Preeclampsia, Pregnancy, and Hypertension

Renin-Angiotensin-Aldosterone Profiles in Pregnant

Women With Chronic Hypertension
Line Malha, Cristina P. Sison, Geraldine Helseth, Jean E. Sealey, Phyllis August

Abstract —Pregnant women with chronic hypertension are at risk for increased blood pressure and superimposed
preeclampsia (SPE) in late pregnancy. Alterations in the renin-aldosterone system are a feature of normal pregnancy;
however, their role in chronic hypertension with and without SPE is less clear. We performed a prospective, longitudinal
trial of 108 women with chronic hypertension and measured plasma renin activity (PRA), 24-hour urine sodium, urine
potassium, and urine aldosterone (Ualdo) at 12, 20, 28, and 36 weeks and postpartum. SPE developed in 34% of
pregnancies. PRA was lower in women who developed SPE at weeks 28 (5.99 versus 6.22 ng/mL per hour; P<0.001)
and 36 (5.71 versus 7.74 ng/mL per hour; P=0.002). Ualdo was lower in women with SPE compared with those without
SPE at 28 weeks (59.6 versus 81.3 μg/d; P=0.039). Mean arterial pressure was inversely related to both PRA (r=−0.23;
P<0.0001) and Ualdo (r=−0.11; P=0.029). PRA and Ualdo were positively associated with each other (r=0.5327;
P<0.0001) after adjusting for urine potassium, urine sodium, serum potassium, and mean arterial pressure. PRA and
Ualdo were lower in women of black race compared with other racial groups (P<0.001). Our results demonstrate that in
women with chronic hypertension PRA and Ualdo increase in early pregnancy and subsequently decrease in women who
develop SPE. These findings are consistent with the hypothesis that sodium retention may contribute to the elevation
in blood pressure in SPE.  (Hypertension. 2018;72:417-424. DOI: 10.1161/HYPERTENSIONAHA.118.10854.) •
Online Data Supplement
Key Words: aldosterone ◼ hypertension ◼ preeclampsia ◼ pregnancy ◼ renin-angiotensin system

A pproximately 1.8% of all pregnancies1 are affected by

chronic hypertension (cHTN) defined as hypertension
aldosterone (Ualdo) are lower when SPE develops,9 simi-
lar to what has been observed in normotensive women who
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detected before 20 weeks of gestation or predating pregnancy.2
The risk for significant maternal and fetal morbidity and death
is increased in women with cHTN and is in part related to the
severity of maternal hypertension. Although some women with
preexisting hypertension experience a decrease in blood pres-
sure (BP) during pregnancy, the risk for superimposed pre-
eclampsia (SPE)3–5 is increased 5-fold, which amplifies the risk
of adverse outcomes. BP regulation during pregnancy is not
fully understood. Vasodilation and lower BP may be caused by
hormonally mediated increases in nitric oxide, accompanied
by resistance to the vascular effects of angiotensin II. All com-
ponents of the renin-angiotensin-aldosterone system (RAAS)
are elevated beginning in early pregnancy, likely in response
to vasodilation and lower BP.6 These changes have been most
often studied in normotensive women, with only few investiga-
tions in women with cHTN with or without SPE.7–9 Although
most studies report elevated plasma renin activity (PRA) and
aldosterone in pregnancy, there is controversy about the factors
that are responsible for these changes.
We previously studied 29 women with cHTN and reported
that the RAAS is upregulated and that PRA and 24-hour urine
develop PE.10–12 We report here a larger study of the RAAS in
110 women with cHTN with and without preeclampsia and
include measurements of BP, as well as serum and urine elec-
trolytes, to further clarify the basis for the alterations in BP,
PRA, and aldosterone in chronic hypertensive pregnancy.
Methods
The data that support the findings of this study are available from the
corresponding author on reasonable request.
Subjects
Clinical data, venous blood, and 24-hour urine were collected as
part of the Chronic Hypertension in Pregnancy Study, a placebo-
controlled, double-blinded, randomized trial of calcium for the
prevention of SPE in women with preexisting cHTN performed at
New York Presbyterian-Weill Cornell, the trial concluded in 2000.
The study protocol was approved by the institutional review board at
Weill-Cornell Medical College, and informed consent was obtained
at the initial visit.13,14 Additional institutional review board approval
was obtained for the analyses performed for this report. The data that
support the findings of this study are available from the correspond-
ing author on reasonable request. Eligible women were 18 to 45 years
old who were 12 to 15 weeks pregnant at the time of screening and

