pregnancy despite the increase in placental hor- mones (Nolten et al. 1980). There is a significant increase in levels of cortisol during the first trimester, and a two to threefold increase in cortisol levels during second and third trimester (Carr et al. 1981). Both ACTH and cortisol levels increase in labour and the diurnal variation of cortisol pro- duction is maintained during pregnancy.
HPA axis normalises in the postpartum period, CRH and ACTH levels decreases within 2 h of delivery and cortisol lev- els within 1 week of delivery (Okamoto et al. 1989). Corticosteroid-binding globulin (CBG) concentrations returns to normal levels in 3-6 weeks post-delivery and occasionally can take up to 3 months (Magiakou et al. 1996).
Many changes occur in renin-angiotensin-aldosterone sys- tem during pregnancy. Renin is produced by the ovaries, decidua and kidney stimulated by oestrogen. Plasma renin activity increases fourfold in early first two months of
pregnancy and then increases minimally over the rest of the pregnancy. (Escher 2009).
Plasma angiotensinogen levels increases fourfold during the first 20 weeks of gestation and then minimally over the subsequent 20 weeks of gestation. This leads to doubling of angiotensin II levels in early pregnancy and a further 3- to 4- fold by the end of pregnancy (Nolten et al. 1980; Escher 2009).
Similarly, plasma aldosterone levels increase 5-fold during first 16 weeks and ultimately 7- to 10-fold by term. These changes reflect in a sevenfold increase in urinary aldosterone levels by first trimester and 12- to 25-fold by term.
Increased aldosterone secretion is a physiological response to sodium loss due to high progesterone levels, which is a competitive inhibitor of aldosterone at the renal tubules. Due to this fine balance between aldosterone and progesterone, no increase in blood pressure is noted in healthy pregnant women (Riester and Reincke 2015).
This relative hypercortisolism and hyperaldosteronism of normal pregnancy are not generally clinically apparent.
Adrenal cortex over-activity
Over-activity of the adrenal cortex is usually due to tumours or hyperplasia. Tumours are usually benign although malig- nant tumours in pregnancy are seen in 10% of the adrenal masses. (Pickard et al. 1990).
Hyperplasia is usually secondary to inappropriate secretion of ACTH by a pituitary or extra-pituitary adenoma leading to Cushing syndrome. It can occasionally be due to defects in the adrenocortical pathways leading to cortisol synthesis.
(A) Cushing syndrome
Cushing syndrome can be due to adrenal adenoma or sec- ondary to pituitary disease or adrenal hyperplasia. Women with Cushing syndrome (caused by pituitary disease and adrenal hyperplasia), are usually amenorrhoeic and infertile. This is due to excess androgen secretion, which inhibits the release of pituitary gonadotrophin. Pregnancy usually occurs in those who have previously been treated. However, women with Cushing syndrome caused by adrenal adenoma (which only produces cortisol) are likely to be fertile.
Diagnosis
It is difficult to distinguish the signs and symptoms of Cushing syndrome from that of a normal pregnancy such as weight gain, abdominal striae, oedema, tiredness and others. The triad of early onset of hypertension, with easy bruising, echymosis and proximal myopathy, should raise a strong sus- picion of Cushing syndrome and should be further evaluated.
Biochemical diagnosis in pregnancy is equally difficult as during pregnancy several endocrine biochemical changes takes place including activation of both the hypothalamic-pi- tuitary-adrenal axis and the renin-angiotensin-aldoster- one system.
An increase in total plasma cortisol during the first trimes- ter is noted and this lasts for the entire pregnancy. However, increased serum cortisol levels without diurnal variation is indicative of Cushing syndrome.
High levels of total cortisol make the dexamethasone sup- pression test very difficult to interpret during pregnancy. It is reported that about 40% of women without Cushing syn- drome have a normal low-dose dexamethasone suppression test with a cortisol level <50 nmol/L (Lindsay et al. 2005). Failure of suppression could also be due to adrenal tumour, adrenal nodule or ectopic ACTH production. However, in most women with adrenocortical hyperplasia, a reduction in plasma and urinary corticosteroids can be seen with a higher dose (8 mg) of dexamethasone.
Urinary free cortisol (UFC) also increases during pregnancy (1.4- to 1.6-fold increase in the 2nd and 3rd trimester, respectively). Therefore, UFC cannot be considered as a reli- able marker after the first trimester, unless levels are increased at least 2- to 3-fold above the upper limit of nor- mal values (Nieman et al. 2008).
Ambroziak et al. (2015) did not show any obvious change in salivary cortisol during pregnancy. It was suggested that reference values for salivary cortisol established for a healthy adult population could be used for pregnant women in the initial diagnostic testing for Cushing syndrome. Lopes et al. (2016) have defined normal threshold values of salivary corti- sol in each trimester of pregnancy: < 6.9 nmol/L for the first, <7.2 nmol/L for the second and <9.1 nmol/L for the third trimester.
Hence, salivary cortisol level could be considered an important criterion for the diagnosis of hypercortisolism (at least during the first 2 trimesters).
Imaging with ultrasound (adrenal) and then MRI (pituitary or adrenal), without contrast is required to identify the source of cortisol production.(Lindsay et al. 2005).
Figure 1 shows the determination of aetiology and diag- nostic algorithm.
Clinical manifestation
More than 220 women with Cushing syndrome in pregnancy have been reported (Caimari et al. 2017). Many of these patients were managed conservatively and only received treatment for associated complications such as hypertension, pre-eclampsia and diabetes (Katulski et al. 2014). Cushing syndrome is associated with high rates of maternal and foetal complications if untreated.
Maternal complications
The most common maternal morbidities include: hyperten- sion (68%), diabetes (25%), pre-eclampsia (14%). (Lindsay et al. 2005). Other rare complications reported are osteopor- osis and fractures (5%), cardiac failure (3%), psychiatric disor- ders (4%), wound infections (2%) and maternal death (2%) (Tomaszewski and Dewailly 2012).
