Association of Uric Acid and C-Reactive Protein with Severity of Preeclampsia in Iranian Women
This study was planned to determine the levels of uric
acid (UA) and CRP at preeclampsia and their association with the severity
of the disease. In a cross-sectional, case-control study we measured UA
and CRP levels in blood samples from 46 women with preeclampsia, 23 normal
pregnant women and 23 non pregnant women matched for age, BMI, parity
and gestational age were measured. Twenty three patients had developed
severe and 23 mild preeclampsia. UA and CRP were measured by enzymatic
method and enzyme-linked immunosorbent assay, respectively. Roc curve
was used to determine the optimal cutoff value. Results showed CRP and
UA concentrations were higher in Preeclamptic group (33.77 ±25.97,
5.93 ±0.75) compared with normal pregnant group (17.31 ±19.54,
5.47 ±0.41). CRP levels were also significantly elevated in women
with severe preeclampsia compared to those mild preeclampsia (42.26 ±24.04,
16.81 ±22.03). Determination of serum CRP levels may be used as
marker for the severity of preeclampsia. We also suggest that serum UA
level of 5.5 mg dL-1 is best cutoff point for the diagnosis
Preeclampsia is a major complication of pregnancy and occurs in about
7-10% of all pregnant women (Ray et al., 1999) and it is still
an important cause of both maternal and fetal morbidity and mortality
(Funai et al., 2005).
The physiopathology of preeclampsia remains uncertain despite many research
efforts (Myatt and Miodovnik, 1999). Several etiologies have been implicated
in the development of preeclampsia. Endothelial cell dysfunction and inflammation
are considered to have a crucial role in the pathophysiologic mechanism
of preeclampsia (Kharb et al., 1998).
Mediators of an inflammatory response are altered in women with preeclampsia,
including increased C-Reactive Protein (CRP) (Teran et al., 2001).
However, little is known about whether or not there is a correlation with
the severity of disease.
Uric Acid (UA) is the major end-product of purine metabolism. The cause
of the hyperuricemia in preeclampsia has been attributed to either a decreased
excretion or to an increased production of uric acid. Decreased uric acid
clearance, reflected by altered tubular function has been documented,
while in 1990 Fay proposed an increased breakdown of purines in the placenta
as a possible explanation for the overproduction of uric acid (Jeyabalan
and Conrad, 2007; Hill, 1987; Fay, 1990). Hyperuricemia in preeclampsia
has generally been regarded as a marker of renal disease rather than as
a risk factor for the progression of the disease. Few studies have reported
correlation of UA with the clinical severity of preeclampsia.
The aim of this study was to determine the levels of UA and CRP in preeclampsia
and their association with the severity of the disease.
MATERIALS AND METHODS
This cross-sectional, case-control study was conducted at the Arak University,
Medical Faculty, Departments of Immunology and Obstetrics and Gynecology,
from April 2006 until May 2007. Ethical approval for this study was obtained
from the Ethical Committee of University of Medical Sciences. The study
included 23 women in the third trimester of pregnancy with mild preeclampsia
at the time of admission (group 1), 23 women in the third trimester of
pregnancy with severe preeclampsia (group 2), 23 healthy normotensive
women in the third trimester of pregnancy (control group, group 3) and
23 non pregnant women (group 4) matched for age, BMI, parity and gestational
Control group was monitored at the Department of Obstetrics and Gynecology
of Taleghani hospital with gestational age 25-40 weeks, no chronic medical
disorders and not in labor. They were normotensive and had normal blood
pressures throughout gestation. Patients with a history of diabetes, renal
disease, hypertension, other cardiovascular illness and symptomatic infectious
diseases were excluded. Abnormal Liver Function Test (LFT) and renal disease
were defined as serum bilirubin >25 μmol L-1 and serum
creatinine >1.0 mg dL-1, respectively.
Inclusion criteria for preeclamptic group were: absence of labor contractions
and premature rupture of membranes or clinical chorioamnionitis. None
of the patients included had underlying diabetes, renal diseases, chronic
hypertension or symptomatic infectious diseases, which were excluded during
routine interviews, clinical investigations and laboratory tests. The
pregnant women were not given corticosteroids at least 7 days prior to
inclusion in the study.
