Prognostic Significance of Serum Uric Acid in Women With Gestational Hypertension

Gianni Bellomo, Sandro Venanzi, Paolo Saronio, Claudio Verdura and Pier Luca Narducci
Hypertension. 2011;58:704-708; originally published online August 29, 2011;
doi: 10.1161/HYPERTENSIONAHA.111.177212
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Pregnancy/Preeclampsia
Prognostic Significance of Serum Uric Acid in Women With
Gestational Hypertension
Gianni Bellomo, Sandro Venanzi, Paolo Saronio, Claudio Verdura, Pier Luca Narducci
See Editorial Commentary, pp 548 549
AbstractAim of our study was to ascertain, prospectively, whether serum uric acid is a suitable predictor of preeclampsia
and/or the delivery of small-for-gestational-age infants in women with gestational hypertension. We screened 206
primiparas, with a singleton pregnancy, referred for recent onset of hypertension. At presentation, we measured serum
uric acid, creatinine, blood glucose, hemoglobin and platelet level, and 24-hour proteinuria, as well as office and 24-hour
blood pressures. We followed the women until 1 month after delivery and recorded pregnancy outcome. After logistic
regression analysis, uric acid resulted a significant predictor of preeclampsia, with an unadjusted odds ratio of 9.1 (95%
CI: 4.8 to 17.4; P0.001); after adjustment for age, gestation week, hemoglobin and platelet levels, serum creatinine,
office and 24-hour average systolic and diastolic blood pressures, it was 7.1 (95% CI: 3.2 to 15.7; P0.001). Regarding
the association between maternal serum uric acid and the chance of giving birth to a small-for-gestational-age infant,
the unadjusted odds ratio was 1.7 (95% CI: 1.4 to 2.2; P0.001), and it was 1.6 (95% CI: 1.1 to 2.4; P0.02) after
adjustment. Receiver operating characteristic analysis showed that serum uric acid, at a 309-mol/L cutoff, predicted
the development of preeclampsia (area under the curve: 0.955), with 87.7% sensitivity and 93.3% specificity, and the
delivery of small-for-gestational-age infants (area under the curve: 0.784) with 83.7% sensitivity and 71.7% specificity.
In conclusion, the results of our study show that serum uric acid is a reliable predictor of preeclampsia in women referred
for gestational hypertension. (Hypertension. 2011;58:704-708.)
Key Words: uric acid preeclampsia gestational hypertension blood pressure small for gestation age
ypertensive disorders complicate 2% to 10% of all
pregnancies.1,2 Among these, preeclampsia remains one
of the largest single causes of maternal and fetal mortality and
morbidity, whereas uncomplicated gestational hypertension
carries a far better prognosis. Clinical prediction of preeclampsia may facilitate initiation of timely management to
avert mortality and morbidity in the mother and infant. Raised
serum uric acid (UA) is one of the characteristic findings in
preeclampsia. In clinical practice, serum UA determination is
considered to be a part of the workup in women with
preeclampsia to monitor disease severity and aid management
of these women. The association between raised serum UA
and preeclamptic pregnancies was first reported almost a
century ago.3 Reduced UA clearance secondary to reduced
glomerular filtration rate, increased reabsorption, and decreased secretion may be at the origin of elevated serum
levels in women with preeclampsia.4,5 Several studies have
reported a positive correlation between elevated maternal
serum UA and adverse maternal and fetal outcomes.6 10 A
number of studies1115 have evaluated several tests and
parameters, including UA, during the first or second trimester

of pregnancy, as potential predictors of preeclampsia, with

mixed results, and generally with unsatisfactory sensitivity
and/or specificity. In this study, we have chosen to restrict our
analysis to pregnant women referred to our unit for suspected
hypertension to evaluate the prognostic value of serum UA
for the subsequent development of preeclampsia and for
giving birth to a small-for-gestational-age (SGA) infant, thus
allowing us to identify the subgroup of hypertensive women
at greater risk, necessitating of closer monitoring and
surveillance.

