Journal of Human Hypertension (2016) 30, 136–140

© 2016 Macmillan Publishers Limited All rights reserved 0950-9240/16

www.nature.com/jhh

ORIGINAL ARTICLE
Serum uric acid may not be involved in the development
of preeclampsia
Q Chen1,2, S Lau3, M Tong2, J Wei2, F Shen1, J Zhao4 and M Zhao4

Higher serum levels of uric acid are associated with preeclampsia and may signal an early change in preeclampsia. However there is
less evidence suggesting there is a meaningful association between uric acid and the development of preeclampsia. A total of 877
women with preeclampsia at presentation and 580 normotensive pregnancies were retrospectively recruited from January 2009 to
May 2014. In addition, 5556 pregnant women were also prospectively recruited from September 2012 to December 2013.
Retrospective serum levels of uric acid were obtained from women with preeclampsia at the time of presentation (n = 877), and
serum levels of uric acid in the first, second and third trimester were prospectively collected in women who later developed
preeclampsia (n = 78), as well as those who did not (n = 5478). The serum levels of uric acid were significantly increased in women
with preeclampsia at presentation from retrospective samples and this increase correlated with the time of onset and the severity
of preeclampsia. However, in prospective samples, serum levels of uric acid were not increased in the first and second trimesters in
women who later developed preeclampsia compared with those who did not. The serum level of uric acid in the first and second
trimesters in women who developed preeclampsia was not different. Our results demonstrate that the serum levels of uric acid
were only increased after the presentation of clinical symptoms of preeclampsia. Therefore, it is likely that uric acid is not involved
in the development of preeclampsia and cannot be an early prediction biomarker of this disease.

Journal of Human Hypertension (2016) 30, 136–140; doi:10.1038/jhh.2015.47; published online 21 May 2015

INTRODUCTION
Preeclampsia is a human pregnancy specific disorder that presents
as maternal hypertension and proteinuria after 20 weeks of
gestation. Preeclampsia affects 3–5% of healthy pregnancies
worldwide and is a major cause of maternal and perinatal
mortality and morbidity.1 Preeclampsia is characterised
by maternal endothelial cell activation and an exaggerated
inflammatory response.2,3 Although the pathogenesis of
preeclampsia is still unclear, a number of studies recently
proposed that higher levels of uric acid are involved in the
pathogenesis of preeclampsia by contributing to the generalised
maternal endothelial activation and exaggerated inflammation
observed.4–6
Preeclampsia is associated with a deterioration renal function.7,8
The renal histologic lesion characteristic in preeclampsia is
glomerular endotheliosis which results in a lower glomerular
filtration rate (GFR) and effective renal plasma flow (ERPF).7,9–12
Higher levels of uric acid correlate with the severity of glomerular
endothelioisis.13 In normal pregnancy, circulating levels of uric
acid are associated with the renal excretion of urate, which
decreases in the first trimester, remains at a stable level in the
second trimester and increases to normal/non-pregnant levels in
the third trimester.14 The association of uric acid and preeclampsia
at presentation has been known for 100 years15 and this was
initially considered as a key diagnostic criterion for preeclampsia.
Its importance has since been diminished because uric acid may
just be a marker of proteinuria, rather than preeclampsia.
However, this association is currently being renewed with the
increasing understanding of the effects of uric acid on endothelial
cell function, oxidative stress and inflammation, which are features
of preeclampsia (reviewed in Martin and Brown16). This suggests
that uric acid may have a pathogenic role in the development of
preeclampsia.17,18 A study recently reported that maternal
hyperuricemia is associated with poor pregnancy outcomes in
preeclampsia and can predict women at increased risk of adverse
maternal and fetal outcomes.19
It is well known that by definition, the clinical symptoms of
preeclampsia only occur after 20 weeks of gestation, but maternal
endothelial cell dysfunction precedes the clinical sign/symptoms
by many weeks. Higher serum levels of uric acid have been
reported to occur before the presentation of preeclampsia.20
Although uric acid appears to correlate with adverse maternal and
neonatal outcomes, studies investigating whether measurements
of serum uric acid levels in the first or second trimesters are useful
in predicting the later development of preeclampsia, or in support
of a reversion of a diagnosis criteria of preeclampsia are limited
and the findings in literature are also controversial.21 In addition,
whether uric acid has a role in the development of preeclampsia is
unclear. Preeclampsia is clinically divided into early onset and late
onset preeclampsia according to the gestation at onset of the
disease, as well as into severe and mild forms.22 Although
circulating levels of uric acid are increased in preeclampsia,
whether this increase correlates with the severity of preeclampsia
or the time of onset of preeclampsia is unclear. Therefore in this
study, we investigated whether the serum levels of uric acid in the
first and second trimester are associated with the later develop-
ment of preeclampsia. We also investigated whether the serum