Mild preeclampsia was defined as a Blood Pressure (BP) 140 mmHg or greater
or a diastolic BP of 90 mmHg confirmed by 6 or more hours apart, where
as proteinuria was defined as < 2+ on urine dipstick were observed
on at least two random specimens collected more than 4 h apart, after
the 20th week of pregnancy. Severe preeclampsia was defined if diastolic
BP increased to at least 110 mmHg or diastolic BP 160 mmHg or higher,
along with proteinuria > 2+ on urine dipstick and the presence of headache,
visual disturbances, upper abdominal pain, oliguria. All women in severe
preeclampsia group had a combination of hypertension and proteinuria.
Gestational age was calculated from the first day of the last menstrual
period, unless ultrasonography results found a discrepancy of 14 days
or more. Blood pressures were measured (and controlled twice) at entrance
into the study (American College of Obstetricians and Gynecologists, 1996;
Kumar et al., 2005).
In all subjects, after gave informed written consent, blood was drawn
on admission in the morning after 8 h fasting. In the preeclampsia group,
blood samples were collected when the patient presented for evaluation
and before initiation of medical therapy. The controls were recruited
when they admitted for their routine third trimester control and then
observed to ensure that they did not develop disease later. In all patients,
UA and CRP were determined. ELISA (STAT FAX 2000-USA) for CRP was performed
using a commercial kit (Monobind, INC High Sensitivity CRP-USA). The assay
has a detection limit of 0.25 μg mL-1. Serum uric acid
was measured by an enzymatic method based on uricase (Ziestchem, Iran).
The sample size was determined by the previous case-control study of
Ustun et al. (2005). Numerical data were expressed as mean±Standard
Deviations (SD). Statistical analysis of the data was performed with the
software package SPSS for windows 11.0 (Statistical package for social
sciences; SPSS Inc., Chicago, IL). Kolmogorov-Smirnov analysis was used
to test if the results were normally distributed. Analysis of variance
with the Kruskal-Wallis test was used when three groups were compared.
After the difference was detected between the groups, the groups were
compared for statistical significance using the Mann-Whitney U-test. A
logistic regression analysis has been performed with the confounding factors
of the study to investigate the relationship between UA and CRP with preeclampsia,
giving an adjusted odds ratio (ORa) and its 95% confidence interval. p<0.05
was considered to be significant. A Receiver Operating Characteristic
(ROC) curve was constructed to evaluate the sensitivity and specificity
of CRP and UA.
RESULTS AND DISCUSSION
Maternal age, gestational age and body mass index were not significantly
different between the groups. As expected, the systolic and diastolic
blood pressure values were higher in the preeclampsia group (Table
1). The value of serum CRP in preeclampsia patients was markedly higher
than that normal third trimester pregnant women and non pregnant women
(Table 2). CRP-a sensitive marker of tissue damage and
inflammation was proposed to play a role in eliciting the inflammatory
response characteristics of preeclampsia (Redman et al., 1999).
CRP acts as a scavenger and is responsible for the clearance of membranes
and nuclear antigens (Du Clos, 1996). The relationship between the levels
of CRP and preeclampsia has already been studied. Higher concentration
of CRP has been reported during preeclampsia (Teran et al., 2001;
Okerengwo et al., 1990). In this study levels of CRP were found
to be significantly higher in women with severe preeclampsia than mild
preeclampsia with similar chronologic age, gestational age and body mass
index (Table 2). Present results support the hypothesis
that systemic inflammation is involved in the pathogenesis of preeclampsia.
In accordance with previous reports, preeclampsia is associated with
increased CRP levels however, there are few studies concerning correlation
of CRP levels due to severity of preeclampsia (Teran et al., 2001;
Okerengwo et al., 1990; Belo et al., 2003; Vickers et
al., 2003; Tjoa et al., 2003). Present results showed that
the diagnosis value of a CRP higher than 30 μg mL-1 was
interesting for sensibility and specificity but if the negative predictive
value is strange (90.9%), then the positive predictive value is weak (57.1%,
Fig. 1). This last point is a limitation for its interest
as a diagnosis test.