Received January 11, 2018; first decision February 8, 2018; revision accepted May 29, 2018.
From the Nephrology and Hypertension Division (L.M., G.H., P.A.) and Department of Medicine (J.E.S.), Weill-Cornell Medicine, New York, NY;
and Biostatistics Unit, Feinstein Institute for Medical Research, Hofstra Northwell School of Medicine, North Shore University Hospital, Manhasset, NY
(C.P.S.).
The online-only Data Supplement is available with this article at https://www.ahajournals.org/journal/hyp/doi/suppl/10.1161/HYPERTENSIONAHA.
118.10854.
Correspondence to Line Malha, Nephrology and Hypertension Division, Weill-Cornell Medicine, 424 E 70th St, New York, NY 10021. E-mail lim9120@
med.cornell.edu
© 2018 American Heart Association, Inc.
Hypertension is available at https://www.ahajournals.org/journal/hyp DOI: 10.1161/HYPERTENSIONAHA.118.10854

417
 418  Hypertension   August 2018
had cHTN, defined as a BP ≥140/90 mm Hg (on ≥2 separate mea-
surements) or being on pharmacological therapy for cHTN before 20
weeks of gestation or preceding pregnancy. Women with white-coat
hypertension based on normal home BP readings were not eligible.
Women with a serum creatinine ≥1.2 mg/dL or a creatinine clearance
<75 m/min, a history of calcium metabolism disorder, a diagnosis of
secondary hypertension, a history of nephrolithiasis, or on chronic
diuretic therapy were excluded.
Study Protocol
Study subjects were randomly allocated to treatment with either
calcium carbonate (2 g daily) or placebo. The baseline study visit
conducted at 12 to 15 weeks of gestation included an evaluation of
medical history, weight, height, heart rate, and BP. Venous blood was
collected for measurement of electrolytes and PRA, and 24-hour
urine was obtained for measurement of creatinine, aldosterone,
protein, sodium, and potassium. BP was measured according to the
American Heart Association criteria15 and was determined as the
average of 3 consecutive measurements that were assessed in a seated
position after a 5-minute rest period. All measurements were made
by 1 observer.
Patients were followed every 4 weeks or more frequently if clini-
cal condition warranted. Laboratory testing was performed at base-
line, 20, 28, 36 weeks of gestation and at 6 weeks postpartum. The
data characterizing BP, RAAS profiles, blood, and urine electrolytes
have not been previously published.
Participants were treated with antihypertensive medications to
maintain their BP at a goal of 140 to 150 mm Hg systolic and 90 to
100 mm Hg diastolic.13 Treatment included methyldopa, labetalol, or
long-acting nifedipine. Medication initiation and titration was man-
aged by the principal investigator for the study.
Pregnancy outcomes (diagnoses) were ascertained after delivery
by the primary investigator as SPE or No SPE after review of the
participant’s chart. There are no unanimously accepted criteria to
define SPE. In accordance with The National High Blood Pressure
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Education Program Working Group on High Blood Pressure in
Pregnancy3 guidelines and our previous studies,14 we diagnosed
SPE after 20 weeks gestation when there was an increase in BP ≥30
mm Hg systolic and 15 mm Hg diastolic compared with baseline, in
association with new-onset proteinuria (either 300 mg per 24 hours
or ≥2+ by dipstick on ≥2 occasions). If proteinuria was present at
baseline, SPE was diagnosed if there was doubling of urinary protein
excretion after 20 weeks’ gestation in association with a significant
increase in BP. Women without increased proteinuria were diagnosed
with SPE if BP was elevated and in association with elevated liver
enzymes (2× baseline) and a low platelet count (<100 000/µL).14
Blood for PRA was drawn into tripotassium ethylenediaminetet-
raacetic acid Vacutainer blood collection tubes (Becton-Dickinson,
Rutherford, NJ) and processed at room temperature to avoid cryoacti-
vation of prorenin.16 Plasma was stored at −40°C and assayed within
2 days of collection by an enzymatic radioimmunoassay in which the
angiotensin I generated at 37°C from endogenous angiotensinogen in
the presence of converting enzyme and angiotensinase inhibitors was
quantified by radioimmunoassay. Results are expressed as nanograms
of angiotensin I per milliliter per hour. The interassay coefficient of
variation for our in-house PRA assay was 7.6%.