CLINICAL FEATURES SUGGESTIVE OF CUSHING’S SYNDROME IN PREGNANCY
Urinary free cortisol 4 times upper limit of normal (non- pregnant)
OR
Salivary cortisol 2-3 times above upper limit of normal
CONFIRM DIAGNOSIS OF CUSHING’S SYNDROME
IDENTIFY THE SOURCE OF CORTISOL
ADRENAL ETIOLOGY (ACTH INDEPENDENT)
PITUITARY ETIOLOGY (ACTH DEPENDENT)
*High dose dexamethasone suppression test- not suppressed *ACTH level- low/borderline ACTH levels
*High dose dexamethasone suppression test- suppressed
*ACTH level- High/not suppressed > 10 pg/ml (4.4 pmol/L)
Adrenal Ultrasound/MRI
Pituitary MRI
Foetal complications
Cushing syndrome in pregnancy is associated with increased perinatal morbidity and mortality (prematurity (43%), intra- uterine growth retardation (21%), stillbirths (6%), spontan- eous abortion or intrauterine death (5%) and hypoadrenalism (2%) (Lim et al. 2013; Bronstein et al. 2015). Foetal loss is higher in women with active Cushing syndrome than in cured women (Caimari et al. 2017). Diagnosis made during pregnancy was associated with the poorest outcome com- pared to antenatal or post-natal diagnosis. Both medical and surgical treatments during pregnancy appeared to reduce the risk of foetal loss.
Management
The aim of management is to reduce maternal and foetal mor- bidity. Initially, the source of cortisol production must be iden- tified. An MRI is advisable if a high dose of dexamethasone fails to suppress excess cortisol production. If the cortisol
excess is due to pituitary adenoma, trans-sphenoidal surgery is the preferred choice (Abbassy et al. 2015).
Treatment of adrenal adenoma includes medical or surgical (unilateral adrenalectomy) therapy after delivery. Surgery is ideally carried out during the second and rarely in the third tri- mester. The perioperative complication of adrenalectomy varies between 1.7% and 30.7% (Aporowicz et al. 2018). Bilateral adrenelectomy is also associated with a higher compli- cation rate. Left and right adrenelectomy is associated with dif- ferent risks, due to asymmetry of the abdomen. Left adrenelectomy is associated with injury to surrounding vascu- lar structures like inferior venacava, spleen, splenic vessels and colon. There is an increased risk of metabolic complications and respiratory insufficiency. These women are also at increased risk of wound infection; poor wound healing, deep vein thrombosis and pulmonary embolism due to anti-inflam- matory and immune suppressive effects of cortisol. Surgical treatment reduces maternal and fetal morbidity with live births close to 87%; however, it does not reduce the incidence of pre- term birth or growth restriction (Choi et al. 2011; Lekarev and
New 2011; Toutounchi et al. 2011; Tomaszewski and Dewailly 2012; Sammour et al. 2012; Nassi et al. 2015).
Laparoscopic adrenelectomy is safe and effective, being the treatment of choice up to 32 weeks of gestation. (Sammour et al. 2012). However, anaesthesia in women with Cushing syndrome can be difficult, especially control of hypertension during surgery (Kimura et al. 2012).
Appropriate positioning of patient during surgery is necessary to ensure adequate uterine blood flow, this can be achieved by placing a wedge underneath the hip to displace the uterus. Anaesthesia considerations include avoidance of anaesthetic agents with possible teratogenic effects, and avoidance of hypoxia and acidosis (Abd-Elsayed et al. 2013). Effort should be made to avoid aspiration, which can be due to both pregnancy and Cushing’s syndrome. Adequate hydration and special attention to fluid and electrolyte bal- ance is important. Continuous foetal monitoring can be con- sidered in case of a viable foetus, if there is a need for immediate delivery (Day and Batjer 1995).
Surgical treatment is usually followed by adrenal insuffi- ciency for the rest of the pregnancy, necessitating replace- ment treatment with hydrocortisone.
Medical treatment with anticortisolic drugs remains a second line of treatment (Lim et al. 2013; Touiti and Mghari 2015; Zieleniewski and Michalak 2017). The drugs commonly used are Metyrapone, Ketoconazole, Cyproheptidine, Amino- glutethemide, Mitotane and Cabergoline. They act by inhibit- ing steroid synthesis. Metyrapone is the most commonly used treatment with no side effects on maternal liver function or foetal development. This has been used in 69% of cases with good control of hyper cortisolism, in most of the cases (Lindsay et al. 2005; Blanco et al. 2006). However, Metyrapone can exacerbate high blood pressure and preeclampsia. Ketoconazole is not advisable in pregnancy because of risk of transplacental passage and its teratogenic and antiandrogenic effects on the fetus. (Berwaerts et al. 1999; Lindsay et al. 2005; Boronat et al. 2011). Mitotane and aminoglutethimide are also contraindicated during pregnancy because of risk of foetal masculinisation and teratogenicity (McClamrock and Adashi 1992). Cabergoline is not commonly used in pregnancy, unless the condition is persistent and recurrent (Woo and Ehsanipoor 2013; Nakhleh et al. 2016; Sek et al. 2017). Medical treatment with anticortisolic drugs could be reserved for special cases, with Metyrapone being the safest option. These drugs should be used with extreme caution in view of the low number of patients reported and limited experience with its use (Brue et al. 2018).
As most women are diagnosed late in pregnancy, manage- ment of co-morbidities like diabetes and hypertension is important to reduce morbidity. Hence, screening and treatment of these conditions is crucial. A subset of patients diagnosed late may benefit with management of these co- morbidities without the use of anticortisolic drugs.
A decision to use of steroids to promote lung maturation and magnesium sulphate for neuro-protection is best taken jointly with the endocrinologist and the neonatalogy team.
(B) Primary aldosteronism (Conn’s syndrome)
Excess production of aldosterone from a tumour of the zona glomerulosa results in the typical hypokalaemic hypertension of Conn’s syndrome.
