Eplerenone as a treatment for resistant hypertension in pregnancy

Abstract

Mineralocorticoid receptor antagonists are highly effective in the management of resistant hypertension and primary hyperaldosteronism. Recent studies demonstrate that mineralocorticoid receptor antagonists significantly reduce blood pressure, severity of obstructive sleep apnoea and arterial stiffness in patients with resistant hypertension and moderate–severe obstructive sleep apnoea. Eplerenone is a selective mineralocorticoid receptor antagonist that does not act as an androgen receptor blocker, thus reducing the risk of fetal anti-androgenic effects. Rat and rabbit studies demonstrated that when exposed to 30 times the equivalent therapeutic human dose, 100 mg/day, there were no teratogenic or demasculinisation effects. To date, the use of eplerenone has been reported in six human pregnancies in women with Gitelman syndrome, primary hyperaldosteronism and cardiac failure, in which no teratogenic effects were seen. Described here is a case of resistant hypertension associated with obstructive sleep apnoea in pregnancy, treated with eplerenone. The potential role of using eplerenone in pregnancy as treatment for resistant hypertension is discussed.

Trial registration: Not applicable.

Introduction

Mineralocorticoid receptor antagonists (MRAs) are highly effective in the management of resistant hypertension. MRAs may have specific benefits in treating resistant hypertension in individuals with obstructive sleep apnoea (OSA), outside of pregnancy.^1,2 Spironolactone, an aldosterone antagonist, was used extensively in the management of hypertensive disorders in pregnancy prior to 1980, when demasculinisation of male rats’ external genitalia was reported.³ Eplerenone, a selective MRA, does not block the androgen receptor, and therefore would not be expected to cause demasculinisation. To date, the use of eplerenone has been reported in six human pregnancies with no adverse effect.^2,4–8 We describe the use of eplerenone in a woman with morbid obesity, OSA and hypertension resistant to three antihypertensive drugs commonly used in pregnancy. Eplerenone stabilised the patient’s blood pressure, enabling an additional 23 days’ gestation prior to delivery.

Case report

A 30-year-old Samoan woman in her third pregnancy was admitted to hospital at 13 weeks' gestation following a blood pressure reading of 170/125 mmHg detected on a routine general practitioner visit. Hypertension with an inactive urine sediment was noted in pregnancy two years prior at 20 weeks’ gestation. Postpartum, primary hyperaldosteronism was excluded with plasma aldosterone 303 pmol/L (non-pregnant reference range 30–800 pmol/L), direct renin concentration (DRC) 51 mU/L (reference range 3–40 mU/L) and aldosterone:renin ratio 6 (<55). These tests were not performed during her pregnancy because of the risk of false negatives.⁹ Pheochromocytoma and renal artery stenosis were also excluded, and the patient declined a renal biopsy postpartum.

The patient’s medical history was significant for a thyroidectomy for Grave’s disease, morbid obesity (body mass index 51.6 kg/m²), polycystic ovarian syndrome (PCOS) and severe OSA (apnoea–hypopnoea index of 58.8 events per hour).

The patient’s first pregnancy resulted in premature delivery of twins at 37 weeks’ gestation, due to concerns regarding fetal well-being. Her second pregnancy was a singleton delivered at 30 weeks for preeclampsia (PET) and small for gestational age.

Prior to admission, the patient had not taken her usual antihypertensive medications or thyroxine for some time, and she could not afford continuous positive airway (CPAP) therapy. Investigations revealed free thyroxine 6.6 pmol/L (normal 9–19pmol/L), thyroid-stimulating hormone 65 mu/L (normal 0.1–4 mu/L) and undetectable thyroid-stimulating receptor antibody. Urine protein:creatinine (PCR) ratio was 280 mg/mmol (normal 0–30 mg/mmol) and serum creatinine 91 µmol/L. Echocardiography revealed moderate left ventricular hypertrophy and right ventricular systolic pressure of 23 mmHg. Oral glucose tolerance testing was normal. A CPAP titration study recommended a pressure of 15 cmH₂O; however, she was intolerant of CPAP therapy. The patient was discharged from hospital the same week on slow-release nifedipine 120 mg/day, labetalol 800 mg/day, thyroxine, aspirin and calcium.

Thyroid function tests performed every two months were consistent with adequate replacement and medication adherence. The patient’s blood pressure was satisfactory until 28 weeks’ gestation when readings of 150/105 mmHg prompted an increase in labetalol dose to 1200 mg/day. At 30 weeks’ gestation, her blood pressure was 180/120 mmHg prompting re-admission. Urine PCR was stable, and there were no features of PET. Methyldopa was added and titrated to 1500 mg/day; however, her BP remained elevated at 165/100 mmHg. Following patient consent, eplerenone 50 mg daily was commenced at 31 weeks’ gestation, with immediate and significant improvement in her blood pressure (Figure 1). Fetal monitoring was performed fortnightly with ultrasound and Doppler measures. Between 28 and 34 weeks’ gestation, the estimated fetal weight on ultrasound increased from 1300 g to 2085 g. The patient remained stable until 34 + 3 weeks’ gestation when a rise in blood pressure to 160/100 mmHg, without other features of PET, prompted delivery by elective caesarean section of a normally masculinised live male, birthweight 1890 g. Postpartum, the mother’s hypertension was controlled with enalapril 10 mg twice daily as a single agent with blood pressures of approximately 135/80 mmHg.