Ualdo was measured after acid hydrolysis of the 3-oxo-conjugate.
The aldosterone formed was then measured with Coat-a-Count al-
dosterone kit (Diagnostic Products, LA).17 The assay was validated
for use in pregnancy by showing that separation of aldosterone from
other steroids by chromatography did not reduce the reported values.
The Ualdo assay had an interassay variability of 12.8%. Twenty-four-
hour Ualdo was measured rather than plasma aldosterone as it reflects
the overall aldosterone production for the day while canceling out the
minute-to-minute variations in plasma aldosterone that can be attrib-
uted to posture, recent salt intake, and circadian rhythm.18
Statistical Analysis
All of the statistical analyses were performed using SAS version 9.3
(SAS Institute, Cary, NC). Continuous variables were summarized
using basic descriptive statistics, such as means, SDs, medians,
quartiles, minimums and maximums, and comparisons between
groups were made using either the Student t test or Mann-Whitney
test, as appropriate for 2-group comparisons and either ANOVA or
Kruskal-Wallis test as appropriate, for multiple group comparisons.
Categorical variables were compared using either the χ2 or Fisher
exact test where appropriate.
We examined the correlations between PRA and Ualdo to deter-
mine whether, within subjects, changes in PRA were associated with
changes in Ualdo over time. We used the ANCOVA methods of Bland
and Altman,19 which allows for the computation of within-subjects
correlations where the pairs of outcome variables are collected as re-
peated measurements. We adjusted for gestational age, 24-hour urine
potassium, 24-hour urine sodium, serum potassium, and mean arterial
pressure (MAP).
A mixed models approach to repeated measures ANOVA was
used to determine whether there was a difference in levels of PRA
between diagnosis group (SPE versus No SPE) and across gestational
ages; the interaction of diagnosis group and gestational age was in-
cluded in the model to examine whether the patterns of change in
levels of PRA differed across visit weeks according to final diagnosis.
A similar analysis was performed separately for Ualdo. Bonferroni-
adjusted pairwise comparisons were applied as necessary to adjust for
multiple comparisons.
Data transformations were applied when the model assumptions
were not met. The log transformation was found to be appropriate
in the analysis for PRA, and therefore, all analysis was performed
using the log-transformed values of PRA; however, results are re-
ported in the original untransformed units for ease of interpretation.
For Ualdo, no data transformations were found to be necessary.
Results
Study Participants
One hundred sixteen pregnancies were included in the
Chronic Hypertension in Pregnancy Study. For this analysis,
we excluded 6 pregnancies that were lost to follow-up and
did not have documented delivery outcomes. An additional
patient was excluded who was diagnosed with primary hyper-
aldosteronism, and another patient was excluded because of
persistent nephrotic syndrome (which may indicate underly-
ing chronic kidney disease). A total of 108 pregnancies were
included in our analysis. The mean±SD age was 33±5.6
years, ranging from 20 to 47 years, 40% were black, and 43%
(47/108) were primiparous. Thirty-two percent (19/60) of
multiparous women had a history of SPE in a prior pregnancy.
Pregnancy Outcomes
Thirty-seven women (34%) developed SPE, whereas 71 did
not. All women with SPE had a significant increase (30/15
mm Hg) in BP.3 Serum uric acid and 24-hour urine protein
excretion was significantly higher in the SPE group at weeks
28 and 36 of gestation (P<0.001; further detailed in Table S1
in the online-only Data Supplement). Eight out of 37 women
diagnosed with SPE did not have proteinuric SPE, whereas 29
of 37 had proteinuric SPE. Women without proteinuric SPE
were diagnosed on the basis of an abrupt increase in BP in
association with other laboratory abnormalities (elevated liver
enzymes, low platelets). Baseline characteristics of those with
and without SPE were similar except for a higher prevalence
of previous SPE in women who developed SPE in the current
pregnancy (Table). Forty-one women (38%) were on antihy-
pertensive medication during the first trimester of pregnancy
and 54 (50%) used antihypertensive medication during their
 Malha et al   RAAS in Pregnancies With Chronic Hypertension   419

