Primary aldosteronism during pregnancy: Case report and literature review

Abstract

We present the case of a 40-year-old woman who experienced severe hypertension during her first pregnancy. Hypertension persisted after delivery, prompting admission to the Department of Endocrinology and Metabolism at our hospital. Examination revealed an aldosterone-producing adenoma, and she was diagnosed with primary aldosteronism. Her hypertension was controlled using methyldopa. She became pregnant again in April 2019, and in the ninth week of pregnancy, she underwent her first medical examination of the artery. Subsequently, the methyldopa dose was increased to control her hypertension. However, her hypertension worsened, and she tested positive for urinary albumin, prompting hospital admission at 32 weeks of gestation. Her oral medication was changed to nifedipine, which was continued after her second delivery. However, her hypertension persisted. Therefore, a selective mineralocorticoid receptor antagonist was administered, and her hypertension improved. Mineralocorticoid receptor antagonists should be considered when blood pressure is poorly controlled owing to worsening primary aldosteronism.

Introduction

Primary aldosteronism accounts for 5%–13% of all hypertension cases and is considered the main cause of secondary hypertension.¹⁾ A limited number of cases of this syndrome during pregnancy have been reported. Nonetheless, we have experienced difficult cases of blood pressure control during pregnancy as well as persistent hypertension after delivery.²⁾ Elevated blood pressure in pregnancy that is complicated by primary aldosteronism is treated using methyldopa, hydralazine, labetalol, and calcium antagonists, similar to the treatment of other types of hypertension during pregnancy. Herein, we report the case of a woman with primary aldosteronism who achieved satisfactory hypertension control after her second delivery through the use of a mineralocorticoid receptor antagonist.

Case report

Informed consent was obtained from the patient before treatment and for the publication of this report. IRB approval was not required as this was a single case report. In April 2018, a woman in the 36^th week of pregnancy presented with a blood pressure of 150/90 mmHg. She was diagnosed with gestational hypertension by her local obstetrician and gynecologist. After parturition, nifedipine was continued at a dose of 20 mg/day. In August 2018, the patient was referred to the Department of Endocrinology and Metabolism of our hospital for investigation and treatment of suspected primary aldosteronism. Blood tests revealed no electrolyte abnormalities or renal dysfunction, and her electrocardiography findings were normal. The patient underwent a captopril challenge test and a saline challenge test at our endocrinology department, both of which were positive, confirming the diagnosis of primary aldosteronism. Computed tomography revealed no apparent tumorous changes in the bilateral accessory kidneys. Considering that the patient had unilateral secondary renal adenocarcinoma, adrenal vein sampling was performed as the patient wanted to undergo surgery. Subsequently, she was diagnosed with bilateral specific aldosteronism, and drug therapy was initiated. In April 2019, she became pregnant for the second time. During the ninth week of gestation, she was hypertensive once more and was referred to our hospital. A 24-h check-up revealed a nondipper subtype of nocturnal blood pressure variability and early morning hypertension. At 32 weeks of gestation, the patient’s hypertension worsened, and her urinary albumin/creatinine ratio increased, prompting hospital admission for blood pressure control. Laboratory findings on admission were as follows: Na, 137 mmol/L; K, 3.7 mmol/L; Cl, 108 mmol/L; urinary protein positive; and urine protein to creatinine ratio, 0.38 g/g-cre. Nifedipine (80 mg/day) was initiated at the time of hospital admission (Figure 1). Thereafter, the dosage was adjusted according to the changes in her blood pressure until delivery; her blood pressure was controlled well using this approach. On the 37^th week of pregnancy, she underwent total cesarean section and delivered a baby without complications. After parturition, the patient was treated with 40 mg of nifedipine, and 1.25–2.5 mg of esaxerenone, a selective mineralocorticoid receptor antagonist, was initiated 2 weeks after delivery to treat the primary disease. Thereafter, the patient showed good blood pressure control. During her pregnancy, her renin levels were low, her aldosterone levels were high, and her potassium levels had slightly decreased, which was consistent with primary aldosteronism (Figure 1).

Figure 1.

Progression of blood pressure control and medication.

sBP, systolic blood pressure; dBP, diastolic blood pressure; UPCR, urine protein/creatinine ratio; PRA, plasma renin activity; PAC, plasma aldosterone concentration.

