Cases

Obstetric Medicine
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Eplerenone as a treatment for resistant ! The Author(s) 2019
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DOI: 10.1177/1753495X19825967
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Jessica Gehlert1 and Adam Morton2

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 demon-
strated 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.

Keywords
Eplerenone, hypertension, mineralocorticoid receptor antagonists, pregnancy, obstructive sleep apnoea
Date Received: 24 July 2018; accepted: 3 January 2019

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 demasculini-
sation. 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 epler-
enone in a woman with morbid obesity, OSA and hypertension resis-
tant to three antihypertensive drugs commonly used in pregnancy.
Eplerenone stabilised the patient’s blood pressure, enabling an addi-
tional 23 days’ gestation prior to delivery.
Case report
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–hypo-
pnoea 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 antihy-
pertensive 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 mmol/L. Echocardiography revealed moderate left ven-
tricular hypertrophy and right ventricular systolic pressure of 23

A 30-year-old Samoan woman in her third pregnancy was admitted

to hospital at 13 weeks’ gestation following a blood pressure reading 1
Clinical Pharmacology Department, Royal Adelaide Hospital, South
of 170/125 mmHg detected on a routine general practitioner visit.
Australia, Australia
Hypertension with an inactive urine sediment was noted in pregnancy 2
Obstetric Medicine and Endocrinology, Mater Health, Brisbane,
two years prior at 20 weeks’ gestation. Postpartum, primary hyper- Queensland, Australia
aldosteronism was excluded with plasma aldosterone 303 pmol/L
(non-pregnant reference range 30–800 pmol/L), direct renin concen- Corresponding author:
tration (DRC) 51 mU/L (reference range 3–40 mU/L) and aldoste- Jessica Gehlert, Royal Adelaide Hospital, North Terrace, Adelaide, SA,
rone:renin ratio 6 (<55). These tests were not performed during her 5000, Australia.
pregnancy because of the risk of false negatives.9 Pheochromocytoma Email: Jessica.Gehlert@sa.gov.au
2 Obstetric Medicine

mmHg. Oral glucose tolerance testing was normal. A CPAP titration adherence. It is possible that the improvement in the patient’s
study recommended a pressure of 15 cmH2O; however, she was intol- blood pressure control from 31 weeks’ gestation was related to
erant of CPAP therapy. The patient was discharged from hospital the improved compliance with conventional antihypertensive therapy;
same week on slow-release nifedipine 120 mg/day, labetalol 800 mg/ however, the absence of a blood pressure response after three days
day, thyroxine, aspirin and calcium. of supervised inpatient treatment and subsequent significant and sus-
Thyroid function tests performed every two months were consis- tained response as an outpatient with the addition of eplerenone is
tent with adequate replacement and medication adherence. suggestive of its effect.
The patient’s blood pressure was satisfactory until 28 weeks’ gesta- MRAs are effective in the treatment of resistant hypertension.2,10
tion when readings of 150/105 mmHg prompted an increase in labe- OSA is recognised as an associated and possible cause of resistant
talol dose to 1200 mg/day. At 30 weeks’ gestation, her blood pressure hypertension.10 However, CPAP treatment may result in only mini-
was 180/120 mmHg prompting re-admission. Urine PCR was stable, mal improvement in blood pressure. Recent studies demonstrated
and there were no features of PET. Methyldopa was added and titrat- that MRAs significantly reduce blood pressure, severity of OSA
ed to 1500 mg/day; however, her BP remained elevated at and arterial stiffness in patients with resistant hypertension and mod-
165/100 mmHg. Following patient consent, eplerenone 50 mg daily erate–severe OSA.1,11 In individuals with resistant hypertension,
was commenced at 31 weeks’ gestation, with immediate and signifi- aldosterone levels correlate with the severity of OSA.12 It is thought
cant improvement in her blood pressure (Figure 1). Fetal monitoring that aldosterone worsens OSA by causing fluid accumulation in the
was performed fortnightly with ultrasound and Doppler measures. upper airways and neck, increasing upper airway resistance particu-
Between 28 and 34 weeks’ gestation, the estimated fetal weight on larly when supine. The use of MRAs in individuals with OSA can
ultrasound increased from 1300 g to 2085 g. The patient remained significantly reduce neck circumference.13
Spironolactone was used extensively between 1960 and 1980 to
stable until 34 þ 3 weeks’ gestation when a rise in blood pressure to
treat hypertension, PET, liver disease and myasthenia gravis in preg-
160/100 mmHg, without other features of PET, prompted delivery by
nancy, until a study demonstrated demasculinisation of male rat
elective caesarean section of a normally masculinised live male, birth-
fetuses when dams were dosed 200 mg/kg/day of spironolactone
weight 1890 g. Postpartum, the mother’s hypertension was controlled
between 13 and 21 days’ gestation.3 A single case of ambiguous
with enalapril 10 mg twice daily as a single agent with blood pressures
genitalia in a human male newborn whose mother was treated
of approximately 135/80 mmHg.
with spironolactone until the fifth week of gestation has
been reported.14
Unlike spironolactone, eplerenone does not bind to the androgen
Discussion receptor. No teratogenic effects or demasculinisation were seen in
This case highlights the difficulty in managing resistant hypertension male rabbit or rat fetuses when dams were dosed at approximately
in pregnancy, particularly in the setting of poor medication 30 times the equivalent of a human dose of 100 mg/day. To date, the

Eplerenone commenced Delivered

180
160
Blood Pressure (mmHg)

140
120
100
80
60
40
20
0
30+5
30+6
31
31+1
31+2
31+3
31+4
31+5
31+6
32
32+1
32+2
32+3
32+4
32+5
32+6
33
33+1
33+2
33+3
33+4
33+5
33+6
34
34+1
34+2
34+3

Gestaon (weeks)
Mean Systolic Mean Diastolic

Figure 1. Changes in mean daily systolic and diastolic blood pressure.

Table 1. Case reports regarding the use of eplerenone in pregnancy.2,4,6–8,16

Gestation exposure Duration
Author Indication (weeks) (weeks) Outcome

Cabassi et al.6 Primary hyperaldosteronism 27–35 8 Healthy masculinised 2280 g male

Morton et al.4 Gitelman 0–39 39 Healthy 3630 g female
Gitelman 0–38 38 Healthy 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 ¼ not available.
Gehlert and Morton
use of eplerenone has been described in six human pregnancies with-
out adverse effect, although this was in the first trimester in only two
cases (Table 1).2,4–8
A recent study in non-pregnant individuals reported that amilor-
ide 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 hyperaldoster-
onism, resistant hypertension, Liddle, Bartter and Gitelman syn-
dromes without adverse effect.16,17
Significant limitations of this case report include the brief dura-
tion 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’ gesta-
tion. The addition of alternative antihypertensives with greater expe-
rience in pregnancy may have had a similar or greater effect. Possible
oral medications would include clonidine, hydralazine, a-blockers,
b-blockers and verapamil. It did not seem logical to trial an a- or
b-blocker, when the patient was already taking labetalol, nor hydral-
azine 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 combina-
tion 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 pregnan-
cy remote from term, eplerenone and amiloride may be useful, par-
ticularly in the setting of moderate–severe OSA.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
Ethical approval
Not applicable.
Informed consent
Written consent was obtained from the patient for their anonymised
information to be published in this article.
Guarantor
JG is the guarantor of the present work.
3
Contributorship
Both authors contributed equally.
ORCID iD
Jessica Gehlert http://orcid.org/0000-0003-2693-9000
Adam Morton http://orcid.org/0000-0001-9887-714X
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