Table.  Baseline Clinical Characteristics in Women With Chronic Hypertension With and Without Superimposed Preeclampsia

Diagnostic Group
Entire Cohort No SPE SPE
(N=108) (N=71) (N=37) P Value
Characteristic, unit n/N (%) or mean±SD
Age, y 33.0±5.6 33.1±5.7 32.8±5.3 NS
Women of black race 43/108 (40) 29/71 (41) 14/37 (38) NS
Previous preeclampsia 20/64 (31.2) 8/39 (20.5) 12/25 (48.0) 0.028
Primiparous 47/108 (43.5) 33/71 (46.5) 14/37 (37.8) NS
On a β-blocker 20/108 (18.5) 10/71(14.1) 10/37 (27.0) 0.121
On methyldopa 34/108 (31.5) 18/71 (25.4) 16/37 (43.2) 0.080
On ≥1 antihypertensive 41/108 (38.0) 24/71 (33.8) 17/37 (46.0) 0.30
Body mass index, kg/m 2
31.6±8.3 30.7±7.7 33.4±9.1 NS
Systolic blood pressure, mm Hg 128±12 127±12 130±12 NS
Diastolic blood pressure, mm Hg 81±10 81±10 82±10 NS
Creatinine, mg/dL 0.69±0.18 0.67±0.19 0.72±0.17 NS
Creatinine clearance, mL/min 151±46 155±44 144±50 NS
Proteinuria, mg/d 357.9±1033.7 405.2±1260.0 264.6±218.8 NS
Family history of preeclampsia 4/46 (8.7) 3/30 (10.0) 1/16 (6.3) NS
Family history of hypertension 85/106 (80.2) 59/69 (85.5) 26/37 (70.3) NS
P value was calculated using the Mann-Whitney U test for continuous variables and by Fisher exact test for categorical variables.
P<0.05 considered significant. NS indicates nonsignificant; and SPE, superimposed preeclampsia. That is, P value ≥0.05.
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pregnancy. At baseline, more women were on antihyperten-
sives in the SPE group (17/37; 46.0%) compared with the No
SPE group (24/71; 33.8% but this difference was not statisti-
cally significant P=0.30). Both SPE and No SPE groups also
had similar office BPs at their initial visit. Among women
who were on antihypertensives, those who later developed
SPE were on a higher number of medications than women
who did not develop SPE at baseline (P≤0.03). The analysis
of antihypertensive medications use is presented in Table S2.
Women with SPE delivered earlier (gestational age at delivery,
34.5±5.0 versus 37.5±4.0 weeks; P<0.001). Women with SPE
had lower birthweight infants (2435±885 versus 3034±745 g;
P<0.001), and higher cesarean section rates (69% versus 41%;
P=0.009) compared with those without SPE (Table S3).
Longitudinal Profiles of MAP, the RAAS, and
Serum and Urine Electrolytes
MAP was significantly higher in women who developed SPE,
starting at 20 weeks of gestation (P<0.001; Figure 1A). MAP
was not significantly different between the groups in early
pregnancy and in the postpartum period.
The change in PRA throughout pregnancy differed in
women with and without SPE (P=0.028). PRA increased
from baseline to week 20 and was similar in both groups
(Figure 1B). At week 28, PRA decreased in the SPE group,
whereas it continued to increase in women without SPE.
Thirty out of 34 patients had a PRA measured at 28 weeks
at least 2 to 3 weeks before preeclampsia being diagnosed.
PRA was significantly lower in women who developed SPE
at week 28 (5.99±2.88 versus 6.22±3.00 ng/mL per hour;
P<0.001) and at week 36 (5.71±3.23 versus 7.74±6.10 ng/mL
per hour; P=0.002). PRA levels later decreased at the end of
pregnancy in both groups. PRA was similar in both groups 6
weeks postpartum.
There was some heterogeneity in the longitudinal changes
in PRA in women with and without SPE. In women without
SPE, 39 of 61 had a significant increase in PRA from 20 to
28 weeks, whereas 21 of 61 had a small decrease and 1 had a
stable PRA. In contrast, in the SPE group, more women had a
decrease in PRA (17/31) and fewer had an increase.
Twenty-four-hour Ualdo levels appeared consistently
higher in women who did not develop SPE compared with
those who did and were parallel to each other throughout
gestation. Ualdo increased throughout pregnancy in women
with and without SPE and mixed model analysis demon-
strated a significant time effect (P<0.0001) but no significant
difference between final diagnosis groups (P<0.0599). The
mixed model analysis also did not reveal a statistically sig-
nificant difference in the pattern of change in Ualdo over time
between the 2 groups (interaction effect P=0.30; Figure 1C).
Ualdo was higher at weeks 28 and 36 compared with week
12 (P<0.0001). Ualdo was also significantly higher at, each
subsequent time point compared with the previous values
(P<0.0001). When levels at specific time points were com-
pared between women with and without SPE, Ualdo at 28
weeks was significantly lower in women with SPE compared
with No SPE (59.6±49.9 versus 81.3±57.9 μg/d; P=0.039 by
Mann-Whitney U).
 420  Hypertension   August 2018

