Hypertension Research

https://doi.org/10.1038/s41440-021-00621-5

CORRESPONDENCE

Eplerenone levels in maternal serum, cord blood, and breast milk

during pregnancy and lactation
Jumpei Saito1 Asako Mito2,3 Naho Yakuwa3 Kayoko Kaneko2 Hiroyo Kawasaki1 Tomo Suzuki3,4
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Akimasa Yamatani1,3 Haruhiko Sago4 Atsuko Murashima2,3

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Received: 28 December 2020 / Revised: 30 December 2020 / Accepted: 3 January 2021

© The Japanese Society of Hypertension 2021

Hypertensive disorders affect ~10% of all pregnant women studies in pregnant women, no adverse or teratogenic
and are leading causes of maternal and perinatal mortality developmental effects were observed in pregnant animals
and morbidity [1]. Primary aldosteronism (PA) is currently receiving eplerenone during organogenesis at doses up to 32
considered one of the most common causes of secondary times the therapeutic dose of 100 mg/day in humans [6].
hypertension and has an estimated prevalence of ~3–6% Furthermore, one case report described an uneventful
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among patients with hypertension [2, 3] and ~20% in pregnancy in a woman treated with eplerenone for an
patients with severe hypertension [4]. PA is characterized aldosterone-producing adenoma. She delivered a healthy
by autonomous aldosterone production with suppressed male infant who did not have any adverse effects during a
renin levels, either involving one adrenal gland (mostly due follow-up of 2 years [8]. In addition, eplerenone was
to an aldosterone-producing adenoma) or both adrenal reported to be safe and effective in pregnant women with
glands. Choices for antihypertensive therapy in pregnant Gitelman syndrome [9] or diastolic heart failure [10].
women with hypertension are limited. Unfortunately, spir- Although there are some data about the safety of eplerenone
onolactone has been shown to have an adverse effect on the in pregnant or lactating women, there is no published
fetus in animal studies. There are no adequately controlled information about placental transfer of eplerenone in
studies in humans. Furthermore, the potent antiandrogenic humans. Regarding the safety of breastfeeding during
effects of spironolactone have the potential to cause eplerenone treatment, preclinical data show that eplerenone
ambiguous genitalia in male fetuses [5]. is detectable in rat breast milk [6]. However, there are no
Unlike spironolactone, the selective aldosterone blocker data regarding eplerenone transfer into human breast milk.
eplerenone is licensed for use in individuals with hyper- In this case report, we discuss the safety of eplerenone with
tension and heart failure after myocardial infarction [6]. reference to drug concentrations in cord blood, maternal
Eplerenone has fewer antiandrogenic effects, such as serum, and breast milk.
gynecomastia, mastalgia, feminization, and impotence [7]. A 44-year-old woman with PA weighing 63 kg became
Eplerenone has the potential to be a safer option than pregnant with her second child. She was diagnosed with
spironolactone. Although there are no adequately controlled early-onset preeclampsia during her first pregnancy, and she
delivered a female infant weighing 1205 g during gesta-
tional week 30 via cesarean section. Thus, in her second
* Jumpei Saito pregnancy, 81 mg of low-dose aspirin was started at
saito-jn@ncchd.go.jp gestational week 11 to prevent the development of pre-
1
eclampsia. Until gestational week 8, she received amlodi-
Department of Pharmacy, National Center for Child Health and
pine at a dose of 10 mg daily. Eplerenone was also
Development, Tokyo, Japan
2
administered for only one week from gestational week 8.
Division of Maternal Medicine, Center for Maternal-Fetal,
Due to elevated blood pressure (BP) during gestational
Neonatal and Reproductive Medicine, National Center for Child
Health and Development, Tokyo, Japan week 25, amlodipine was converted to combination therapy
3 consisting of nifedipine 40 mg twice daily and eplerenone
Japan Drug Information Institute in Pregnancy, National Center for
Child Health and Development, Tokyo, Japan 50 mg once daily (0.79 mg/kg/day). After the dose of
4 nifedipine was increased to 60 mg twice daily and methyl-
Division of Obstetrics, Center for Maternal-Fetal, Neonatal and
Reproductive Medicine, National Center for Child Health and dopa 250 mg was added as needed, her systolic BP was
Development, Tokyo, Japan controlled between 100 and 120 mmHg, and her diastolic
 J. Saito et al.

Table 1 Eplerenone
Postpartum day Maternal serum Umbilical cord blood Breast milk
concentrations in serum and
breast milk samples after Time EPL Time EPL Time EPL
administration of oral after EPL concentration after EPL concentration after EPL concentration
eplerenone 50 mg dose (ng/mL) dose (ng/mL) dose (ng/mL)
(hours) (hours) (hours)

−1 1.3 505.2
0 3.9 309.5 3.9 209.7
1 22.9 1.0
6 143.7 0.0
7 1.0 0.0
1.5 104.1
11.5 61.3
35 1.0 130.2
4.0 161.2
6.5 55.8
13.5 6.0
18.5 0.7
22.0 0.3
36 17.8 8.4
EPL eplerenone