Many studies have been devoted to the association of hyperuricemia and
preeclampsia (Redman et al., 1976; Acien et al., 1990; Boneu
et al., 1980; Lancet and Fisher, 1956; Yoshimura et al.,
1990). Present results show that UA level was significantly higher in
the severe preeclamptic group than in the control group and non pregnant
women (Table 2). Although elevated, the lack of significant
differences between mild and severe preeclampsia regarding UA level may
be due to small sample size and corresponding low statistical power.
Redman (1987) showed that the basal serum uric acid level in normal women
in the third trimester was 2.112±0.40 mg dL-1, with
an increase of 1.20 mg dL-1 between 16 and 40 weeks of gestation.
In the same study, the serum uric acid levels in the preeclamptic women
were observed between 3.27±1.02 (preeclampsia severity 1+)
||Demographic and medical characteristics of study subjects
|Values are given as mean±SD, PE: Preeclampsia
||Laboratory data of study subjects
|Values are given as mean±SD, PE: Preeclampsia,
*p<0.05 compared with normal pregnant group and non pregnant group,
**p: Not significant compared with mild preeclampsia, ***p<0.05
compared with mild preeclampsia
||Receiver Operating Characteristic (ROC) curve of CRP
to predict women with preeclampsia. Best cutoff value for CRP is 30
μg mL-1, which gives a sensitivity of 87% and specificity
of 66.7%. The ROC curve revealed the continuum of sensitivity and
specificity encountered as the cutoff point was varied. CRP with a
cutoff point of 30 μg mL-1 identified women with preeclampsia
with sensitivity of 87% (95% CI, 65.3-96.6) and specificity of 66.7%
(95% CI, 50.9-79.6). Its negative predictive value of 90.9% (95% CI,
74.5-97.6) was high; the positive predictive value of 57.1% (95% CI,
39.5-73.2) was low
||Receiver operating characteristic (ROC) curve of UA
to predict women with preeclampsia. Best cutoff value for UA is 5.5
mg dL-1, which gives a sensitivity of 65.2% and specificity
of 71.1%. UA with a cutoff point of 5.5 mg dL-1 identified
women with preeclampsia with sensitivity of 65.2% (95% CI, 42.8-82.8)
and specificity of 71.1% (95% CI, 55.5-83.2). Its negative predictive
value of 80% (95% CI, 63.9-90.4) was high; the positive predictive
value of 53.6% (95% CI, 34.2-72) was low. The study revealed that
when UA and CRP were high the risk of preeclampsia was high.
The adjusted odds ratio were 4.62 (95% CI, 1.58-13.5; p> 0. 001)
and 13.33 (95% CI, 3.41-52.09; p>0.001), respectively and 4.59±0.91
mg dL-1 (severity 3+). These values were smaller than the
maximal level reported in our study (6.01 mg dL-1). Dekker
and Sibai (1991) reached the opposite conclusion in their study, compared
to ours where the only case of preeclampsia occurred in the control
Serum uric acid was like in other studies (Frenkel et al., 1991;
Sanchez-Ramos et al., 1991) of course, significantly higher in
preeclamptic women than in controls. Maternal serum uric acid level of
5.5 mg dL-1 was found to be the most useful cutoff values for
the diagnosis of preeclampsia (Fig. 2).
We found evidence of inflammation in preeclampsia. High CRP level was
associated with severe preeclampsia. CRP correlated positively and significantly
with the severity of disease in preeclampsia.
This research was supported by Research Council of Arak University of
Medical Sciences, Project No. 174.
Acien, P., G. Lloret and M. Lloret, 1990.
Perinatal morbidity and mortality in pregnancy hypertensive disorders: Pronostic value of the clinical and laboratory findings. Int. J. Gynaecol. Obstet., 32: 229-235.PubMed |
American College of Obstetricians and Gynecologists, 1996.
Hypertension in pregnancy. Am. Coll. Obset. Gynecol. Technol. Bull., 219: 1-8.
Belo, L., A. Santos-Silva and M. Caslake, 2003.
Neutrophil activation and C-reactive protein concentration in preeclampsia. Hypertens Pregnancy, 22: 129-141.Direct Link |
Boneu, B., A.S.P. Fournie, H. Grandjean, R. Bierme and J. Pontonnier, 1980.
Platelet production time, uricemia and some hemostasis tests in pre-eclampsia. Eur. J. Obstet. Gynecol. Reprod. Biol., 11: 85-94.PubMed |
Dekker, G.A. and B.M. Sibai, 1991.
