Primary hyperaldosteronism presenting as persistent postpartum hypertension: Illustrative case and systematic review

Short abstract

We present a case of persistent postpartum hypertension found to be secondary to primary hyperaldosteronism in a woman with a history of recurrent hypertensive disorders of pregnancy and associated fetal complications. Our systematic review revealed only 18 cases of primary aldosteronism diagnosed in women with postpartum hypertension, suggesting that this disorder is under-studied in the postpartum period. A review of these cases suggests that women with primary hyperaldosteronism commonly present with hypertensive disorders of pregnancy, but may only be identified de novo postpartum. However, a high index of suspicion is needed to diagnose primary hyperaldosteronism in the postpartum period, guided by a woman’s obstetric history.

Background

Hypertension in the postpartum period can occur de novo following a normotensive pregnancy, or as persistent hypertension following a hypertensive disorder of pregnancy.¹ Predisposing factors include chronic hypertension, hypertensive disorders of pregnancy, excess fluid administration at delivery, pain, anxiety, and use of nonsteroidal anti-inflammatories.² Persistent postpartum hypertension (persisting beyond six weeks postpartum in previously normotensive women) occurs more often in women with higher body mass index, smokers, and in those with severe early onset preeclampsia.³ While the prevalence of all hypertensive disorders of pregnancy has been estimated at 5–10%,⁴ considerably less is known about the incidence and prevalence of persistent postpartum hypertension.⁵ As a result, available clinical practice guidelines vary in their recommendations regarding management of persistent postpartum hypertension. The Society of Obstetricians and Gynaecologists of Canada (SOGC) and the American College of Obstetricians and Gynecologists (ACOG) recommend measurement of blood pressure and basic cardiovascular risk assessment for those who remain hypertensive, but does not specify screening for the secondary causes of hypertension.^6,7 In contrast, experts in the UK suggest investigation for the secondary causes of hypertension in all cases of persistent postpartum hypertension,² despite limited evidence for this approach.

Primary hyperaldosteronism (also known as primary aldosteronism or PA) is a neuroendocrine cause of hypertension either due to bilateral adrenal hyperplasia or a hyperfunctioning secretory nodule.⁸ PA was previously thought to be an uncommon cause of hypertension in the general population (<1%).⁸ However, owing to changes in diagnostic testing, recent studies suggest the prevalence of PA may exceed 10% among hypertensive patients, and affect between 5% and 15% of the general population.^8,9

Current knowledge regarding PA during pregnancy and the postpartum period is derived mostly from case reports and case series. It has been documented that pregnancy may unmask previously quiescent hyperaldosteronism, and may be a relatively frequent cause of persistent postpartum hypertension.^10,11 It remains unclear who should be screened for this disorder in the postpartum period and whether the clinical presentation and course of postpartum PA differs from antepartum disease. We report a case of PA diagnosed postpartum in a woman with prior recurrent preeclampsia, and performed a systematic review of PA diagnosed in the postpartum period.

The case

A 38-year-old woman with a history of four previous pregnancies resulting in a live birth, and three previous fetal losses, originally from the Republic of Congo was referred to the postpartum maternal cardiovascular health clinic at our center in Montreal, Canada for the evaluation of persistent postpartum hypertension. Her recent pregnancy was complicated by preeclampsia resulting in delivery at 38 weeks to a healthy girl approximately six weeks prior to her visit.

Obstetric history was notable for severe, recurrent ischemic placental syndromes, and hypertensive disorders of pregnancy. Her first pregnancy took place 15 years prior and was complicated by eclampsia in the Republic of Congo necessitating urgent caesarean delivery. The following three pregnancies resulted in intrauterine fetal demise at 11 weeks, 24 weeks, and 20 weeks, respectively. She subsequently underwent two deliveries at another center in Quebec, Canada that were complicated by prematurity (31 weeks), and preeclampsia at term (38 weeks). Her most recent pregnancy was complicated by gestational hypertension with superimposed preeclampsia necessitating semi-urgent delivery of a healthy female fetus at 38 weeks by repeat caesarean delivery. The patient reported normal blood pressure between pregnancies.