1
Department of Obstetrics, The Hospital of Obstetrics & Gynaecology, Fudan University, Fudan, China; 2Department of Obstetrics & Gynaecology, The University of Auckland,
Auckland, New Zealand; 3Department of Physiology, Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand and 4Department of Gynae-oncology,
Wuxi Maternity and Children Health Hospital, Nanjing Medical University, Nanjing, China. Correspondence: Dr M Zhao, Wuxi Maternity and Children Health Hospital, Nanjing
Medical University, 48 Huaishu Street, Wuxi 200011, China.
E-mail: q.chen@auckland.ac.nz
Received 12 January 2015; revised 18 March 2015; accepted 9 April 2015; published online 21 May 2015

levels of uric acid are correlated with the time of onset of
preeclampsia and the severity of preeclampsia.
MATERIALS AND METHODS
This study was approved by the Ethics Committee of Wuxi Maternity and
Children Health Hospital, Nanjing Medical University, China. All patient-
derived blood samples were obtained with written informed consent.
Study populations
Blood samples from 877 women with preeclampsia at presentation, and
580 gestation-matched normotensive pregnant women retrospectively
recruited were collected by venepuncture into plain Vaccutainer tubes
prior to any treatment between January 2009 and December 2013 at the
Wuxi Maternity and Children Health Hospital of Nanjing Medical University
of China. The blood was allowed to clot, centrifuged at 2500 g and the
serum was aspirated and stored in aliquots at − 80 °C. Blood samples from
normotensive pregnant women were confirmed to be without complica-
tions of pregnancy before use. The clinical characteristics of 877
preeclamptic women and 580 gestation-matched normotensive pregnant
women were summarised in Table 1.
In addition, 5556 pregnant women were prospectively recruited into the
study from September 2012 to December 2013 from the same hospital (the
total number of births were more than 13 000 during the period of sample
collection). Their blood samples were collected in the first trimester (11–
13 weeks of gestation) and second trimester (15–18 weeks of gestation), and
third trimester. Of this prospective group, there were 78 pregnant women
who later developed preeclampsia. The details of the 78 preeclamptic
women at presentation are summarised in Table 1. None of the pregnant
women in the prospective and retrospective cohorts were smokers.
In both retrospective and prospective cohorts, women were excluded if
they had developed gestational hypertension, had a previous history of
preeclampsia or other obstetrical complications (including gestational
diabetes and preterm birth). Preeclampsia was defined as a maternal
systolic blood pressure ⩾ 140 mm Hg and/or diastolic blood pressure ⩾ 90
mm Hg measured on two occasions separated by at least 6 h, and
proteinuria 4300 mg on a 24 h urinary collection or qualitatively, 41+,
after 20 weeks of gestation following the guidelines of the American College
of Obstetricians and Gynaecologists.23 Since recruiting the patients for this
study new guidelines for the definition of preeclampsia have been issued by
the American College of Obstetricians and Gynaecologists.24 The new
guidelines did not alter the eligibility of any of the patients. Maternal systolic
blood pressure ⩾ 160 mm Hg and/or diastolic blood pressure ⩾ 110 mm Hg
on admission was defined as severe preeclampsia. Early onset preeclampsia
was defined as occurring at less than 34 weeks.
Uric acid and preeclampsia
Q Chen et al
137
Determination of serum levels of uric acid
The levels of uric acid in the collected serum samples were measured
colorimetrically using Uric Acid plus kit (Roche Diagnostics GmbH,
Shanghai, China) following the manufacturer’s instructions.
Statistical analysis
Clinical data were presented as median and range. The statistical
differences in the serum levels of uric acid between women with
preeclampsia and gestation-matched normotensive pregnancy were
analysed by the Mann–Whitney Test using Prism software package
(GraphPad Software, Inc, San Diego, CA, USA). The statistical differences
in the serum levels of uric acid between women at the first trimester, the
second trimester or the third trimester who later developed preeclampsia
and those who did not were assessed by the Mann–Whitney Test or one-
way ANOVA using the Prism software package, with Po0.05 being
considered as statistically significant. Logistic regression was analysed
using the continuous model using SPSS, version 12 (IBM, Chicago, IL, USA).
RESULTS
Demographic information of the study population
The clinical characteristics of the 877 women with preeclampsia at
presentation from the retrospective cohort are summarised in
Table 1. The overall incidence of preeclampsia during the study
period was 1.78%. Of the 877 preeclamptic women, 307 women
were diagnosed with severe preeclampsia and 570 were
diagnosed with mild preeclampsia. Of the 877 preeclamptic
women, 253 women were diagnosed with early onset preeclamp-
sia and 624 women were diagnosed with late onset preeclampsia.
117 (13.3%) of the preeclamptic women also had pregnancies
complicated by fetal growth restriction (FGR). The median
maternal age at diagnosis of preeclampsia was 27 (range 16–48)
years old. The median gestation week at diagnosis was 36+3
(range 20+2–41+2) in women with preeclampsia (Table 1).
Of 5556 prospective samples, 78 (1.5%) women developed
preeclampsia later. The clinical characteristics of these 78 women
who later developed preeclampsia are summarised in Table 1. Of
them, 13 (16.6%) women were diagnosed with early onset
preeclampsia and 14 (17.9%) were diagnosed with severe
preeclampsia.