Patients and Methods

Between July 2008 and July 2010, after obtaining their consent, we
screened 206 nulliparous women submitted to our unit for suspected
hypertension during pregnancy. Inclusion criteria were age 18
years, singleton pregnancy beyond the 20th week, blood pressure
(BP) 140 mm Hg systolic or 90 mm Hg diastolic, and 24-hour
proteinuria 300 mg. Known heart disease, nephropathy, or hypertension preceding pregnancy were reasons for exclusion from the
study.
None of the subjects were treated with antihypertensive drugs on
entry. As the patients entered the study, BP was obtained on 2
separate occasions, 6 hours apart, in a quiet environment with the

Received May 30, 2011; first decision June 19, 2011; revision accepted August 5, 2011.
From the Departments of Nephrology and Obstetrics and Gynecology, San Giovanni Battista Hospital, Foligno, Italy.
Correspondence to Gianni Bellomo, Department of Nephrology, San Giovanni Battista Hospital, via Arcamone,1, 06034 Foligno(Pg), Italy. E-mail
assidial@tin.it
2011 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org

DOI: 10.1161/HYPERTENSIONAHA.111.177212

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by guest on November 14, 2014
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Bellomo et al
Table 1.

Uric Acid in Gestational Hypertension

705

Demographic, Laboratory, Blood Pressure, and Perinatal Parameters of the Subjects Studied
All
(n163)

Gestational
Hypertension (n90)

Preeclampsia
(n73)

P Preeclampsia
vs Gestational
Hypertension

Age, y

30.44.1

31.75.2

28.84.6

0.001

Gestation wk at inclusion

34.43.0

34.52.9

34.22.9

0.3

BMI, kg/m2

24.32.9

24.63.0

24.02.7

0.22

Hemoglobin, g/L

11413

11213

11811

0.002

Platelets, 1000/mm

19555

21651

17048

0.001

Glycemia, mmol/L

4.40.7

4.40.7

4.30.6

0.21

Creatinine, mol/L

69.915.7

63.37.8

78.118.9

0.001

UA, mol/L

297101

23248

39377

0.001

First-trimester UA, mol/L

19618

20219

19023

0.18

Proteinuria, mg/24 h

10476

8846

12284

0.001

Gestation wk at delivery

38.72.3

39.60.9

37.62.9

0.001

Neonatal birth weight, g

3060740

3397447

2645819

0.001

27.6

9.0

47.9

0.001

613139

66890

542158

0.001

28.8

23.3

35.6

0.09

Parameter
Demographic and laboratory parameters

Perinatal parameters

SGA, %
Placental weight, g
Apgar score, 1 min (% 10)
Cesarean section, %

39.0

32.0

48.0

0.03

Length of hospital stay, newborn, d

10.713.8

5.73.1

16.614.5

0.001

Length of hospital stay, mother, d

6.63.3

5.41.9

8.83.9

0.001

Blood pressure parameters

Clinic systolic BP, mm Hg

14610.4

143.98.4

149.011.7

Clinic diastolic BP, mm Hg

94.66.7

91.56.6

96.16.2

0.001

0.002

ABPM, systolic BP, 24-h average, mm Hg

123.813.7

118.212.3

130.712.2

0.001

ABPM, systolic BP, daytime average, mm Hg

126.914.1

122.213.5

132.712.5

0.001

ABPM, systolic BP, nighttime average, mm Hg

117.915.4

110.812.9

126.613.7

0.001

ABPM, diastolic BP, 24-h average, mm Hg

73.89.8

68.77.6

80.08.9

0.001

ABPM, diastolic BP, daytime average, mm Hg

76.310.1

71.38.2

82.48.7

0.001

ABPM, diastolic BP, nighttime average, mm Hg

69.110.7

63.78.4

75.710.3

0.001

BMI indicates body mass index; UA, uric acid; BP, blood pressure; ABPM, ambulatory blood pressure measurement; SGA, small for
gestational age.