Following the birth of her fourth child, the patient reported frontal tension-type headaches occurring over two months without associated neurological features. She also denied any cardiorespiratory symptoms, although she reported an inactive lifestyle. She denied use of tobacco, alcohol, or illicit substances. At the time of her first visit, she was taking no medication including no nonsteroidal anti-inflammatory drugs. She was breastfeeding exclusively.

On examination, her body mass index was 27.5 kg/m² (weight 74 kg). Automated office blood pressure (BP) average was 147/92 mmHg (BP-Tru™) and pulse was 73 beats per minute and regular. Physical exam revealed a euvolemic patient without signs of structural heart disease, and with normal peripheral pulses. There was no goitre and no features to suggest hypercortisolism. Neurological examination including fundoscopy was normal. Laboratory data were significant for hypokalemia at 3.2 mmol/L, a preserved glomerular filtration rate (creatinine 60 µmol/L), and normal thyroid profile (TSH 0.5 mIU/L). Review of cardiovascular screening revealed a glycosylated haemoglobin 5.5%, total cholesterol 6.15 mmol/L, and LDL 4.43 mmol/L. Screening for anti-phospholipid syndrome was negative.

A 24-hour ambulatory blood pressure monitor (ABPM) confirmed hypertension with mean overall 150/90 mmHg. She was diagnosed with persistent postpartum hypertension and PA was suspected. Potassium supplementation and amlodipine were prescribed while awaiting further investigations.

She returned to clinic one month later. Blood pressure was 150/100 mmHg, and she was noted to have persistent hypokalemia (2.5 mmol/L) due to noncompliance with supplements. Plasma aldosterone levels were 2149 pmol/L and plasma renin was undetectable. She underwent noncontrast abdominal CT adrenal protocol which revealed a right adrenal gland nodule measuring 1 cm × 1.2 cm with pre-contrast density 25 Hounsfield Units (HU), post-contrast enhancement density 81 HU and 39 HU density on the 15-minute delay. The calculated abdominal CT washout was 75% consistent with adrenal adenoma. Measurements of urine metanephrines and cortisol in 24-hour urinary collection were normal. PA was diagnosed, and spironolactone was prescribed and up-titrated with gradual discontinuation of potassium supplementation. Amlodipine was discontinued. She underwent bilateral adrenal vein sampling, which lateralized to the right. A surgical consultation was requested at the adrenal clinic at our center where elective adrenalectomy for a functional adenoma was performed without complication. One year later, she was noted to have improvement in blood pressure, although it was still borderline elevated (130–140/80–90 mmHg on serial office visits and home blood pressure measurements). No further pregnancy was planned.

Systematic review

Methodology

We searched MEDLINE (via Ovid, 1946 to 26/Jan/2017) and Embase (via Ovid, 1947 to 26/Jan/2017) without language restriction for publications, including case reports, case series, case-control, and cohort studies where PA was either suspected or diagnosed in women with postpartum hypertension. Our goal was to characterize the antenatal and postpartum characteristics and outcomes of women who were diagnosed with postpartum PA. The search strategy used text words and relevant indexing to identify studies on PA in pregnancy and postpartum. Publications were assessed for inclusion according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines).¹² Two independent reviewers (CK and TO) screened the abstracts, titles, and full texts. Bias assessment was not performed since the publications included were largely case reports and case series.

Results

Our searched yielded 316 titles and abstracts, of which 14 publications were retrieved for full text review. Eighteen cases of postpartum PA were identified; 16 were documented in case reports^10,13–24 and two were identified in a retrospective cohort study²⁵ (data provided by T Podymow) (Figure 1). Six cases (33%) experienced complications in pregnancy including gestational hypertension (n = 2), preeclampsia (n = 2), small for gestational age (n = 1), or stillbirth (n = 1). However, eight cases (44%) were normotensive during pregnancy and only experienced hypertension in the postpartum period^{10,13,18,19,21} (Table 1). Blood pressure was elevated in the severe range after delivery in all cases. Fifteen cases were noted to have hypokalemia postpartum;^{10,13,15,16,18–25} however, most studies did not report potassium concentration during pregnancy. Aldosterone to renin ratios ranged from 20 to >1400. All but one of the cases were noted to have an adrenal adenoma (one woman had adrenal hyperplasia).¹⁴

Figure 1.

PRISMA flow diagram of the articles selection process.

Table 1.

Characteristics and findings of the studies included in the systematic review.