Discussion

In patients with primary aldosteronism, excessive aldosterone secretion results in increased Na reabsorption in the renal tubules, resulting in increased circulating plasma volume and hypertension. In this report, we summarized 26 cases of pregnancies complicated by primary aldosteronism reported since 2015 (Table 1). In 46% patients, pregnancies complicated with hypertension developed aggravated gestational hypertensive nephropathy, whereas 42% pregnancy cases complicated with hypertension resulted in preterm delivery. During pregnancy, hypertension treatment with drugs, such as methyldopa and calcium channel blockers, and potassium supplementation are often the first-choice treatments.⁹⁾ Moreover, hypertension may be exacerbated after delivery; thus, aldosterone receptor antagonists should be considered for the treatment of the primary disease.⁹⁾

Table 1. Evaluation of 26 cases with primary aldosteronism combined with pregnancy in 2015

Case	Age	Illness	Type	Weeks of delivery	Type of birth	Birth weight	Timing of primary aldosteronism diagnosis	Medications
								Before conception	During pregnancy	After delivery
1	30	IHA	CH	30 w	em C/S	1,559 g	Before conception	Amiloride	Labetalol	Labetalol
2	36	IHA	SPE	27 w	em C/S	555 g	Before conception	—	Nicardipine, labetalol	Nicardipine, enalapril, spironolactone
3	35	IHA	SPE	30 w	em C/S	1,179 g	Before conception	Nifedipine, enalapril	Nifedipine, labetalol	Enalapril
4	29	IHA	SPE	33 w	C/S	1,800 g	After delivery	Antihypertensive	—	Spironolactone
5	33	IHA	SPE	36 w	em C/S	2,632 g	Before conception	None	Nifedipine	Captopril
6		IHA	SPE	37 w	em C/S	2,820 g	Before conception	None	Nifedipine	Enalapril
7		IHA	SPE	38 w	C/S		After delivery	—	—	Amiloride
8	33	IHA	SPE	40 w	em C/S		Before conception	Amiloride	None	Enalapril, spironolactone
9	29	APA	CH	35 w	em C/S		Before conception	—	Labetalol, nifedipine	None
10	26	APA	CH	36 w	C/S	3,550 g	After delivery	—	—	ACE inhibitors, indapamide→ Adrenalectomy
11	28	APA	CH	36 w	C/S	2,410 g	After delivery	—	—	Amlodipine→Adrenalectomy
12	36	APA	CH	38 w	NVD	3,230 g	After delivery	—	Labetalol, nifedipine	—
13	30	APA	CH	40 w	NVD	3,220 g	After delivery	—	Alpha-methyldopa	Spironolactone→Adrenalectomy
14	25	APA	CH	39 w	C/S	3,450 g	After delivery	—	—	Spironolactone, MRA→ Adrenalectomy
15	35	APA	CH	40 w	C/S	3,690 g	After delivery	—	—	Spironolactone→Adrenalectomy
16	36	APA	CH	40 w	NVD	2,710 g	After delivery	—	—	Adrenalectomy
17	31	APA	CH	40 w	C/S	3,100 g	After delivery	—	Alpha-methyldopa	Verapamil→Adrenalectomy
18	31	APA	CH	40 w	NVD	3,830 g	After delivery	—	—	Adrenalectomy
19	26	APA	CH	40 w	C/S	2,640 g	After delivery	—	Alpha-methyldopa, metoprolol, KCl	Verapamil, doxazosine→ Adrenalectomy→Lacidipine, betaxolol
20	27	APA	CH	40 w	NVD	3,620 g	After delivery	—	—	Adrenalectomy→Antihypertensive
21	31	APA	PE	28 w	em C/S		After delivery	—	Eplerenone→ Adrenalectomy	—
22	29	APA	SPE	27 w	em C/S	860 g	After delivery	Antihypertensives	Natrium nitroprusside	Spironolactone→Adrenalectomy
23	22	APA	SPE	31 w	C/S	1,310 g	After delivery	—	Antihypertensives	Adrenalectomy
24	38	APA	SPE	38 w	em C/S		After delivery	—	—	Spironolactone
25	36	APA	SPE	39 w	NVD	3,470 g	During pregnancy	—	Potassium chloride	Ramipril, spironolactone
26	32	APA	SPE	39 w	NVD	3,550 g	After delivery	—	—	Spironolactone→Adrenalectomy

IHA, idiopathic aldosteronism; APA, aldosterone-producing adenoma; CH, pregnancy complicated by hypertension; PE, pregnancy-induced hypertensive nephropathy; SPE, weighted hypertensive nephropathy

Case 1, 3, 5–8²⁾; 2, 25³⁾; 4, 10,11, 13–20, 22, 23, 26⁴⁾; 9⁵⁾; 12⁶⁾; 21⁷⁾; 24⁸⁾

Treatment with general antihypertensive agents indicated for pregnant women or mineralocorticoid receptor antagonists before pregnancy and antihypertensive agents during pregnancy and lactation should be the basic treatment course for patients with idiopathic aldosteronism, a bilateral disease. In cases of hypertension and hypokalemia, mineralocorticoid receptor antagonist treatment should be considered. Cases of idiopathic aldosteronism were treated with medications, mainly mineralocorticoid receptor antagonists, after delivery (62%, 5/8 cases in Table 1). In addition, in cases with unilateral aldosterone-producing adenomas, adrenalectomy is an option.⁹⁾ As per the data in Table 1, adrenalectomy was performed in 13 of the 18 (72%) cases with aldosterone-producing adenomas.