subject seated. A physician on the hospital staff measured BP with a

standard mercury sphygmomanometer. In our institution, all of the
mercury sphygmomanometers are calibrated every 3 months against
an electronic pressure generator. Diastolic BP was taken at Korotkoff
phase 5, which has been shown to correspond more closely with
intra-arterial measurement and be less dependent on the examiners
skill than Korotkoff phase 4.16 Three measurements were taken, 5
minutes apart, and the average was recorded: the mean of the
averages recorded on the 2 occasions was considered the actual BP.
BP values 140 mm Hg systolic or 90 mm Hg diastolic were
considered abnormal and used for diagnosis of hypertension. Also,
after an overnight fast, blood samples were taken for routine tests,
including serum creatinine, UA, blood glucose, and a full blood cell
count, and a 24-hour collection was started for the measurement of
proteinuria. First-trimester (determined between the ninth and 12th
weeks of gestation) serum UA was taken from the womans clinical
record and was measured at the same laboratory at our hospital.
Within 4 days from the first visit, all of the women underwent
ambulatory BP monitoring. An oscillometric pressurometer
(TM2430, A&D Company, Tokyo, Japan) was used to measure
24-hour BP. Device accuracy was checked in every session against
a mercury sphygmomanometer, and a difference 5 mm Hg was
reason for exclusion from the study.

BP was recorded at 15-minute intervals both during the day and

night for 25 hours, starting between 9:00 and 11:00 AM. Cuffs of
appropriate size were used, always applied to the left arm.
All of the BP recordings from the first hour of monitoring were
removed from analysis because they might be influenced by an alarm
reaction. All of the readings with a pulse pressure 20 mm Hg, a
diastolic BP 140 mm Hg or 40 mm Hg, or a systolic BP
250 mm Hg or 60 mm Hg were automatically rejected. The
quality of 24-hour BP monitoring was judged satisfactory when
70% of the readings passed the editing criteria and 1 recording
per hour was obtained. Daytime was defined as 7:00 AM to 11:00 PM.
All of the women were followed up at our hospital until the end of
pregnancy and regularly 1 month after delivery, unless their
clinical conditions dictated otherwise. The outcome of pregnancy
was recorded, and clinical parameters regarding the newborn
(weight, Apgar score, and duration of hospital stay) were also
recorded. Preeclampsia was defined as gestational hypertension and
proteinuria 300 mg in a timed 24-hour sample. Transient gestational hypertension was defined as the presence of normal office BP
140 mm Hg systolic and 90 mm Hg diastolic) 4 weeks after
delivery in untreated women who had hypertension without preeclampsia during the third trimester of pregnancy. For the purpose of

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Table 2.

October 2011

Results of Logistic Regression

Preeclampsia

Parameter

Odds Ratio

SGA

95% CI

Odds Ratio

95% CI

UA, per 59.48 mol/L, 1 mg/dL

7.08

3.20 to 15.69

0.001

1.58

1.06 to 2.37

0.02

First-trimester UA, per 59.48 mol/L, 1 mg/dL

1.23

0.85 to 3.07

0.27

1.15

0.32 to 4.19

0.79

Hemoglobin, per 10 g/L

1.57

0.95 to 2.59

0.10

1.24

0.88 to 1.74

0.22

Platelets, per 1000/mm3

0.994

0.98 to 1.10

0.31

1.00

0.99 to 1.01

0.84

Serum creatinine, per 8.84 mol/L, 0.1 mg/dL

1.21

0.56 to 2.61

0.63

0.76

0.56 to 1.04

0.10

Ambulatory 24-h average, systolic BP, per mm Hg

1.01

0.94 to 1.07

0.91

1.02

0.98 to 1.07

0.33

Ambulatory 24-h average, diastolic BP, per mm Hg

1.08

0.99 to 1.18

0.07

1.07

1.00 to 1.14

0.04

Office systolic BP, per mm Hg

1.06

0.97 to 1.15

0.20

0.97

0.93 to 1.02

0.33

Office diastolic BP, per mm Hg

0.99

0.86 to 1.12

0.74

1.07

0.98 to 1.17

0.13

Gestation wk

1.05

0.82 to 1.35

0.68

0.84

0.73 to 0.98

0.02

Age, per y

0.80

0.71 to 0.92

0.006

1.01

0.92 to 1.10

0.47

Dependent variables were preeclampsia and SGA; explanatory variables were as follows: age, gestation wk, serum creatinine, UA
(current and first-trimester levels), hemoglobin and platelet levels, office and ambulatory systolic and diastolic BPs. UA indicates uric
acid; BP, blood pressure; SGA, small for gestational age.