In pregnancy, the renin-angiotensin-aldosterone system plays vital role in the balance of salt and water metabolism and hence affects the well-being of both mother and foetus. Many studies have shown that in normal pregnancy, there is an increase in almost all the components of this system (Derkx et al. 1987; Verdonk et al. 2014). Renin concentrations are elevated due to extra-renal release from ovaries through oestrogen stimulation and maternal decidua (Derkx et al. 1987). There is an increase in the production of angiotensino- gen in liver during pregnancy, but the angiotensinogen- converting enzyme is reduced. This results in an elevation of aldosterone and angiotensin II levels (Irani and Xia 2008).
Aldosterone secretion is also increased due to a physio- logical response to sodium loss in response to high proges- terone concentrations, which is a competitive inhibitor of aldosterone at the renal tubulus. This balance between pro- gesterone and aldosterone, ensures that there is no increase in blood pressure in healthy pregnant women.
Incidence
It is estimated that 0.6-0.8% of all pregnant women suffer from primary aldosteronism which is usually caused by idio- pathic bilateral hyperplasia of the adrenal gland or aldoster- one producing adenoma. Fewer than 40 patients have been reported in the medical literature, with majority of them were presenting as aldosterone-producing adenomas.
Causes of aldosteronism
a. Aldosterone-producing adenomas (APAs)
b. Aldosterone-producing renin-responsive adenomas
C. Bilateral idiopathic adrenal (glomerulosa) hyperplasia or IAH (also known as primary adrenal hyperplasia or PAH)
d. Familial
e. Ectopic secretion of aldosterone (Rarely ovaries and kid- neys can be ectopic sources of aldosterone)
f. Pure aldosterone-producing adrenocortical carcinomas Bilateral idiopathic adrenal hyperplasia is responsible for 75% of case of primary aldosteronism. The other common cause of primary aldosteronism is aldosteronomas.
The distinction between the two major causes of primary aldosteronism is vital as the treatment of choice for each is markedly different. The treatment of choice for aldosterono- mas is surgical resection, while that of bilateral adrenal hyperplasia is medical therapy with aldosterone antagonists.
Genetic-familial primary aldosteronism
Three distinct genetic-familial varieties of primary aldosteron- ism have been described. The first is type 1 variety of familial primary aldosteronism, glucocorticoid-remediable aldosteron-
ism (GRA). In GRA, small doses of glucocorticoids in addition to other antihypertensive agents is used to control hyperten- sion (Dluhy and Lifton 1994).
The type-2 variant of familial primary aldosteronism is not glucocorticoid sensitive, whereas the type-3 variant of familial primary aldosteronism is due to potassium chan- nel mutations.
Diagnosis
Diagnosis of primary aldosteronism is a challenge. If recog- nised early, hypertension associated with primary aldosteron- ism can be cured or optimally controlled with surgical or medical intervention. The management involves initial screening, confirmation of the diagnosis, and a determination of the specific subtype of primary aldosteronism. Hypokalaemia and/or severe hypertension in a pregnant woman should prompt screening, especially if the onset is before the 20th week of gestation.
Diagnosis is made by measuring plasma renin levels, which is suppressed in women with primary aldosteronism. Plasma aldosterone levels more than 10 ng/dl is a positive case-detection test for primary aldosteronism. Renin level is normally elevated during pregnancy. Aldosterone-to-renin ratio (ARR) is low in normal pregnant women, whereas, with primary aldosteronism, this ratio is elevated. Confirmation of diagnosis of primary aldosteronism in pregnancy is by meas- urement of sodium and aldosterone in a 24 h urine collection on an ambient sodium diet.
In pregnant women with hypokalaemia, high aldosterone levels of more than 20 ng/dl and a suppressed renin, con- firmatory tests are not necessary. MRI and ultrasound of the adrenal gland is recommended to aid in the diagnosis.
Management
The main aim of treatment in aldosteronism is to manage hypertension and hypokalaemia. Medical management of pri- mary aldosteronism includes Spironolactone and Eplerenone. However, Spironolactone is not recommended in pregnancy as the FDA classifies it as a category C drug. It crosses the placenta and has antiandrogenic activity although several case reports have suggested no adverse effects (Groves and Corenblum 1995; Rigo et al. 1996).
Eplerenone is a category B drug (no adequate and well- controlled studies in pregnant women are available) and has been used with good results during pregnancy and breast- feeding (Riester and Reincke 2015; Gunganah et al. 2016). It is recommended that hypertension in pregnant women with aldosteronism be managed with standard antihypertensive drugs approved for use in pregnancy. Hypokalaemia is man- aged with oral potassium supplements.
If an aldosterone producing adenoma is diagnosed, lap- aroscopic adrenectomy is the treatment of choice, especially if hypokalemia and hypertension are uncontrollable (Eguchi et al. 2014; Morton 2015; Assoufi et al. 2016). This is ideally carried out in the second trimester.
Adrenal cortex insufficiency
Addison’s disease
Adrenal insufficiency in pregnancy is rare and is associated with significant maternal and foetal morbidity. It can be either primary Addison disease (AD) due to autoimmune destruction, or secondary due to pituitary failure or adrenal suppression from steroid replacement. This can result in defi- ciency of cortisol, aldosterone and androgens.
Prevalence
The prevalence of Addison disease is believed to be increas- ing (Lindsay et al. 2005). It affects women more frequently than men during their reproductive years (Arlt and Allolio 2003). A recent cohort study has reported the prevalence of AD in pregnancy to be 5.5/100 000, this has been steadily increasing to 9.6/100 000 (p =. 0001) (Schneiderman et al. 2017).
Diagnosis
The diagnosis of Addison disease in pregnancy is difficult as signs and symptoms such as nausea, fatigue and hypotension may resemble that of normal pregnancy. An early morning plasma cortisol concentration of <3.0 u g/dl confirms adrenal insufficiency. (Grinspoon and Biller 1994). A paired sampling of cortisol and ACTH levels showing low levels of cortisol and elevated levels of ACTH is diagnostic. A short Synacthen test should be performed to confirm the diagnosis. The short Synacthen test involves an intravenous administration of 0.25 mg of Cortrosyn, with a demonstration of a twofold rise in plasma cortisol. A failure to respond suggests adrenal insufficiency. Measurement of ACTH levels also helps to dis- tinguish primary adrenal insufficiency from hypo-pituitrism.