Table 1. Clinical characteristics of women with preeclampsia from retrospective and prospective cohorts

Retrospective Cohort Prospective cohort

Preeclampsia (n = 877) Control (n = 580) Developed preeclampsia (n = 78) Not develop

preeclampsia
(n = 5478)

Maternal age (years old, median, range) 27 (16–48) 29 (21–35) 28 (20–34) 26 (18–42)
Gestation week at diagnosis (median, range) 36+3 (20+2–41+2) N/A 37+2 (23–40+6) N/A
Systolic blood pressure (mm Hg, median, range) 150 (114–234)a 125 (90–135) 147 (131–160)a 120 (90–138)
Diastolic blood pressure (mm Hg, median, range) 100 (67–160)a 76 (65–88) 95 (75–117)a 74 (60–90)
Proteinuria 41+ Negative 41+ Negative
Birth weight (g, median, range) 2850 (900–4700)a 3450 (3300–4200) 3150 (750–4500)a 3560 (3250–4285)
FGR (number, %) 117 (13.3%) 0 7 (8.9%) 0
BMI (kg m−2, median, range) 28.7 (16.5–41.5)a 25.1 (18.1–32.5) 29.2 (18.7–43.7)a 25.7 (23.3–33.5)
Gestation week at delivery (median, range) 38 (21+1–41+5)a 38 (37+2–40+1)
+5
39 (28–42+6)a
+2
39 (37 –41+2)
+1 +3

Delivery mode
Caesarean section (n) 788 232 65 2191
Vaginal delivery (n) 89 348 13 3287
Abbreviations: BMI: body mass index; FGR, fetal growth restriction. aPo 0.05 compared with control groups in the corresponding cohorts.