Figure 1.  Plasma renin activity (PRA) and 24-hour urine aldosterone (U aldo) during pregnancy in women with chronic hypertension who develop
superimposed preeclampsia (SPE) and who do not develop SPE. Mean arterial pressure (MAP) and renin-angiotensin-aldosterone system (RAAS) profiles
were studied in 108 women with chronic hypertension in pregnancy. A, displays the mean MAP (in mm Hg) in women who develop SPE group in red and
in women who do not develop SPE (No SPE group). B, The mean PRA (in ng/mL per hour) for the SPE group (in red) and for the No SPE group (in blue). C,
The mean U aldo (in μg/d) for the SPE group (in red) and for the No SPE group (in blue). The 95% confidence interval is represented by error bars. A mixed
models approach to repeated measures ANOVA was used to compare longitudinally logPRA and Ualdo across diagnostic groups. MAP was compared
across diagnostic groups using Mann-Whitney U testing. Bonferroni-adjusted pairwise comparisons are applied so that P value <0.008 between both group
is considered to be statistically significant and is denoted by an asterisk (*). P value <0.001 is denoted by (**).

An additional mixed model analysis of both PRA and The ratio of Ualdo/PRA was similar in women with and
Ualdo was performed, adjusting for the use of β-blockers and without SPE throughout most of pregnancy and pairwise
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methyldopa, and the results for both PRA and Ualdo remained comparisons failed to demonstrate a significant difference
unchanged, suggesting that the patterns of change in PRA and between SPE and No SPE at the different time points in preg-
Ualdo were not affected by use of medications that may affect nancy. The Ualdo/PRA ratio was significantly higher in the
the RAAS (Table S2). SPE compared with the No SPE group only at the postpartum