Management
Treatment of AD is with replacement doses of steroids (hydrocortisone 15-25 mg in 2-3 divided doses) and fludro- cortisone (50-100 mcg), hydrocortisone is the preferred ster- oid in pregnancy as it does not cross the placenta and is more physiological than other available glucocorticoids (Bornstein et al. 2016). However, oral prednisolone (3-5 mg/d) once or twice daily can be used especially in patients with reduced compliance or in situations when hydrocortisone is not available. These women should be cared for jointly, by an Endocrinologist and a Maternal Medicine team.
Glucocorticoid replacement
Pregnant women with primary adrenal insufficiency should be monitored for clinical symptoms and signs of glucocortic- oid over- and under-replacement. This can be done by moni- toring for signs and symptoms like weight gain, fatigue, postural hypotension or hypertension and hyperglycaemia. These women should be reviewed at least once in every
trimester (Bornstein et al. 2016). An increase in dose of hydrocortisone may be required during third trimester.
Mineralocorticoid replacement
Similarly, mineralocorticoid replacement is also monitored by clinical assessment (salt craving, postural hypotension, or oedema), and blood electrolyte measurements.
Delivery
Delivery must be planned and monitored by a multidisciplin- ary team including endocrinologist in a tertiary centre. A written therapeutic plan should be available to the obstetric team involved in managing labour. Intravenous glucocortic- oid cover should be started before the active phase of labour. This is with an initial bolus of 100 mg of hydrocorti- sone followed by continuous perfusion 100-200 mg/24 h dur- ing the second stage of labour (Anand and Beuschlein 2018). Similar doses can be used during caesarean section as well.
After delivery
During the first 24-48 h after delivery, a stepwise reduction in the dose of hydrocortisone supplementation is advisable. The dose can be tapered to pre-pregnancy dose according the clinical condition.
Management of adrenal crisis
Adrenal crisis is a rare life-threatening condition, which requires treatment in an intensive care setting. A low index of suspicion is necessary in acutely unwell patients especially with history of persistent nausea, fatigue, hyperemesis gravi- darum and hypotension.
Women should be treated with immediate parenteral injection of 100 mg hydrocortisone along with fluid resuscita- tion and 200 mg of hydrocortisone/24 h (via continuous iv therapy or 6 hourly injection).
Prevention of adrenal crisis is important, and this can be achieved by patient education concerning glucocorticoid adjustments in stressful events. Medical kits for parenteral self or lay-administration of emergency glucocorticoids should be available to every woman with adrenal insuffi- ciency in pregnancy.
All women should be equipped with a steroid emergency card or bracelet and medical alert identification. This provides information to the health care provider of the need for increased glucocorticoid doses to avert or treat adrenal crisis in case of an emergency (Bornstein et al. 2016).
Addison’s disease is associated with significant increase in severe adverse maternal and neonatal outcomes. This includes increased risk of congenital anomalies, growth restriction, preterm delivery, caesarean section, impaired wound healing, infections, thromboembolism and prolonged post-partum admissions. (Schneiderman et al. 2017). In the absence of any contraindications vaginal delivery should be encouraged.
Maternal mortality was as high as 35% before the intro- duction of steroid treatment (Abdelmannan and Aron 2011), this has been reduced to 0.5% in a recent case series (Schneiderman et al. 2017).
Adrenal medulla
Pheochromocytoma
Incidence
This is a rare catecholamine-producing tumour arising from the chromaffin cells of the adrenal medulla. Harrington et al. in 1999 reported an incidence of 0.007% in a large series describing 30,246 pregnancies collected over 20 years. Maternal and foetal mortality is approximately 40-50% if untreated (Schenker and Granat 1982) decreasing to less than 5% for maternal mortality and less than 15% for foetal mortality after treatment (Sarathi et al. 2010). Hence, a prompt diagnosis during pregnancy is paramount.
In about 90% of women, the tumour arises from the adrenal gland. The incidence of metastatic pheochromocy- toma is 10% with metastasis commonly reported in lymph nodes, liver, lungs and spine (Kaloostian et al. 2013). Five- year survival rates range from 84% to 96% for benign pheo- chromocytoma, and 40% for malignant pheochromocytoma (Kaloostian et al. 2014). About 10% of pheochromocytomas are extra adrenal, arising from the remnants of the organs of Zuckerkandl-neural crest tissue, which lies along the abdom- inal aorta. This incidence is increased to 80% in multiple endocrine neoplasia (MEN) IIA cases (van der Vaart et al. 1993). Pheochromocytoma should be suspected if there is a family history of von Recklinghausen’s syndrome (neuro- fibromatosis) or of medullary carcinoma of thyroid or other components of the multiple endocrine neoplasia (MEN) syn- dromes (Bravo and Tagle 2003).
Signs and symptoms
The signs and symptoms of pheochromocytoma mimic those of severe pregnancy-induced hypertension. This can be asso- ciated with other sympathetic symptoms and signs such as palpitations, tachycardia, sweating, seizure disorders, anxiety attacks, chest pain, dyspnoea, nausea and vomiting, pallor, and flushing. Pheochromocytoma should be considered in cases of refractory hypertension in pregnancy and appropri- ate investigations should be carried out to differentiate from pre-eclampsia. The presence of paroxysmal hypertension after 20 weeks of pregnancy with orthostasis and absence of pro- teinuria and oedema helps in differentiating from other causes of hypertension in pregnancy. It is also necessary to distinguish from hyperthyroidism, where significant diastolic hypertension is not seen.
Diagnosis
Diagnosis of pheochromocytoma can be made by measuring catecholamine and metanephrine levels in the plasma (blood) and a 24 h urine collection for VMA (Kaloostian et al. 2014).
Suspect Pheochromocytoma If pregnant woman presents with following features:
Severe/Paroxysmal hypertension Adrenergic signs-pallor, anxiety, headaches, palpitations, chest pain Orthostatic hypotension
Plasma/urine 24 hour metanephrine *avoid false +ve results due to methyldopa, labetalol, tricyclic antidepressants
If elevated, confirm pheochromocytoma
Localise tumour with Ultrasonography/MRI
Elevated metanephrine excretion is the most sensitive test (Harrington et al. 1999).