© 2016 Macmillan Publishers Limited Journal of Human Hypertension (2016) 136 – 140
 Uric acid and preeclampsia
Q Chen et al
138
The serum levels of uric acid were significantly increased in pregnancy between women who later developed preeclampsia
preeclampsia at presentation and correlated with the time of and those who did not (Tables 3, P = 0.16).
onset and the severity of preeclampsia After adjusting for maternal age, the odds ratio for the
Overall from the retrospective data, the serum levels of uric acid development of preeclampsia for each 1 μM increase in serum
were significantly increased in women with preeclampsia at the uric acid in the first trimester or in the second trimester was 1.005
time of presentation compared with gestation-matched normoten- (95% CI: 1.001–1.009) or 1.001 (0.996–1.006) without significant
sive pregnant women (Table 2, P = 0.0001, Mann–Whitney). difference, respectively.
We then analysed whether the increased serum levels of uric In addition, there was also no difference in serum levels of uric
acid were correlated with the time of onset or the severity of acid in women who later developed preeclampsia during the first
preeclampsia at presentation. The serum levels of uric acid were (11–13 weeks of gestation) and second trimesters (15–18 weeks of
significantly higher in severe preeclampsia than in mild pre- gestation) (P = 0.61). Similar to observations from the retrospective
cohort, the serum levels of uric acid were significantly increased in
eclampsia (Table 2, P = 0.0018, Mann–Whitney). The serum levels
these women at the presentation of preeclampsia (Tables 3,
of uric acid were also significantly higher in early onset
P = 0.0001, ANOVA).
preeclampsia than in late onset preeclampsia at the time of
presentation (Table 2, P = 0.0001, Mann–Whitney). The serum
levels of uric acid were significantly higher in mild preeclampsia or DISCUSSION
late onset preeclampsia than in gestation-matched normotensive An association between uric acid and preeclampsia has been
pregnancies (P = 0.001 and 0.0001, respectively). known for 100 years.15 However whether uric acid has a
pathogenic role in the development of preeclampsia is still
The serum levels of uric acid were correlated with fetal growth unclear. In our current study, our retrospective data confirms that
restriction the serum levels of uric acid were significantly increased in
We further investigated whether the serum levels of uric acid at preeclampsia at presentation; however, our prospective data
presentation were correlated with FGR. The serum levels of uric shows that the levels of uric acid was not elevated in the first or
acid in women with preeclampsia with FGR (n = 117) were second trimester in women who later developed preeclampsia.
significantly higher than those in women with preeclampsia To date, no clear evidence can convincingly show that the
without FGR (n = 760) (Table 2, P = 0.0001, Mann–Whitney). measurement of uric acid can be a predictive biomarker for the
development of preeclampsia.16,21 Whether the increased levels of
serum uric acid are causal of the symptoms of preeclampsia is
The levels of uric acid were not increased in the first or second unclear. A study reported that the serum levels of uric acid were
trimesters in women who later developed preeclampsia higher in the first trimester in women with pre-gestational
In order to further investigate whether serum levels of uric acid diabetes who later developed preeclampsia in the third trimester
can be a potential predictive biomarker of preeclampsia, we compared with those who did not.25 Another study reported that
screened the levels of uric acid in maternal serum from the serum levels of uric acid were higher in the second trimester in
prospective samples (n = 5556) obtained in the first trimester women with gestational hypertension who later developed
and second trimester of pregnancy. Of them, there were 78 preeclampsia compared with those who did not.26 A prospective
women who later developed preeclampsia and were included in study with a moderate sample size (n = 1541) recently reported
this study. There was no significant difference in the serum levels that the serum levels of uric acid were increased in the first
of uric acid in the first trimester or in the second trimester of trimester in women who later developed preeclampsia (n = 60)
compared with those who did not.27
In our current study, our prospective data (n = 5556) shows that
Table 2. The serum levels of uric acid (μM) in retrospective cohort 78 (1.5%) women who later developed preeclampsia. Our
prospective data showed that the serum levels of uric acid in
Uric acid (median/ P-value the first trimester (11–13 weeks of gestation) were not increased
range) in women who later developed preeclampsia compared with
Preeclampsia (n = 877) 374 (117–710) P = 0.0001 those who did not. Interestingly, the serum levels of uric acid were
Normotensive (n = 580) 279 (144–535) also not increased in the second trimester (15–18 weeks of
Severe preeclampsia (n = 307) 389 (180–710) P = 0.0018 gestation) in women who later developed preeclampsia compared
Mild preeclampsia (n = 570) 363 (117–698) with those who did not. The serum levels of uric acid were not
Early preeclampsia (n = 253) 399 (166–710) P = 0.0001 different between the first trimester and the second trimester in
Late preeclampsia (n = 624) 363 (117–694) women who later developed preeclampsia. However, our pro-
Preeclampsia with FGR (n = 117) 421 (138–673) P = 0.0001 spective data did show that the serum levels of uric acid were
Preeclampsia without FGR 365 (117–710) significantly increased at the time of presentation with pre-
(n = 760)
eclampsia. Although uric acid has some effects on endothelial cell
Abbreviation: FGR, fetal growth restriction. function,16,28 increased uric acid is not currently part of the
diagnostic criteria for preeclampsia. In addition, studies have

Table 3. The serum levels of uric acid (μM) in the first, second and third trimester in the prospective cohort

Women who developed preeclampsia (n = 78) Women who did not develop preeclampsia (n = 5478) P-value

First trimester (n = 78) 191 (120–457) 185 (28.7–642) P = 0.16

Second trimester (n = 78) 215 (130–428) 217 (102–428) P = 0.957
Third trimester (n = 78) 350 (157–720)a 278 (68.4–535) P = 0.0001
Abbreviation: ANOVA, analysis of variance. aP = 0.0001 (ANOVA, detecting a statistical difference of third trimester compared with the first and second
trimester in women who developed preeclampsia).