Figure 1.

Changes in mean daily systolic and diastolic blood pressure.

Discussion

This case highlights the difficulty in managing resistant hypertension in pregnancy, particularly in the setting of poor medication adherence. It is possible that the improvement in the patient’s blood pressure control from 31 weeks’ gestation was related to improved compliance with conventional antihypertensive therapy; however, the absence of a blood pressure response after three days of supervised inpatient treatment and subsequent significant and sustained response as an outpatient with the addition of eplerenone is suggestive of its effect.

MRAs are effective in the treatment of resistant hypertension.^2,10 OSA is recognised as an associated and possible cause of resistant hypertension.¹⁰ However, CPAP treatment may result in only minimal improvement in blood pressure. Recent studies demonstrated that MRAs significantly reduce blood pressure, severity of OSA and arterial stiffness in patients with resistant hypertension and moderate–severe OSA.^1,11 In individuals with resistant hypertension, aldosterone levels correlate with the severity of OSA.¹² It is thought that aldosterone worsens OSA by causing fluid accumulation in the upper airways and neck, increasing upper airway resistance particularly when supine. The use of MRAs in individuals with OSA can significantly reduce neck circumference.¹³

Spironolactone was used extensively between 1960 and 1980 to treat hypertension, PET, liver disease and myasthenia gravis in pregnancy, until a study demonstrated demasculinisation of male rat fetuses when dams were dosed 200 mg/kg/day of spironolactone between 13 and 21 days' gestation.³ A single case of ambiguous genitalia in a human male newborn whose mother was treated with spironolactone until the fifth week of gestation has been reported.¹⁴

Unlike spironolactone, eplerenone does not bind to the androgen receptor. No teratogenic effects or demasculinisation were seen in male rabbit or rat fetuses when dams were dosed at approximately 30 times the equivalent of a human dose of 100 mg/day. To date, the use of eplerenone has been described in six human pregnancies without adverse effect, although this was in the first trimester in only two cases (Table 1).^2,4–8

Table 1.

Case reports regarding the use of eplerenone in pregnancy.^2,4,6–8,16

Author	Indication	Gestation exposure (weeks)	Duration (weeks)	Outcome
Cabassi et al.6	Primary hyperaldosteronism	27–35	8	Healthy masculinised 2280 g male
Morton et al.4	GitelmanGitelman	0–390–38	3938	Healthy 3630 g femaleHealthy female
Gunganah et al.7	Primary hyperaldosteronism	18–28	10	Growth-restricted masculinised male
Hutter et al.8	Diastolic heart failure	32–NA	NA	Healthy – sex, weight unknown
Morton and Laurie2	Resistant hypertension, OSA	23–27	4	490 g masculinised male

NA = not available.

A recent study in non-pregnant individuals reported that amiloride was equally effective as spironolactone in managing resistant hypertension.¹⁵ The use of amiloride has been described in 21 human pregnancies in the management of primary hyperaldosteronism, resistant hypertension, Liddle, Bartter and Gitelman syndromes without adverse effect.^16,17

Significant limitations of this case report include the brief duration of exposure to eplerenone with respect to safety in pregnancy particularly in first trimester, and the temporary effect observed on blood pressure which allowed only an additional three weeks’ gestation. The addition of alternative antihypertensives with greater experience in pregnancy may have had a similar or greater effect. Possible oral medications would include clonidine, hydralazine, α-blockers, β-blockers and verapamil. It did not seem logical to trial an α- or β-blocker, when the patient was already taking labetalol, nor hydralazine when already taking nifedipine as a vasodilator. While four studies in non-pregnant adults have shown an additive and possibly synergistic effect in the use of combined dihydropyridine/non-dihydropyridine calcium blockers, the use of verapamil in combination with labetalol may be concerning with regard to negative inotropic and chronotropic effect.¹⁸ We are not aware of any studies comparing the efficacy of oral medications in the setting of chronic resistant hypertension in pregnancy. A meta-analysis of the treatment for severe hypertension in pregnancy found similar efficacy between oral nifedipine, intravenous hydralazine and intravenous labetalol; however, the evidence was inadequate for other drugs.¹⁹

OSA and metabolic syndrome are significantly more prevalent in women with PCOS compared with women matched for age and body mass index (17% vs. 0.6%, p < 0.0001).²⁰ OSA may be worsened as a result of physiologic changes of pregnancy.²¹ In prospective studies, PCOS is associated with a three-fold greater risk of PET and pregnancy-induced hypertension.^22,23

Conclusion

Increasing obesity is likely to result in a greater incidence of OSA and possibly resistant hypertension in pregnancy. Where hypertension is unresponsive to antihypertensive agents customarily used in pregnancy remote from term, eplerenone and amiloride may be useful, particularly in the setting of moderate–severe OSA.