The tumour is generally localised by MRI and ultrasonography.
Following a diagnosis of pheochromocytoma, genetic counselling can be offered in the follow-up appointments as disease-causing mutations can be found in up to 20-30% of all patients (Amar et al. 2005; Buffet et al. 2012; Lenders et al. 2014).
Figure 2 shows the diagnosis of pheochromocytoma in pregnancy.
Management
Recommendations for the treatment of pheochromocytoma in pregnancy is based on case reports, case series and expert opinion. It is crucial that diagnosis is made in the antepartum period as timely treatment reduces the maternal and foetal mortality rates.
Definitive treatment of pheochromocyoma is surgical but initial medical treatment is advisable to control blood pres- sure. This is achieved with a-adrenergic blockers (Lenders et al. 2014), which is continued for at least two weeks before surgery. This lowers the risk of perioperative and postopera- tive complications. The medical treatment requires a cautious balance between hemodynamic control and its effects on the utero-placental circulation.
Commonly used alpha-adrenergic blockade drugs are phe- noxybenzamine (foetal risk category C) (generally used
dosages: 10-40 mg twice a day) and doxazosin (foetal cat- egory risk C) (generally used dosages: 4-16 mg twice a day) (Lenders et al. 2014). Phenoxy benzamine crosses the pla- centa and can cause neonatal hypotension and respiratory depression (Aplin et al. 2004). Therefore, neonates must be monitored closely following delivery and involvement of the neonatal team is advisable.
Doxazocin is more commonly used in pregnancy due to less risk of reflex tachycardia and post-operative hypotension. Although it does cross the placenta, neonatal hypotension and respiratory depression has not been described. (Versmissen et al. 2016)
B-Adrenergic receptor blockers can be used to treat tachyarrhythmias. However, they have been associated with intrauterine growth restriction and hence should only be used for short durations during pregnancy (Butters et al. 1990). Calcium channel blockers can be used if hypertension is not adequately controlled with a-adrenergic receptor blockers and in the absence of tachycardia. Labetalol and methyldopa are not routinely recommended (Lenders 2012; Prete et al. 2016). Pre-treatment also involves adequate res- toration of intravascular fluid volume to support the foetopla- cental unit and to prevent fluctuations in blood pressure.
Surgery is the definitive management of pheochromocy- toma. Timing and modalities for tumour removal and deliv- ery, including anaesthetic management, depend on gestational age, maternal and foetal well-being, and location of tumour (Prete et al. 2016). The ideal time for surgery is in the second trimester. If diagnosed late in the third trimester, then surgery should be delayed until after delivery. Laparoscopy is the preferred method of choice in view of the reduced morbidity (Biggar and Lennard 2013; van der Weerd et al. 2017).
Timing and mode of delivery for women with pheochro- mocytoma depends on obstetric history. Recent literature describes successful and safe vaginal delivery under adequate epidural analgesia to reduce pain and stress (Kapoor et al. 2013). Oxytocin and uterotonic agents should be used with caution as they can disturb the hemodynamic balance by causing tachycardia and hypotension (Prete et al. 2016). Caesarean section provides a controlled environment but can cause excessive blood loss and catecholamine excess caused by manipulation of peritoneum, or even of the tumour.
Decisions regarding timing and route of delivery should be made on an individual basis by an experienced and dedi- cated multidisciplinary team. Obstetric history (mainly parity and route of previous deliveries), maternal and foetal condi- tions, response to treatment and the preference of the patient should be taken in to consideration. For an optimal maternal and foetal outcome, a multidisciplinary team com- prising of anaesthetists, maternal medicine physicians and neonatologists should be involved in a tertiary setting.
Adrenocortical carcinoma
Adrenocortical carcinoma (ACC) is a rare tumour with an esti- mated incidence between one and two cases per million adults (Grumbach et al. 2003). It has an extremely poor
prognosis with a survival rate of <30% at 5 years (Luton et al. 1990; Allolio and Fassnacht 2006). Adrenocortical tumours are more common in women with a sex ratio of 4.2 (Luton et al. 1990).
Diagnosis
The commonest presentation is Cushing syndrome with viril- isation, hypertension and prematurity (Kopf et al. 2001). Diagnosis of adrenocortical carcinoma is difficult as signs and symptoms overlap due to overproduction of several hor- mones from the adrenal gland like cortisol (30%), androgens (20%), oestrogens (10%) and aldosterone (2%) (Gicquel et al. 2000; Dackiw et al. 2001; Abiven-Lepage et al. 2010)
Previous studies have shown that hypercortisolism is itself associated with frequent maternal morbidity and poor fetal prognosis (Lindsay et al. 2005).
In a case series of 12 women with ACC, it was noted that pregnancy-associated adrenocortical carcinoma were gener- ally discovered at a more advanced stage and with larger tumours than that observed in non-pregnant patients (Abiven-Lepage et al. 2010). Foetal prognosis is poor with premature births, intrauterine growth restriction, stillbirths and intrauterine deaths. The prognosis can be improved with treatment of hypercortisolism. (Lindsay et al. 2005)
The prognosis of pregnancy associated ACC is extremely poor with shorter survival periods than that associated with non-pregnant controls (Abiven-Lepage et al. 2010). The most important and validated prognostic factor is tumour stage and maternal age at the initial diagnosis (Abiven et al. 2006).
Approximately 60 percent of ACCs present with clinical syndrome of hormone excess (Luton et al. 1990; Crucitti et al. 1996; Ng and Libertino 2003; Allolio and Fassnacht 2006). They usually present with either Cushing’s syndrome alone (45%), or as a mixed Cushing’s and virilisation syndrome, with overproduction of both glucocorticoids and androgens (25%) (Ng and Libertino 2003).