Figure 2.  Longitudinal levels of serum potassium, serum uric acid, urine sodium, and urine potassium in pregnancy in women with chronic hypertension.
Gestational age is depicted on the x axis. Mean values are represented on the y axis. The variable is color coded with units detailed in the legend. A, The
levels of serum uric acid (in orange) and serum potassium (in green) through pregnancy. B, The levels of urine sodium (in orange) and urine potassium (in
green) through pregnancy.
 Malha et al   RAAS in Pregnancies With Chronic Hypertension   421

Figure 3.  Renin-angiotensin-aldosterone system profiles in women with chronic hypertension in pregnancy. A, The mean plasma renin activity (PRA in ng/
mL per hour) in women from black racial background (in black) when compared with women from racial backgrounds other than black (in gray). The patterns
of change in PRA are not statistically different; however, PRA levels are consistently lower in the black race group (P<0.0001) by mixed model analysis, which
adjusts for multiple measurements and gestational age. B, The mean urine aldosterone (Ualdo; 24-h aldosterone urinary excretion in μg/d) for the other
than black racial group (in gray) and for the black racial group (in black). Patterns of change in Ualdo are not statistically different; however, Ualdo levels are
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consistently lower in the black race group (P<0.0003) by mixed model analysis. The 95% confidence interval is represented by error bars.

visit (22.0 versus 12.7; P<0.02). Serum potassium, fractional
excretion of potassium, 24-hour urine excretion of potassium
and sodium were stable throughout pregnancy (Figure 2) and
were similar in SPE and No SPE (Table S1).
We compared RAAS profiles in black and nonblack women
(Figure 3). The patterns of change in PRA and Ualdo were not
significantly different between race groups (P<0.607), and the
PRA levels did not differ significantly over time (P<0.456).
Despite a similar pattern of change, we found that PRA was
consistently lower throughout pregnancy in black women
compared with other groups (white, Hispanic, and Asian;
P<0.0001). Ualdo was also consistently lower in black women
(P<0.0003). Levels increased throughout pregnancy with a
similar pattern to what was found in the entire cohort.
Fetal outcomes are shown in Table S3. There were 5 small
for gestational age (with birthweight below the 10th percentile
for gestational age) infants, all in the SPE group (Table S3).
The mean maternal PRA decreased in all 5 women from 20
to 28 weeks (mean decrease, 2.1 ng/mL per hour). The mean
PRA was 4.19 and 2.04 ng/mL per hour, respectively, at 20
and 28 weeks and was lower than women without small for
gestational age infants. This observation is consistent with
previous reports that low PRA (unadjusted) is associated with
poor fetal outcomes, including low birth weight.20,21
MAP was inversely related to both PRA (r=−0.23;
P<0.0001) and Ualdo (r=−0.11; P=0.029). As expected, PRA
and Ualdo were significantly and positively associated with
each other (r=0.5327; P<0.0001) after adjusting for urine
potassium, urine sodium, serum potassium, and MAP.
We performed a multivariable analysis to determine signifi-
cant predictors of PRA and Ualdo, separately, during gestation
(ie, excluding postpartum) while adjusting for diagnosis (SPE
and No SPE), MAP, urine sodium, urine potassium, serum K, and
PRA or Ualdo, respectively (Figure 4). Both Ualdo (P<0.0001)
and nonblack race (P<0.0002) were positively associated with
PRA. Gestational age (P<0.0001), PRA (P<0.0001), urine potas-
sium (P<0.0001), and urine sodium (P<0.0005) were significant
predictors of Ualdo excretion. For every unit (in ng/mL per hour)
increase in PRA, there was a 2.41 μg/d increase in Ualdo.
Discussion
Striking alterations in the renin-angiotensin system in preg-
nancy are well documented; however, their significance
remains controversial. The lower BP, apparent in early preg-
nancy, along with increased cardiac output, renal blood flow,
and glomerular filtration rate22 suggest to us that the basis for
the stimulated RAAS in pregnancy is generalized vasodila-
tion resulting in baroreceptor mediated increased maternal
renal renin secretion. This study confirms our prior report9
and shows that when BP increases in pregnant women with
cHTN who develop SPE, either in the second or third trimester,
PRA and Ualdo excretion both decrease, suggesting that pri-
mary stimulation of the RAAS is not the cause of preeclamp-
tic hypertension. The high incidence of SPE reported in our
 422  Hypertension   August 2018