the present study, SGA infants were defined as those weighing less
than the 10th centile, based on nationwide derived centile charts for
singleton births.17
All of the results are expressed as meanSD, unless otherwise
indicated. Comparisons between groups were performed using the
unpaired Student t test for continuous variables and the Fisher exact
test for proportions. Strength of association of UA with the outcomes
(development of preeclampsia and SGA) was assessed by binary
logistic regression, unadjusted first, and after adjustment for age,
gestation week, serum creatinine, hemoglobin and platelet levels,
and both office and ambulatory BPs; association of serum UA and
other variables with birth weight centiles was evaluated by a multiple
linear regression model. Predictive accuracy of laboratory and BP
parameters was assessed by calculating the areas under the receiver
operating characteristic curves, which were compared according to
the method of Hanley and McNeil18; optimal cutoff values were
chosen as the point on the receiver operating characteristic curve,
closest to the top left corner. P values 0.05 were considered as
significant. All of the calculations were performed using the SPSS
15.0 (SPSS Inc, Chicago, IL), and Medcalc 9.1 (Mariakerke,
Belgium) software.
The study was approved by the hospital ethics committee. Because
the study parameters were noninvasive and obtained as part of a
routine clinical management, the committee did not require signed
informed consent; however, verbal informed consent was obtained in
all of the cases.

Results
Overall, 163 women completed the study; among those who
did not, 20 were excluded because they did not meet the BP
criteria on entry, 3 because of proteinuria 300 mg/24 hours,
7 because of incomplete clinical data, and 11 because of
insufficient quality of the ambulatory BP monitoring recordings, and 2 withdrew their consent.
Seventy-three women (44.7%) developed preeclampsia,
and 43 SGA infants (26.4%) were born. One stillbirth
occurred. The average interval between time of study entry
and preeclampsia diagnosis was 14.75.1 days.
Demographic, laboratory, perinatal, and BP parameters are
shown in Table 1. Women who developed preeclampsia
tended to be younger and have higher levels of UA, hemoglobin, and creatinine; lower levels of platelets; a higher

incidence of cesarean section and SGA infants; and both

higher office and monitored BP.
Table 2 shows the results of logistic regression analysis:
the unadjusted odds ratio for UA associated with the development of preeclampsia was 9.1 (95% CI: 4.8 to 17.4;
P0.001), and after adjustment for age, gestation week,
hemoglobin and platelet levels, serum creatinine, office
systolic and diastolic BPs, and 24-hour average systolic and
diastolic BPs, it was 7.1 (95% CI: 3.2 to 15.7; P0.001).
When the association between maternal serum UA and the
chance of giving birth to an SGA infant was considered, the
unadjusted odds ratio was lower (1.6; 95% CI: 1.1 to 2.4;
P0.001), and after adjusting for confounders it was 1.6
(95% CI: 1.1 to 2.3; P0.02). In this regression model,
first-trimester UA was not significantly associated with either
preeclampsia or SGA (Table 2). Table 3 shows the results of
multiple linear regression, with birth weight centile as the
dependent variable: again, serum UA and monitored diastolic
BP 24-hour average were the only variables significantly
associated with birth weight centile. Hyperuricemic (UA
309 mol/L; n9) women who did not develop preeclampsia had a higher incidence of SGA compared with normouricemic women (22.2% versus 4.9%; P0.05).
Receiver operating characteristic analysis (Table 4)
showed that serum UA was an accurate predictor of preeclampsia in this population (areas under the receiver operating characteristic curve: 0.955; sensitivity: 87.7%; specificity: 93.3%; positive predictive value: 91.4%; negative
predictive value: 9.6%, for a cutoff of 309 mol/L [5.2
mg/dL]), as well as serum UA increase from first trimester
(areas under the receiver operating characteristic curve:
0.961; sensitivity: 90.4%; specificity: 97.8%; positive predictive value: 97.1%; negative predictive value: 7.4%, for a
cutoff of 113 mol/L [1.9 mg/dL]); a combination of the
above criteria (either UA level 309 mol/L or an increase
113 mol/L) yielded a sensitivity of 93.6% and a specificity of 91.8% (positive predictive value: 90.2%: negative
predictive value: 5.2%).