The secretory activity of the tumour can be assessed by fasting blood glucose, serum potassium, cortisol, cortico- tropin (ACTH), 24 h urinary free cortisol, fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bed- time, adrenal androgens (dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, 17-hydroxyproges- terone), and serum estradiol.
MRI is the investigation of choice due to limited radiation exposure and in addition provides information on local inva- sion and involvement of vena cava.
Management
Recommendations for the management of ACC in pregnancy are difficult in view of the rarity of the condition. From the limited number of case series, adrenal surgery after MRI evaluation is possible. As complete resection of the tumour is the most efficient treatment with the best prognosis, it should be recommended in any trimester of pregnancy. As preterm delivery is high collaboration with the obstetric and neonatal team is important. In view of the very poor progno- sis of pregnancy-associated tumours, Mitotane treatment
could be offered, even in tumours limited to the adrenal gland. Mitotane is not advisable during pregnancy, however, can be prescribed post-delivery. Breastfeeding is not advis- able while on Mitotane.
Termination of pregnancy can be discussed with the parents if the tumour is diagnosed in the first trimester, espe- cially in advanced stages.
In view of its rarity, treatment is advisable in a tertiary centre and requires a multidisciplinary approach with individ- ualised treatment strategy for each patient (Lacroix 2010).
Conclusion
Adrenal disorders in pregnancy are extremely rare with man- agement strategies based on case reports, case series and population-based studies. Multidisciplinary team involvement with delivery in a tertiary centre is mandatory to improve maternal and foetal prognosis. Establishment of registries to record adrenal disorders in pregnancy will help gather evi- dence and help formulate management strategies to reduce the morbidity and mortality.
Disclosure statement
All authors have no conflicts of interests to declare.
References
Abbassy M, Kshettry VR, Hamrahian AH, Johnston PC, Dobri GA, Avitsian R. 2015. Surgical management of recurrent Cushing’s disease in preg- nancy: a case report. Surgical Neurology International 6:S640-S645. Abdelmannan D, Aron DC. 2011. Adrenal disorders in pregnancy. Endocrinology and Metabolism Clinics of North America 40:779-794. Abd-Elsayed AA, Díaz-Gómez J, Barnett GH, Kurz A, Inton-Santos M, Barsoum S, et al. 2013. A case series discussing the anaesthetic man- agement of pregnant patients with brain tumours. F1000Res 2:92.
Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, et al. 2006. Clinical and biological features in the prognosis of adrenocortical can- cer: poor outcome of cortisol-secreting tumors in a series of 202 con- secutive patients. The Journal of Clinical Endocrinology & Metabolism 91:2650-2655.
Abiven-Lepage G, Coste J, Tissier F, Groussin L, Billaud L, Dousset B, et al. 2010. Adrenocortical carcinoma and pregnancy: clinical and biological features and prognosis. European Journal of Endocrinology 163: 793-800.
Allolio B, Fassnacht M. 2006. Clinical review: adrenocortical carcinoma: clinical update. The Journal of Clinical Endocrinology and Metabolism 91:2027-2037.
Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, et al. 2005. Genetic testing in pheochromocytoma or func- tional paraganglioma. Journal of Clinical Oncology 23:8812-8818.
Ambroziak U, Kondracka A, Bartoszewicz Z, Krasnodębska-Kiljańska M, Bednarczuk T. 2015. The morning and late-night salivary cortisol ranges for healthy women may be used in pregnancy. Clinical Endocrinology 83:774-778.
Anand G, Beuschlein F. 2018. Fertility, pregnancy and lactation in women with adrenal insufficiency. European Journal of Endocrinology 178: R45-R53.
Aplin SC, Yee KF, Cole MJ. 2004. Neonatal effects of long-term maternal phenoxybenzamine therapy. Anesthesiology 100:1608-1610.
Aporowicz M, Domosławski P, Czopnik P, Sutkowski K, Kaliszewski K. 2018. Perioperative complications of adrenalectomy- 12 years of experience from a single centre/teaching hospital and literature review. Archives of Medical Science 14:1010-1019.
Arlt W, Allolio B. 2003. Adrenal insufficiency. Lancet (London, England) 361:1881-1893.
Assoufi N, Bahadi N, Omri NE, Sekkach Y, Ameziane T, Ghafir D. 2016. Tetraparesis revealing Conn adenoma in a pregnant woman. The Pan African Medical Journal 25:24.
Berwaerts J, Verhelst J, Mahler C, Abs R. 1999. Cushing’s syndrome in pregnancy treated by ketoconazole: case report and review of the lit- erature. Gynecological Endocrinology 13:175-182.
Biggar MA, Lennard TW. 2013. Systematic review of phaeochromocytoma in pregnancy. The British Journal of Surgery 100:182-190.
Blanco C, Maqueda E, Rubio JA, Rodriguez A. 2006. Cushing’s syndrome during pregnancy secondary to adrenal adenoma: metyrapone treat- ment and laparoscopic adrenalectomy. Journal of Endocrinological Investigation 29:164-167.
Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, et al. 2016. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism 101:364-389.
Boronat M, Marrero D, López-Plasencia Y, Barber M, Schamann Y, Nóvoa FJ. 2011. Successful outcome of pregnancy in a patient with Cushing’s disease under treatment with ketoconazole during the first trimester of gestation. Gynecological Endocrinology 27:675-677.
Bravo EL, Tagle R. 2003. Pheochromocytoma: state of the art and future prospects. Endocrine Reviews 24:539-553.
Bronstein MD, Machado MC, Fragoso MC. 2015. Management of endo- crine disease: management of pregnant patients with Cushing’s syn- drome. European Journal of Endocrinology 173:R85-R91.
Brue T, Amodru V, Castinetti F. 2018. Management of Cushing’s syn- drome during pregnancy: solved and unsolved questions. European Journal of Endocrinology 178:R259-R266.
Buffet A, Venisse A, Nau V, Roncellin I, Boccio V, Le Pottier N, et al. 2012. A decade (2001- 2010) of genetic testing for pheochromocytoma and paraganglioma. Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones et Metabolisme 44:359-366.
Butters L, Kennedy S, Rubin PC. 1990. Atenolol in essential hypertension during pregnancy. BMJ (Clinical Research ed.) 301:587-589.
