We present the case of Mrs OA, a 36-year-old woman, G3P1, who presented to hospital at six weeks gestation in hypertensive crisis. She described symptoms of exertional dyspnoea, intermittent chest pain and headaches of increasing severity over the preceding few weeks. At presentation, she had a blood pressure of 220/120 mmHg with a sinus tachycardia of 120 beats per minute. She gave a history of miscarriage earlier this year at 8 weeks gestation.
ECG revealed changes consistent with left ventricular hypertrophy with strain. Mrs OA was sequentially started on methyldopa 500mg QID, nifedipine XR 30mg daily and labetalol 100mg BD for the management of her hypertension. Echocardiogram revealed features of hypertensive cardiomyopathy, with left ventricular ejection fraction 35%.
Mrs OA had a similar presentation two years earlier, with hypertensive crisis requiring ICU admission. She was treated at that time with alpha and beta blockade after a CT pulmonary angiogram captured a right adrenal mass measuring 34 x 21 mm. Further investigation during that admission revealed normal plasma metanephrines and a 24-hour urine free cortisol of 1191 nmol/24 hour (0-150). Unfortunately, Mrs OA was lost to follow-up after failing to attend her clinic appointments. She stopped her anti-hypertensive medication shortly after.
History obtained during her current admission revealed weight gain of 50kg in the intervening 2 years. A repeat 24-hour urine free cortisol was similarly elevated at 1034 nmol/24 hour, while ACTH was suppressed at < 3 ng/L consistent with an ACTH independent cause for Cushing’s syndrome. Her fasting plasma glucose was 5.4mmol/L. Imaging with an MRI of her adrenals again revealed a 34 x 23 mm right adrenal mass. Our patient was counselled regarding the high risk associated with continuing her pregnancy but expressed her wish to proceed with her pregnancy. At day 6 of her admission, in the setting of her significant hypertensive heart disease, metyrapone was started.
A diagnosis of Cushing’s syndrome in pregnancy is rare, due to cortisol and androgen excess resulting in impaired fertility.¹ Cortisol inhibits GnRH secretion, and thus LH and FSH release. Oligomenorrhoea and amenorrhoea are reported in 75% of cases.² In addition, due to the overlap of the signs and symptoms of cortisol excess and pregnancy, such as weight gain, hypertension and hyperglycaemia - Cushing’s syndrome is generally a delayed diagnosis in pregnancy.³ A triad of hypertension, ecchymoses and muscle weakness has been suggested to suspect Cushing’s syndrome in pregnancy.¹ As of 2018, there have been 200 case reports of Cushing’s syndrome in pregnancy,⁴ of which 50% have been of adrenal Cushing’s. Despite Cushing’s disease representing the majority of cases of Cushing’s syndrome in non-pregnant women, it is less represented in pregnancy.⁵
Normal hormonal changes occurring during pregnancy may contribute to difficulty in making a diagnosis of Cushing’s syndrome in pregnancy. A high index of clinical suspicion is required. Placental corticotropin-releasing hormone (CRH) and cortisol-binding globulin (CBG) are responsible for the physiological hypercortisolism in pregnancy (5). Placental CRH rises several hundred-fold during pregnancy. Placental CRH regulates placental ACTH and maternal ACTH release.⁶ As a result, ACTH levels rise dramatically throughout pregnancy, with a surge at week 11, a further rise after 16-20 weeks and a final surge at labour.⁶ The circadian rhythm of the HPA axis is preserved during normal pregnancy, although may be blunted.⁶ In addition, placental oestrogen increases hepatic CBG production. This results in an increase in bound cortisol, which transiently reduces free cortisol levels, and thus stimulates pituitary ACTH secretion, also leading to in an increase in cortisol levels.³ Therefore, total and free cortisol levels rise 2-3 fold throughout pregnancy, typically from the 11th week of gestation, and urine free cortisol levels increase from the second trimester.³ 24-hour urine free cortisol is the recommended screening test for the diagnosis of Cushing’s syndrome in pregnancy, with a reference range of 2-3 times the upper limit of normal from the second trimester.³⁷ ACTH levels are generally unhelpful, particularly from the second trimester.⁵
Cushing’s syndrome is an important diagnosis to establish during pregnancy, due to its significant associated maternal and foetal morbidity and mortality.⁸ Maternal morbidity occurs in 70% of cases with hypertension, diabetes mellitus and pre-eclampsia the most common complications. Maternal mortality is estimated at 2% compared with a background risk of < 0.01% in normal pregnancy.⁸ The most common foetal complications are prematurity, intrauterine growth restriction and early spontaneous abortion, with foetal mortality estimated at 11%.⁴
The management of Cushing’s syndrome in pregnancy is guided by disease severity and the time of gestation.⁵ Surgical management is the first line option, with livebirth rates reported in up to 87% following surgical resolution.⁶ Adrenalectomy has been found to be safe up to 32 weeks of gestation, however ideally surgery should be performed within the second trimester.¹ In some cases a conservative management approach may be possible. This depends on the degree of cortisol excess, and whether the associated comorbidities are able to be adequately controlled.³ Cushing’s syndrome diagnosed late in pregnancy may necessitate observation as the best management approach.³
Where surgery is contraindicated, and observation is not a feasible approach, medical management is available. Medical treatment is usually avoided in order to minimise the teratogenic risk and risk of induction of fetal adrenal insufficiency.⁵ The agent most used in pregnancy is metyrapone, an inhibitor of 11 beta-hydroxylase leading to inhibition of cortisol production.⁴ While it does cross the placenta, there is currently no evidence that it is teratogenic.⁵ Metyrapone should be used with caution due to the total low number of reported cases, and the potential risk of hypertension due to deoxycorticosterone accumulation.⁴ Another medical treatment option is ketoconazole which inhibits 11 alpha-hydroxylase and also leads to the inhibition of cortisol production.⁴ It however has been associated with an increased rate of abortion in animal studies and crosses the placenta, hence carrying a possible teratogenic risk.¹
Returning to our case, while control of Mrs OA’s hypertension improved, and 24-hour urine cortisol reduced to 240 nmol/24 hour, pelvic ultrasound at week 8 gestation revealed a non-viable pregnancy. She underwent a dilatation and curettage with Mirena insertion and is currently awaiting a right adrenalectomy.
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