The process for selecting the mineralocorticoid receptor antagonists is discussed below. Spironolactone has been used to treat primary aldosteronism for a while.^2,3,4,8) However, spironolactone has not been widely used during pregnancy as it is associated with feminization of the fetal genitalia and decreased live birth rates.⁸⁾ Eplerenone is recommended for use during pregnancy because of its higher mineralocorticoid receptor selectivity and lower antiandrogenic effects compared with spironolactone.⁹⁾ The newly developed esaxerenone is more effective than eplerenone in reducing excessive activation of the mineralocorticoid receptor and the volume load in blood vessels.¹⁰⁾

Although mineralocorticoid receptor antagonists are used during pregnancy and after parturition, spironolactone is not suitable for use in fertile women due to potential interference with conception. Although eplerenone has not been sufficiently tested in clinical trials, several reports indicate that the treatment of primary aldosteronism using eplerenone during pregnancy does not result in adverse effects on the child.^9,10) No reports have described the effects of esaxerenone on infertility in women, and its effects remain unclear. Esaxerenone is a nonsteroidal mineralocorticoid receptor antagonist that is used to effectively treat patients with bilateral primary aldosteronism who are not responsive to eplerenone.¹⁰⁾ In the future, mineralocorticoid receptor antagonists may become the first choice for the treatment of primordial aldosteronism in pregnant women.

Conclusion

Mineralocorticoid receptor antagonists may become the first-line treatment for patients with poor postpartum blood pressure control owing to exacerbation of primary aldosteronism. However, the treatment strategies for primary aldosteronism before conception, during pregnancy, and after delivery have not been established yet. This case report and review of cases can be used as a reference for establishing treatment methods for primary aldosteronism during pregnancy.

Acknowledgments

The authors are grateful to Dr. Aya Ishiguro for their collaboration and feedback on this report.

Conflict of interest

All authors declare no possible conflicts of interest.

References

• 1.   Käyser  SC,  Dekkers  T,  Groenewoud  HJ, et al. Study heterogeneity and estimation of prevalence of primary aldosteronism: A systematic review and meta-regression analysis. J Clin Endocrinol Metab. 2016; 101: 2826–2835.
• 2.   Morton  A. Primary aldosteronism and pregnancy. Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health. 2015; 5: 259–262.
• 3.   Piccoli  GB,  Mannucci  C. Preeclampsia: A diagnosis-nondiagnosis that is too easily made: The case of primary hyperaldosteronism. Kidney Blood Press Res. 2020; 45: 363–367.
• 4.   Zelinka  T,  Petrák  O,  Rosa  J,  Holaj  R,  Štrauch  B,  Widimský  J. Primary aldosteronism and pregnancy. Kidney Blood Press Res. 2020; 45: 275–285.
• 5.   Shekhar  S,  Haykal  R,  Kamilaris  C,  Stratakis  CA,  Hannah-Shmouni  F. Curative resection of an aldosteronoma causing primary aldosteronism in the second trimester of pregnancy. Endocrinol Diabetes Metab Case Rep. 2020; 2020: 5.
• 6.   Berberich  AJ,  Penava  D,  Sun  D,  MacDougall  A,  Lum  A,  Van Uum  S. High aldosterone, hypertension and adrenal adenoma in a 36-year-old pregnant patient: Is this primary aldosteronism? Obstet Med. 2020; 13: 88–91.
• 7.   Gunganah  K,  Carpenter  R,  Drake  WM. Eplerenone use in primary aldosteronism during pregnancy. Clin Case Rep. 2016; 4: 8–82.
• 8.   Kilmartin  C,  Opu  T,  Podymow  T,  Dayan  N. Primary hyperaldosteronism presenting as persistent postpartum hypertension: Illustrative case and systematic review. Obstet Med. 2019; 2: 90–95.
• 9.   Riester  A,  Reincke  M. Progress in primary aldosteronism: Mineralocorticoid receptor antagonists and management of primary aldosteronism in pregnancy. Eur J Endocrinol. 2015; 172: R23–R30.
• 10.   Okamura  K,  Matsushima  M,  Yamamoto  F. A patient with bilateral primary aldosteronism refractory to oral eplerenone who responded to esaxerenone with increased renin activity. Am J Case Rep. 2020; 21: 1–7.