Caimari F, Valassi E, Garbayo P, Steffensen C, Santos A, Corcoy R, et al. 2017. Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases. Endocrine 55:555-563.
Carr BR, Parker CR, Madden JD, MacDonald PC, Porter JC. 1981. Maternal plasma adrenocorticotropsin and cortisol relationship throughout human pregnancy. American Journal of Obstetrics and Gynecology 139:416.
Choi WJ, Jung TS, Paik WY. 2011. Cushing’s syndrome in pregnancy with a severe maternal complication: a case report. Journal of Obstetrics and Gynaecology Research 37:163-167.
Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P. 1996. The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multi- institutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 119:161.
Dackiw AP, Lee JE, Gagel RF, Evans DB. 2001. Adrenal cortical carcinoma. World Journal of Surgery 25:914-926.
Day J, Batjer HH. 1995. Operative positioning and fetal monitoring con- siderations. In: Loftus M, editor. Neurosurgical aspects of pregnancy. Illinois: American Association of Neurological Surgeons. p. 183-190.
Derkx FHM, Alberda AT, De Jong FH, Zeilmaker FH, Makovitz JW, Schalekamp MADH. 1987. Source of plasma prorenin in early and late pregnancy: observations in a patient with primary ovarian failure. The Journal of Clinical Endocrinology & Metabolism 65:349-354.
Dluhy RG, Lifton RP. 1994. Glucocorticoid-remediable aldosteronism. Endocrinology and Metabolism Clinics of North America 23:285-297. [Medline].
Eguchi K, Hoshide S, Nagashima S, Maekawa T, Sasano H, Kario K. 2014. An adverse pregnancy-associated outcome due to overlooked primary aldosteronism. Internal Medicine 53:2499-2504.
Escher G. 2009. Hyperaldosteronism in pregnancy. Therapeutic Advances in Cardiovascular Disease 3:123-132.
Gicquel C, Bertherat J, Le Bouc Y, Bertagna X. 2000. Pathogenesis of adrenocortical incidentalomas and genetic syndromes associated with
adrenocortical neoplasm. Endocrinology and Metabolism Clinics of North America 29:1-13.
Grinspoon SK, Biller BM. 1994. Clinical review 62: laboratory assessment of adrenal insufficiency. The Journal of Clinical Endocrinology & Metabolism 79:923-931.
Groves TD, Corenblum B. 1995. Spironolactone therapy during human pregnancy. American Journal of Obstetrics and Gynecology 172: 1655-1656.
Grumbach MM, Biller BMK, Braunstein GD, Campbell KK, Carney JA, Godley PA, et al. 2003. Management of the clinically unapparent adrenal mass (“incidentaloma”). Annals of Internal Medicine 138: 424-429.
Gunganah K, Carpenter R, Drake WH. 2016. Eplerenone use in primary aldosteronism during pregnancy. Clinical Case Reports 4:81-82.
Harrington JL, Farley DR, van Heerden JA, Ramin KD. 1999. Adrenal tumors and pregnancy. World Journal of Surgery 23:182-186.
Irani RA, Xia Y. 2008. The functional role of the renin-angiotensin system in pregnancy and preeclampsia. Placenta 29:763-771.
Kaloostian PE, Zadnik PL, Awad AJ, McCarthy E, Wolinsky J-P, Sciubba DM. 2013. En bloc resection of a pheochromocytoma metastatic to the spine for local tumor control and for treatment of chronic cat- echolamine release and related hypertension. Journal of Neurosurgery Spine 18:611-616.
Kaloostian PE, Zadnik PL, Kim JE, Groves ML, Wolinsky J-P, Gokaslan ZL, et al. 2014. High incidence of morbidity following resection of meta- static pheochromocytoma in the spine. Journal of Neurosurgery Spine 20:726-733.
Kapoor G, Salhan S, Sarda N, Sarda AK, Aggarwal D. 2013. Phaeochromocytoma in pregnancy: safe vaginal delivery, is it pos- sible? Journal of the Indian Medical Association 111:266-267.
Katulski K, Podfigurna-Stopa A, Maciejewska-Jeske M, Ruchala M, Gurgul E, Szymankiewicz M, et al. 2014. Cushing’s syndrome in pregnancy: a case report and mini review of the literature. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology 30:345-349.
Kimura Y, Okuyama K, Mitsui K, Tamaki F, Nonaka A, Matsukawa T. 2012. Anaesthetic management for laparoscopic adrenalectomy in a preg- nant patient with Cushing’s syndrome. Masui 61:605-609.
Kopf D, Goretzki PE, Lehnert H. 2001. Clinical management of malignant adrenal tumors. Journal of Cancer Research and Clinical Oncology 127:143-155.
Lacroix A. 2010. Approach to the patient with adrenocortical carcinoma. The Journal of Clinical Endocrinology and Metabolism 95:4812-4822.
Lekarev O, New MI. 2011. Adrenal disease in pregnancy. Best Practice & Research. Clinical Endocrinology & Metabolism 25:959-973.
Lenders JW. 2012. Pheochromocytoma and pregnancy: a deceptive con- nection. European Journal of Endocrinology 166:143-150.
Lenders JWM, Duh Q-Y, Eisenhofer G, Gimenez-Roqueplo A-P, Grebe SKG, Murad MH, et al. 2014. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism 99:1915-1942.
Lim WH, Torpy DJ, Jeffries WS. 2013. The medical management of Cushing’s syndrome during pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology 168:1-6.
Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. 2005. Cushing’s syndrome during pregnancy: personal experience and review of the literature. The Journal of Clinical Endocrinology & Metabolism 90:3077-3083.
Lopes LML, Francisco RPV, Galletta MAK, Bronstein MD. 2016. Determination of nighttime salivary cortisol during pregnancy: com- parison with values in non-pregnancy and Cushing’s disease. Pituitary 19:30-38. https://doi.org/10.1007/s11102-015-0680-3
Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, et al. 1990. Clinical features of adrenocortical carcinoma, prog- nostic fac- tors, and the effect of mitotane therapy. New England Journal of Medicine 322:1195-1201.