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Bellomo et al
Table 3.

Results of Multiple Linear Regression

Parameter

B
Coefficient

Standardized

UA, mol/L

4.28

0.28

0.01

1.46

0.02

0.80
0.16

First-trimester
UA, mol/L

2.05

0.10

Platelets, 1000/mm3

0.02

0.04

0.61

Serum creatinine, mol/L

9.80

0.07

0.52

Ambulatory 24-h average,

systolic BP, mm Hg

0.04

0.02

0.84

Ambulatory 24-h average,

diastolic BP, mm Hg

0.69

0.26

0.01

Office systolic BP, mm Hg

0.21

0.08

0.33

Gestation wk

0.95

0.11

0.13

0.16

0.04

0.63

Hemoglobin, g/L

Office diastolic
BP, mm Hg

707

we are reporting. Recently, several studies,4,7,9,10,14 mostly

retrospective, have shown an association between firsttrimester UA and the later development of preeclampsia
and/or SGA. In our sample of patients (which included only
women with suspected gestational hypertension), firsttrimester UA was not associated so strongly with adverse
outcomes; actually, although a fairly sensitive marker for
SGA (86.0% sensitivity), it lacked specificity. Conversely,
when measured at the moment of initial hospital admission, at
first diagnosis of pregnancy-induced hypertension, UA (and
even better, its increase from first trimester) carries a much
higher prognostic value, with a strong correlation to adverse
maternal outcomes, as reported in 2 recent retrospective
studies.19,20 However, retrospective, case-control studies are
known to provide more optimistic results regarding the
predictive capability of a model, with respect to cohort
studies,21 because of the fact that, in case-control studies,
controls are generally on the healthy side of the disease
spectrum, whereas cases generally display the most severe
presentation of a given disease. In this respect, we believe our
prospective study lends stronger support for a role of UA as
a predictor of preeclampsia and/or SGA.
The debate is still open whether UA is a simple marker of
disease or has a causal role in the development of preeclampsia and/or retarded fetal growth. Although the cause of
hyperuricemia in preeclampsia has not definitively been
elucidated, current evidence suggests that decreased renal
clearance is probably the most important mechanism. However, the increase in UA levels is too large to be attributed
solely to the reduction of glomerular filtration rate; thus, there
must also be decreased secretion or increased reabsorption.
This phenomenon appears to be analogous to the decrease in
urate clearance produced by the infusion of vasoconstrictors,
such as norepinephrine,22 and to the increase of blood UA
level and diminution in its clearance observed in glomerulonephritis.23 According to these considerations, UA could be
an early marker of preeclampsia. Other than reduced renal
clearance, there may occur increased placental production of
UA secondary to placental ischemia and increased tropho-

Dependent variables was birth weight centile; independent variables were as

follows: age, gestation wk, serum creatinine, UA (current and first-trimester
levels), hemoglobin and platelet levels, office and ambulatory systolic and
diastolic BPs. UA indicates uric acid; BP, blood pressure.

First-trimester UA was a poor predictor of preeclampsia,

and it showed a sensitivity of 80% but unacceptably poor
specificity for SGA prediction (Table 4). Regarding BP
parameters (Table 4), monitored BP performed better than
office BP and diastolic better than systolic BP for the
prediction of both preeclampsia and SGA, although not as
well as UA.

Discussion
In this sample of women with gestational hypertension, we
have identified UA as a reliable predictor of preeclampsia.
Although the literature reporting predictive indicators for
preeclampsia is fairly extensive, evidence on the accuracy of
various tests to predict preeclampsia in women with gestational hypertension is sparse and based mostly on retrospective analyses, rather than on cohort studies, such as the one
Table 4.