BP was controlled to 60–70 mmHg at home. During which was 67.8% of the level in maternal serum. At 22.9 h
gestational week 38, a healthy male infant weighing 2918 g after the last dose, the concentration of eplerenone decreased
was born by cesarean section. Superimposed preeclampsia to 1.0 ng/mL.
did not develop during her second pregnancy. During a In breast milk, eplerenone concentrations at 1.0, 1.5, and
3-month lactation period, the infant was partially breastfed, 11.5 h after the last dose on postpartum day 7 were 0.0,
with over 50% of nutrition derived from breastfeeding. The 104.1, and 61.3 ng/mL, respectively. On postpartum day 35,
infant in this case demonstrated normal developmental eplerenone concentrations at 1.0, 4.0, 6.5, 13.5, 18.5, and
progress and had no detectable drug-related adverse effects 22.0 h after the last dose were 130.2, 161.2, 55.8, 6.0, 0.7,
at the 1-month or 3-month postpartum health checkups. and 0.3 ng/mL, respectively (Table 1). The calculated daily
To evaluate eplerenone exposure in utero and during dose of eplerenone ingested by the infant via breast milk,
infancy, maternal serum samples were collected after oral based on the maximum detected eplerenone concentration
eplerenone 50 mg was administered. Umbilical cord blood in breast milk (161.2 ng/mL) and average breast milk intake
was collected after delivery, and the serum was immedi- (150 mL/kg/day), was 0.024 mg/kg/day; this was low
ately separated by ultracentrifugation. Breast milk sam- compared to the weight-adjusted therapeutic dose of
ples were collected several times after eplerenone eplerenone for adults (50–100 mg once daily). The relative
administration and stored below –20 °C until analysis. infant dose via breast milk based on the maternal daily dose
The timing of sample collection after eplerenone admin- was 3.0%, which was higher than that of labetalol (0.004%)
istration is presented in Table 1. Eplerenone in serum and [11], methyldopa (0.01%) [12], nifedipine (0.1%) [13],
breast milk samples was determined using a modified benazepril (0.1%) [14], enalapril (0.27%) [15] and captopril
version of a previously validated method based on liquid (1.0%) [16] and was the same level as that of amlodipine
chromatography tandem mass spectrometry. This study (4.2%) [17].
was approved by the ethics committee of the National To the best of our knowledge, this is the first report
Center for Child Health and Development. The participant describing the transfer of eplerenone across the placenta and
provided written informed consent. into breast milk. In our case, eplerenone was detected in
Eplerenone concentrations in maternal serum were cord blood and breast milk. Although the patient received
505.2 ng/mL at 1.3 h after the last eplerenone dose and eplerenone in early pregnancy, no birth defects were found
309.5 ng/mL at delivery (3.9 h after the last dose). The in her infant. The dose of eplerenone consumed by the
eplerenone concentration in cord blood collected immediately infant via breastmilk was less than 10%, and this level was
after delivery (3.9 h after the last dose) was 209.7 ng/mL, considered to be acceptable [18]. Further studies are needed
Eplerenone levels in maternal serum, cord blood, and breast milk during pregnancy and lactation

to evaluate potential harmful effects following exposure to 6. G.D. Searle LLC. INSPRA oral tablets, eplerenone oral tablets.
eplerenone in utero and during breastfeeding. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/
021437s013lbl.pdf. Accessed 17 Dec 2020.
7. Ye P, Yamashita T, Pollock DM, Sasano H, Rainey WE. Con-
Acknowledgements We would like to thank Ms. Mariko Takagai for
trasting effects of eplerenone and spironolactone on adrenal cell
her expert research assistance. We are also grateful to the lactating
steroidogenesis. Horm Metab Res. 2009;41:35–39.
mother for donating her precious breast milk.
8. Cabassi A, Rocco R, Berretta R, Regolisti G, Bacchi-Modena A.
Eplerenone use in primary aldosteronism during pregnancy.
Compliance with ethical standards Hypertension. 2012;59:e18–e19.
9. Morton A, Panitz B, Bush A. Eplerenone for Gitelman syndrome
Conflict of interest AM has received research grants from Astellas in pregnancy. Nephrol. 2011;16:349.
Pharma, Inc. and Chugai Pharmaceutical Co., Ltd. and lecture fees 10. Hutter DA, Berkowitz R, Davis SE, Ashtyani H. Application of
from Astellas Pharma, Inc., Chugai Pharmaceutical Co., Ltd., and continuous positive airway pressure in hypoxemic acute respira-
Bristol-Myers KK. All other authors declare no conflicts of interest. tory failure associated with diastolic dysfunction in pregnancy.
Congest Heart Fail. 2006;12:174–5.
11. Leitz F, Bariletto S, Gural R, Jaworsky L, Patrick J, Symchowicz
Publisher’s note Springer Nature remains neutral with regard to
S. Secretion of labetalol in breast milk in lactating women. Fed
jurisdictional claims in published maps and institutional affiliations.
Proc. 1983;42:378.
12. White WB, Andreoli JW, Cohn RD. Alpha-methyldopa disposi-
tion in mothers with hypertension and in their breast-fed infants.
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