Magiakou MA, Mastorakos G, Rabin D, Dubbert B, Gold PW, Chrousos GP. 1996. Hypothalamic corticotropin-releasing hormone suppression dur- ing the postpartum period: implications of the increase in psychiatric manifestations at this time. Journal of Clinical Endocrinology & Metabolism 81:1912-1917.
McClamrock HD, Adashi EY. 1992. Gestational hyperandrogenism. Fertility and Sterility 57:257-274.
Morton A. 2015. Primary aldosteronism and pregnancy. Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 5:259-262.
Nakhleh A, Saiegh L, Reut M, Ahmad MS, Pearl IW, Shechner C. 2016. Cabergoline treatment for recurrent Cushing’s disease during preg- nancy. Hormones 15:453-458.
Nassi R, Ladu C, Vezzosi C, Mannelli M. 2015. Cushing’s syndrome in pregnancy. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology 31:102-104.
Ng L, Libertino JM. 2003. Adrenocortical carcinoma: diagnosis, evaluation and treatment. The Journal of Urology 169:5.
Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, et al. 2008. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism 93:1526-1540. https://doi.org/10.1210/jc. 2008-0125.
Nolten WE, Lindheimer MD, Rueckert PA, Oparil S, Ehrlich EN. 1980. Diurnal patterns and regulation of cortison secretion in pregnancy. The Journal of Clinical Endocrinology and Metabolism 51:466.
Okamoto E, Takagi T, Makino T, Sata H, Iwata I, Nishino E, et al. 1989. Immunoreactive corticotropin-releasing hormone, adrenocorticotropin and cortisol in human plasma during pregnancy and delivery and postpartum. Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones et Metabolisme 21:566-572.
Pickard J, Jochen AL, Sadur CN, Hofeldt FD. 1990. Cushings syndrome in pregnancy. Obstetrical & Gynecological Survey 45:87-93.
Prete A, Paragliola RM, Salvatori R, Corsello SM. 2016. Management of catecholamine secreting tumours in pregnancy: a review. Endocrine Practice 22:357-370.
Riester A, Reincke M. 2015. Progress in primary aldosteronism: mineralo- corticoid receptor antagonists and management of primary aldoster- onism in pregnancy. European Journal of Endocrinology 172:R23-30.
Rigo J, Jr Glaz E, Papp Z. 1996. Low or high doses of spironolactone for treatment of maternal Bartter’s syndrome. American Journal of Obstetrics and Gynecology 174:297.
Sammour RN, Saiegh L, Matter I, Gonen R, Shechner C, Cohen M, et al. 2012. Adrenalectomy for adrenocortical adenoma causing Cushing’s syndrome in pregnancy: a case report and review of literature. European Journal of Obstetrics & Gynecology and Reproductive Biology 165:1-7.
Sarathi V, Lila AR, Bandgar TR, Menon PS, Shah NS. 2010. Pheochromocytoma and pregnancy: a rare but dangerous combin- ation. Endocrine Practice: Official Journal of the American College of
Endocrinology and the American Association of Clinical Endocrinologists 16:300-309.
Schenker JG, Granat M. 1982. Pheochromocytoma and pregnancy- an updated appraisal. The Australian and New Zealand Journal of Obstetrics and Gynaecology 22:1-10.
Schneiderman M, Czuzoj-Shulman N, Spence AR, Abenhaim HA. 2017. Maternal and neonatal outcomes of pregnancies in women with Addison’s disease: a population-based cohort study on 7.7 million births. BJOG: An International Journal of Obstetrics & Gynaecology 124:1772-1779.
Sek KS, Deepak DS, Lee KO. 2017. Use of cabergoline for the manage- ment of persistent Cushing’s disease in pregnancy. BMJ Case Report: bcr-2016-217855. doi:10.1136/bcr-2016-217855.
Tomaszewski C, Dewailly D. 2012. Hypercorticism and pheochromocy- toma during pregnancy. In: Letombe B, Catteau-Jonard S, editors. Endocrinology in Gynecology and Obstetrics. Paris (France): Masson Elsevier; p. 233-240.
Touiti A, Mghari GE. 2015. Cushing syndrome during pregnancy: about a case of adrenal adenoma. Pan African Medical Journal 21:81.
Toutounchi S, Makowska A, Krajewska E, Fiszer P, Cieśla W, Pogorzelski R, et al. 2011. Laparoscopic treatment of Cushing’s syndrome in a woman in late pregnancy - a case presentation. Videosurgery and Other Miniinvasive Techniques 6:261-226.
van der Vaart CH, Heringa MP, Dullaart RP, Aarnoudse JG. 1993. Multiple endocrine neoplasia presenting as phaeochromocytoma during preg- nancy. British Journal of Obstetrics and Gynaecology 100:1144-1145.
van der Weerd K, van Noord C, Loeve M, Knapen MFCM, Visser W, de Herder WW, et al. 2017. Endocrinology in pregnancy. Pheochromocytoma in pregnancy: case series and review of literature. European Journal of Endocrinology 177:R49-R58.
Verdonk K, Visser W, Van Den Meiracker AH, Danser AHJ. 2014. The renin-angiotensin aldosterone system in pre-eclampsia: the delicate balance between good and bad. Clinical Science (London, England: 1979) 126:537-544.
Versmissen J, Koch BCP, Roofthooft DWE, ten Bosch-Dijksman W, van den Meiracker AH, Hanff LM, et al. 2016. Doxazosin treatment of phaeochromocytoma during pregnancy: placental transfer and dispos- ition in breast milk. British Journal of Clinical Pharmacology 82: 568-569.
Woo I, Ehsanipoor RM. 2013. Cabergoline therapy for Cushing disease throughout pregnancy. Obstetrics and Gynecology 122:485-487.
Zieleniewski W, Michalak R. 2017. A successful case of pregnancy in a woman with ACTH-independent Cushing’s syndrome treated with ketoconazole and metyrapone. Gynecology and Endocrinology 33: 349-352. May