References	Study type	Number of cases		Timing of presentation	Pregnancy		Postpartum				Diagnosis
					BP	Complications	BP	Potassium	Plasma aldosterone	Plasma renin
Morton21	Case report	1		40th week of gestation	150/110 mmHg	Gestational hypertension and emergency C-section	160/100 mmHg	–	–	–	Bilateral adrenal hyperplasia
Eguchi et al.17	Case report	1		26th week of gestation	177/117 mmHg	Preeclampsia	Elevated	3.8 mEq/L	4 pmol/L	0.2 ng/mL/h	Left adrenal adenoma
Bretherton et al.13	Case report	1		9 days postpartum	<120/80 mmHg	–	200/110 mmHg	3.3 mmol/L	227 pmol/L	<0.10 ng/mL/h	Right adrenal adenoma (1.6 cm)
Krysiak et al.16	Case report	1		20th week gestation	200/110 mmHg	Stillbirth	170/100 mmHg	2.8–3.2 mmol/L	101.4 pmol/L	0.03 ng/mL/h	Bilateral adrenal hyperplasia
Albiger et al.15	Case report	1		26th week of gestation	155/95 mmHg at 28th week of gestation	Gestational hypertension	180/120 mmHg	2.2 mmol/L	14.6 pmol/L	0.2 ng/mL/h	Left adrenal adenoma (2 cm)
Podymow and August25	Retrospective cohort study	2	A	36th week of gestation	110/70 until 36th week	–	160/100 mmHg	3.7 mmol/L	–	–	Left adrenal adenoma (2.3 cm)
			B	Preeclampsia at 35 weeks	Normotensive	Preeclampsia	190/100 mmHg	2.5 mmol/L	–	–	Right adrenal adenoma (1.8 cm)
Nezu et al.10	Case report	2	A	30 days postpartum	110/70 mmHg	–	140–190/90–110 mmHg	2.7 mEq/L	7.9 pmol/L	Low	Right adrenal adenoma (1.7 cm)
			B	18 days postpartum	118/68 mmHg	–	180/110 mmHg	3.2 mEq/L	5 pmol/L	Low	Left adrenal adenoma (1.1 cm)
Murakamiet al.21	Case report	1		Postpartum	Normotensive	–	178/106 mmHg	2.3 mmol/l	1496 pmol/L	<0.1 ng/mL/h	Left adrenal tumor
Wang et al.23	Case report	1		36th week of gestation	150/105 mmHg	Small for gestational age infant	150/105 mmHg	2.72 mmol/L	45.92 ng/dL	–	Right adrenal tumor (5 cm)
Miles et al.26	Case report	1		36th week of gestation	Hypertensive	–	160–180/110–120	2.8 mmol/L	1278 pmol/L	0.1 ng/mL/h	Right adrenal adenoma
Gordon and Tunny19	Case report	2	A	1 month postpartum	Mild hypertension	–	180/110 mmHg	2.2 mEq/L	–	Undetectable	Right adrenal adenoma
			B	7 weeks postpartum	Normotensive	–	150–190/100–110 mmHg	2.2 mEq/L	–	0.002 ng/mL/h	Right adrenal adenoma
Aoi et al.18	Case report	2	A	1 week before delivery	150/100 mmHg		220/110 mmHg	2.0 mEq/L	282 pg/mL	Undetectable	Left adrenal adenoma (1.8 cm)
			B	Near the end of pregnancy	190/100 mmHg		230/130 mmHg	2.3 mEq/L	506 pg/mL	Undetectable	Left adrenal adenoma (1.6 cm)
Aloia and Beutow18	Case report	1		2 months postpartum	Normotensive		2 months postpartum	2.2 mEq/L	4.5 pmol/L	0.02 ng/mL/h	Right adrenal adenoma
Stein22	Case report	1		38th week of gestation	160/100 mmHg		38th week of gestation	2.6 mEq/L	–	–	Right adrenal adenoma 1 cm)