A B

Figure 4.  Multivariable modeling of plasma renin activity (PRA) and 24-h urine aldosterone (Ualdo) excretion in pregnancies affected by chronic hypertension.
A, A multivariable model was performed using PRA as the dependent the variable and the following covariates: 24-h Ualdo, urine potassium (UK), urine sodium
(UNa), serum potassium (serum K), mean arterial pressure (MAP), gestational age, black race (when compared with other racial groups), and superimposed
preeclampsia (SPE). The variables in the green circles were associated with an increase in PRA, whereas the red circles were associated with a decrease in PRA. B,
A multivariable model was performed using 24-h Ualdo as the dependent the variable and the following covariates: PRA, UK, UNa, serum K, MAP, gestational age,
black race (when compared with other racial groups), and SPE. The variables in green circles were associated with an increase in Ualdo, whereas those in red circles
were associated with a decrease in Ualdo. Circles and arrows drawn with a solid line represent statistically significant effects (P value <0.05), whereas circles and
arrows drawn with broken lines represent effects that are not statistically significant (P value ≥0.05). The numbers represent the numeric effect of the variable on PRA
(A) or Ualdo (B). For example, an increase in 1 μg/d in Ualdo is associated with a 0.02 ng/mL per hour increase in PRA.
Downloaded from http://ahajournals.org by on March 17, 2019