Journal of Human Hypertension (2016) 136 – 140 © 2016 Macmillan Publishers Limited

suggested that treating hyperuricemia did not influence the
course of preeclampsia.29,30 The increased levels of uric acid may
be associated with hypertension and proteinuria which are the
clinical symptoms of preeclampsia.17 The incidence of preeclamp-
sia in this study is 1.78% which is lower than other studies on
Caucasian populations. We have also previously reported that the
incidence of preeclampsia in China is low ( o2%)31 and this may
be one confounding factor which may affect the observations in
changes in uric acid levels in different ethnic groups.
The reasons for elevated serum uric acid levels at the
presentation of preeclampsia are unclear. One possibility is
decreased renal excretion of uric acid. The renal histologic lesion
characteristic in preeclampsia is glomerular endotheliosis which
results in a lower GFR and effective ERPF,7,9–12 which may reduce
the clearance of uric acid. In addition, higher levels of uric acid is
correlated with the severity of glomerular endotheliosis.13 Taken
together, our prospective and retrospective data may suggest that
the increased serum levels of uric acid at the presentation of
preeclampsia could be reflective of the maternal response rather
than a cause of preeclampsia and that the serum levels of uric acid
may not be a suitable early clinical prediction biomarker of
preeclampsia.
Although our prospective data suggests that serum levels of
uric acid are not involved in the development of preeclampsia,
other studies suggested that higher levels of uric acid correlated
with significant maternal and fetal morbidity and mortality
observed in preeclampsia.32–34 In addition, the degree of increase
in uric acid above normal levels may reflect the severity of
preeclampsia as well. Although the clinical symptoms of
preeclampsia only occur after 20 weeks of gestation, maternal
endothelial cell dysfunction precedes the clinical sign/symptoms
by many weeks prior to the presentation of clinical symptoms.
Because the incidence of preeclampsia is lower in China, there
were only 78 (1.5%) women who later developed preeclampsia in
our prospective samples. Therefore we were not able to analyse
whether the increased serum levels of uric acid correlated with the
time of onset or the severity of preeclampsia from our prospective
data. However our retrospective data shows that the serum levels
of uric acid were higher in early onset preeclampsia than in late
onset preeclampsia, as well as in severe preeclampsia, compared
with mild preeclampsia.
Early onset preeclampsia results in increased morbidity and
mortality in both the mother and the fetus/neonate.1 In addition,
early onset preeclampsia is also usually associated with FGR.1 Our
retrospective data also shows that higher levels of uric acid were
seen in preeclampsia with FGR at presentation. The serum levels
of uric acid are also frequently associated with the severity of
adverse maternal and neonatal outcomes including higher rate of
preterm birth and small for gestation age infants,4,35 although
increased serum levels of uric acid are not always present in these
complications. One possible speculation is that women with
severe or early onset preeclampsia typically have higher blood
pressures and more severe proteinuria. Given that uric acid is a
marker of renal dysfunction and therefore proteinuria, the higher
levels of uric acid in women with more severe forms of
preeclampsia may reflect the severity of renal dysfunction. Lower
serum levels of uric acid in women with preeclampsia at
presentation has been reported to be linked to the prolongation
of pregnancy for more than one week compared with higher
serum levels of uric acid at presentation of preeclampsia.36 In our
current study, our retrospective data shows that the serum levels
of uric acid in severe preeclampsia are higher than in mild
preeclampsia. Taken together, consistent with another study,22
our study further provides support for the association between
higher serum levels of uric acid and the severity of preeclampsia.
Increased dietary fructose has been proposed to increase the
serum levels of uric acid.37 Although we do not have data about
food intake in the study population, most of these women were
© 2016 Macmillan Publishers Limited
Uric acid and preeclampsia
Q Chen et al
139
from Wuxi, China, a wealthy city. The main diet in Wuxi is rice
therefore, fructose intake may not be a factor to increase the
levels of uric acid in these women.
Whether increased levels of serum uric acid are causal of the
symptoms of preeclampsia is unclear. In conclusion, in this large
prospective and retrospective study, our data demonstrates that
serum levels of uric acid are not increased in the first and second
trimester in women who later developed preeclampsia, suggest-
ing that uric acid may not be an early prediction biomarker of
preeclampsia and may not be involved in the early development
of preeclampsia. However, the increased serum levels of uric acid
at diagnosis/ in the third trimester were correlated with the time
of onset and the severity of preeclampsia. The increased serum
levels of uric acid were also correlated with FGR. These results
suggest that serum uric acid could be a biomarker of poor
outcome in preeclampsia at the time of presentation.
What is known about the topic
● Higher serum levels of uric acid are associated with preeclampsia.
● Whether there is a meaningful association between uric acid and
preeclampsia has been debated over many years.
What this study adds
● The serum levels of uric acid may not be an early prediction
biomarker of preeclampsia.
● The serum levels of uric acid may not be involved in the early
development of preeclampsia.
● The association of uric acid and preeclampsia could be reflective of
the maternal response.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This study was supported by the Chinese National Nature Sciences Foundation (grant
number 81100437 to MZ). We thank all the women who donated blood for this study.
We thank Dr Joanna James from The University of Auckland for editing this
manuscript.
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