BP: blood pressure

Discussion

PA was previously considered a rare diagnosis among hypertensive individuals.²⁶ Improved screening using the aldosterone-to-renin ratio (ARR) increases the rate of identification by a factor of 10–15, resulting in an estimated prevalence of 15% in hypertensive patients.²⁶ This makes PA the most common treatable secondary cause of hypertension.²⁶ Proper identification and diagnosis is important as surgical resection of secreting adenomas can lead to resolution or marked improvement of hypertension, and a reduced risk for downstream cardiovascular events.²⁷ Current Canadian hypertensive guidelines recommend screening for PA in patients who have spontaneous hypokalemia, as was present in this woman.²⁶ However, the absence of hypokalemia cannot be solely used to rule out a diagnosis of PA. Some reports have found that only 50% of confirmed cases of PA were found to be hypokalemic.²⁸ The American Heart Association report on resistant hypertension indicates that serum potassium levels are not universally low in patients confirmed to have PA, suggesting that hypokalemia is a late manifestation of the disorder.²⁹ Moreover, hypokalemia may be masked in pregnancy.^13,14 This can be explained by the direct natriuretic effect of high progesterone levels during pregnancy acting on the renal proximal tubule and competitive inhibition of aldosterone at the mineralocorticoid receptors in the distal tubules, interrupting the effects of aldosterone.¹³ The withdrawal of circulating progesterone levels towards the end of pregnancy allows the increased aldosterone to act unopposed, thereby precipitating the peri-partum and postpartum presentation of hypertension.¹³ Activating somatic mutations involved in the Wnt cell-differentiation pathway may also play a potential role in PA with worsening in pregnancy.³⁰

The women in our review who were diagnosed with an aldosterone-producing adenoma were identified postpartum. It is common for women to experience a rise in blood pressure in the immediate postpartum period, which can often be attributed to physiologic volume expansion and fluid mobilization, or use of nonsteroidal anti-inflammatory drugs for postpartum analgesia.³¹ Thus, it can be a challenge to suspect a secondary cause of hypertension and to determine who might benefit from dedicated screening for PA. A recent review by Morton et al.¹⁴ acknowledges the variable course of PA during pregnancy and suggests there is a high risk of false negative results of screening throughout pregnancy. In contrast, our review has focused on cases in which a diagnosis was made postpartum, perhaps representing a more reliable time for screening for the secondary causes of hypertension. As demonstrated in this case as well as in our review, a secondary cause of hypertension may underlie some cases of preeclampsia or other ischemic placental syndromes and should be considered especially in the presence of persistent postpartum hypertension. A recent review by Bramham et al.² suggests that consideration of ARR and an in-depth screening for a secondary cause of hypertension should be part of an evaluation for women with a recent pregnancy complicated by an ischemic placental syndrome and who are diagnosed with persistent postpartum hypertension. However, while SOGC as well as ACOG both provide specific detailed recommendations for postpartum evaluation of women who had hypertension in pregnancy and in whom hypertension persists postpartum, neither society comments on the need to screen for PA.^6,7 Use of the ARR to diagnose PA in hypertensive pregnant populations is complex due to physiological changes in serum aldosterone and renin during pregnancy. While aldosterone production increases during pregnancy, the relatively higher increase in renin results in a lowering of the ARR.³² ARR could be measured in hypertensive women up to eight weeks’ gestation, after which time aldosterone levels start to rise. Our results suggest that screening for PA using the ARR could play a greater role in the postpartum period in women with persistent postpartum hypertension. However, given the paucity of literature in this area, further studies are needed before recommending this approach in all women after hypertension in pregnancy.

This case and our review highlight the importance of investigating for secondary causes of hypertension such as PA in women with a history of severe hypertensive disorders of pregnancy. Clinicians should have a high level of suspicion for PA in women with a history of ischemic placental syndromes in pregnancy who have persistent postpartum hypertension. Larger population-based cohort studies of women with postpartum hypertension would clarify the proportion with PA, and evaluation for recently discovered mutations involved in the Wnt adrenocortical cell differentiation pathway in such patients can improve our understanding of this disorder in peripartum women.

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) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical approval

The patient provided written informed consent for her case to be included and published in this report.

Guarantor

ND.

Contributorship

C Kilmartin conceived the study, collected data on the case, conducted the review as first reviewer, and drafted the paper; T Opu conducted the systematic review as second reviewer and revised the paper for important intellectual content; T Podymow provided data for the systematic review and revised the paper for important intellectual content; N Dayan, physician of the patient in this report, conceived of the study, and revised the paper for important intellectual content.