study is attributed to a referral bias as our participants were all
patients at a specialized hypertension center. Nevertheless, a
similar suppression of the RAAS has also been described in
women who were normotensive during most of their pregnancy
and then develop preeclampsia.8,10,11,23,24 The increases in BP in
women with either preeclampsia or SPE have been attributed
to endothelial dysfunction with decreases in vasodilatory fac-
tors, such as nitric oxide, prostacyclin, and VEGF (vascular
endothelial growth factor), and increases in vasoconstrictors,
such as endothelin.25 Our finding that both PRA and Ualdo lev-
els are suppressed when SPE develops is consistent with the
notion that preeclamptic hypertension may also be associated
with decreased sodium excretion and volume expansion. This
mechanism of BP elevation may be similar to the hypertension
observed in patients with glomerulonephritis and nephrotic
syndrome.26,27 Evidence that both urinary plasminogen and
plasmin levels are increased in women with preeclampsia, pos-
sibly resulting in activation of ENaC (epithelial sodium chan-
nel)28–31 is particularly intriguing and consistent with a role of
excess sodium volume in preeclamptic hypertension.
Surprisingly, plasma volume, which is difficult to accu-
rately measure in women, has been reported to be decreased in
women with preeclampsia and has been attributed to an increase
in vascular permeability and increased interstitial volume.32–34
However, the findings of increased atrial natriuretic factor and
increased NT-proBNP (N-terminal pro-B-type natriuretic pep-
tide) in preeclampsia35 are more suggestive of an overfilled,
rather than an underfilled circulation. Our study did not involve
plasma volume monitoring or NT-proBNP measurement;
however, the decrease in PRA seen in women with SPE is also
consistent with an increased effective arterial blood volume sta-
tus as perceived by the RAAS. Other studies have suggested
additional, mechanisms for decreased RAAS profiles associ-
ated with preeclampsia, including impaired VEGF-mediated
stimulation of aldosterone synthase because of increases in
sFlt-1 (soluble fms-like tyrosine kinase 1).36 VEGF blockade
has also been reported to decrease renal renin secretion.37
There is some disagreement on the basis for the changes in
the RAAS in preeclampsia. Wu et al38,39 report a dissociation
between renin and aldosterone when preeclampsia develops.23,35
Some suggest that lower renin and aldosterone is a primary event
in women with preeclampsia and that this causes sodium leak-
ing24 and decreased plasma volume. We suggest that based on
our findings, the RAAS is responding appropriately and physi-
ologically to primary increased vasoconstriction and sodium
reabsorption. It is worth pointing out that, despite the stimulation
of the RAAS in pregnancy, and the suppression with preeclamp-
sia, serum potassium levels were remarkably constant suggest-
ing that a primary disturbance in the RAAS is not the cause of
preeclamptic hypertension. Furthermore, our findings of a con-
stant Ualdo/PRA ratio, a consistent positive association between
PRA and Ualdo, and an inverse relationship between BP and
both PRA and Ualdo are consistent with this notion.
Our study has limitations. The collection of specimens in
this study was protocol driven, and in some women, blood and
urine were obtained from 2 to 4 weeks before the development
of preeclampsia, whereas in others, specimens were obtained
closer to the time of diagnosis.
 Malha et al   RAAS in Pregnancies With Chronic Hypertension   423
Although our subjects were not on a fixed sodium intake,
24-hour urine excretion was similar in women with and with-
out SPE, suggesting that differences in dietary sodium were
not the main cause of the differences in RAAS profiles.
Antihypertensive medication, such as β-blockers, may sup-
press PRA; however, our analysis of medication suggests that
differential use of β-blockers was not responsible for the sup-
pressed PRA in women with SPE.
In conclusion, longitudinal profiling of the RAAS in
women with cHTN demonstrates elevated PRA and Ualdo
beginning in the first trimester, and remaining elevated
unless SPE develops. These alterations are associated with
normal levels of serum potassium and stable urinary elec-
trolyte excretion, consistent with the notion that the stimu-
lated RAAS in pregnancy is an appropriate physiological
response to early pregnancy vasodilation, lower BP, and
possible transient underfilling of the circulation. Finally, the
basis for the lower levels of PRA and Ualdo in black com-
pared with nonblack pregnant women are consistent with
reports in nonpregnant individuals in whom lower PRA and
increased prevalence of salt sensitivity are observed40 but
remain poorly understood.
Perspectives
Women with preexisting or cHTN are at risk for consider-
able morbidity during pregnancy because of accelerating
hypertension and the development of preeclampsia. Our study
addresses the longitudinal alterations in the RAAS and serum
and urine electrolytes during pregnancy in women with cHTN
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with and without SPE and sheds light on the pathogenesis of
hypertension in pregnancy. Whether the suppressed RAAS in
women with SPE is because of primary renal vasoconstric-
tion, or primary renal sodium retention mediated by plasmin
induced stimulation of ENaC,28–31 is worthy of further study.
Our data suggest that a second-trimester decrease in PRA
(compared with first trimester) in a woman with rising BP and
signs of preeclampsia may provide additional support for the
diagnosis of SPE. Our study is the first report, to our knowl-
edge, of lower PRA and Ualdo throughout pregnancy in black
women compared with other racial groups.
Sources of Funding
This work was partly supported by the National Institutes of Health
grant R01 HL 488-46 (PI: P. August) and by the Brodsky Family
Foundation.
Disclosures
None.
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Novelty and Significance
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gitudinally through pregnancy in women with hypertension in pregnancy
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• Starting at 28 weeks of gestation, plasma renin activity is significantly
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with women without superimposed preeclampsia.
• Urine aldosterone is lower during pregnancy in women who develop su-
perimposed preeclampsia compared with women without superimposed
preeclampsia, but difference is not statistically significant.
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What Is Relevant?
• As described in normotensive pregnancies, the renin-angiotensin-­
aldosterone system is stimulated during pregnancy in women with
chronic hypertension.
• Superimposed preeclampsia is associated with a low renin state during
pregnancy in women with chronic hypertension.
• The renin-aldosterone system responds to physiological stimuli during
pregnancy (mean arterial pressure, renin, and aldosterone levels).
Summary
More mechanistic studies to explain the low renin state and vol-
ume retention in preeclampsia and in women of black race are
warranted.