Uric Acid in Gestational Hypertension

Results of ROC Analysis

Preeclampsia

SGA

Parameter

AUC (95% CI)

Optimal
Cutoff

Sensitivity/
Specificity, %

AUC (95% CI)

Optimal
Cutoff

Sensitivity/
Specificity, %

UA, mol/L

0.955 (0.911 to 0.981)*

309

87.7/93.3

0.784 (0.712 to 0.844)

309

83.7/71.7

First-trimester UA (mol/L)

0.659 (0.580 to 0.691)

196

61.6/61.1

0.527 (0.447 to 0.605)

208

86.0/24.2

DUA, mol/L

0.961 (0.918 to 0.985)*

113

90.4/97.8

0.779 (0.709 to 0.840)

101

86.0/70.8

Hemoglobin, g/L

0.660 (0.582 to 0.732)

113

65.8/62.2

0.606 (0.526 to 0.681)

123

39.5/83.3

Platelets, 1000/mm3

0.758 (0.685 to 0.822)

196

79.5/65.6

0.692 (0.615 to 0.762)

164

57.5/78.3

Serum creatinine, mol/L

0.842 (0.777 to 0.895)

67

83.6/75.6

0.726 (0.651 to 0.793)

67

86.0/61.7

Ambulatory 24-h average, systolic BP, mm Hg

0.775 (0.704 to 0.837)

121

79.5/66.7

0.696 (0.619 to 0.766)

126

62.8/70.8

Ambulatory 24-h average, diastolic BP, mm Hg

0.832 (0.766 to 0.886)

77

71.2/86.7

0.790 (0.719 to 0.850)

79

69.8/82.5

Office systolic BP, mm Hg

0.615 (0.536 to 0.690)

148

42.5/78.9

0.552 (0.472 to 0.630)

147

48.8/65.0

Office diastolic BP, mm Hg

0.683 (0.606 to 0.724)

93

61.6/65.6

0.716 (0.640 to 0.784)

93

69.8/82.5

AUC indicates area under the curve; BP, blood pressure; UA, uric acid; ROC receiver operating characteristic.
*P0.001 vs hemoglobin, platelets, creatinine, first-trimester UA, and all BP parameters.
P0.01 vs hemoglobin, first-trimester UA, and office and systolic BPs.

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October 2011

blast shedding, leading to further purine availability for

breakdown. Fetuses exposed to hypoxia (eg, secondary to
decreased placental perfusion) have been shown to have
increased serum levels of purine metabolites.24 In preeclampsia, therefore, it is conceivable that these metabolites can
cross into the maternal circulation to be degraded by maternal
xanthine oxidase. These latter mechanisms might explain the
relationship between raised UA levels and fetal growth
retardation. An active role for UA in the development of
preeclampsia has been proposed: studies in animals have
suggested that UA may play a more active part in the
development of hypertension in preeclampsia and perhaps
later in life.25,26 UA has been shown to induce endothelial
dysfunction in humans27,28 and, recently, to be able to induce
human trophoblast production of interleukin 1 by activating
the Nod-like receptor Nalp 3, thus stimulating the expression
of inflammasome components.29
Finally, regarding BP parameters, the findings of our study
show that ambulatory BP monitoring derived measures are
better predictors of preeclampsia and (to a lesser extent)
SGA, with respect to office BP, probably because of the high
prevalence of white-coat hypertension in the pregnant population30; however, only 24-hour average diastolic BP was
significantly associated with SGA and birth weight centile
and showed a borderline significant association with
preeclampsia.

Perspectives

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

In conclusion, we believe the findings of our study show that,

in women with suspected hypertension in pregnancy, serum
UA 309 mol/L can accurately predict the later development of preeclampsia and, more so, an increment
113 mol/L from first-trimester levels. We provide threshold values that might prove useful in clinical practice,
although, of course, further studies are necessary.

Disclosures
None.

19.

20.

21.

22.
23.

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