Early detection of pre-eclampsia. Am. J. Obstet. Gynecol., 165: 160-172.PubMed |
Du Clos, T.W., 1996.
The interaction of C-reactive protein and serum amyloid P component with nuclear antigens. Mol. Biol. Rep., 23: 253-260.PubMed |
Fay, R.A., 1990.
Uric acid in pregnancy and preeclampsia: An alternative hypothesis. Aust. N.Z. J. Obstet. Gynecol., 30: 141-142.PubMed |
Frenkel, Y., G. Barkai, S. Mashiach, E. Dolev, R. Zimlichman and M. Weiss, 1991.
Hypocalciuria of preeclampsia is independent of parathyroid hormone level. Obstet. Gynecol., 77: 689-691.PubMed | Direct Link |
Funai, E.F., Y. Friedlander, O. Paltiel, E. Tiram, X. Xue, L. Deutsch and S. Harlap, 2005.
Long-term mortality after preeclampsia. Epidemiology, 16: 206-215.Direct Link |
Jeyabalan, A. and K.P. Conrad, 2007.
Renal function during normal pregnancy and preeclampsia. Front Biosci., 1: 2425-2437.Direct Link |
Hill, L.M., 1978.
Metabolism of uric acid in normal and toxemic pregnancy. Mayo Clin. Proc., 53: 743-751.PubMed |
Kharb, S., N. Gulati, V. Singh and G.P. Singh, 1998.
Lipid peroxidation and vitamin E levels in preeclampsia. Gynecol. Obstet. Invest., 46: 238-240.PubMed |
Kumar, A., B.K. Ghosh and N.S. Murthy, 2005.
Maternal thyroid hormonal status in preeclampsia. Indian J. Med. Sci., 59: 57-63.PubMed | Direct Link |
Lancet, M. and I.L. Fisher, 1956.
The value of blood uric acid levels in toxaemia of pregnancy. J. Obstet. Gynaecol. Br. Emp., 63: 116-119.CrossRef |
Myatt, L. and M. Miodovnik, 1999.
Prediction of preeclampsia. Semin Perinatol., 23: 45-57.Direct Link |
Okerengwo, A.A., A.I. Williams and P.A. Ibeziako, 1990.
Immunological studies on preeclampsia in Nigerian women. Int. J. Gynaecol. Obstet., 33: 121-125.CrossRef |
Ray, J., K. Vasishta, S. Kaur, S. Majumdar and H. Sawhney, 1999.
Calcium metabolism in pre-eclampsia. Int. J. Gynecol. Obstet., 66: 245-250.Direct Link |
Redman, C.W., L.G. Beilin, J. Bonnar and R.H. Wilkinson, 1976.
Plasma-urate measurements in predicting fetal death in hypertensive pregnancy. Lancet, 1: 1370-1373.PubMed |
Redman, C.W., 1987.
Hypertension in pregnancy: A case discussion. Kidney Int., 32: 151-160.PubMed |
Redman, C.W., G.P. Sacks and I.L. Sargent, 1999.
Preeclampsia: An excessive maternal inflammatory response to pregnancy. Am. J. Obstet. Gynecol., 180: 499-506.Direct Link |
Sanchez-Ramos, L., S. Sandroni, F.J. Andres and A.M. Kaunitz, 1991.
Calcium excretion in preeclampsia. Obstet. Gynecol., 77: 510-513.PubMed |
Teran, E., C. Escudero, W. Moya, M. Flores, P. Vallance and P. Lopez-Jaramillo, 2001.
Elevated C-reactive protein and pro-inflammatory cytokines in Andean women with preeclampsia. Int. J. Gynecol. Obstet., 75: 243-249.Direct Link |
Tjoa, M.L, J.M.G. Van Vugt, A.T.J.J. GO, M.A. Blankenstein, C.B.M. Oudejans and I.J. Van Wijk, 2003.
Elevated C-reactive protein levels during first trimester of pregnancy are indicative of preeclampsia and intrauterine growth restriction. J. Reprod. Immunol., 59: 29-37.Direct Link |
Ustun, Y., Y. Engin-Ustun and M. Kamaci, 2005.
Association of fibrinogen and C-reactive protein with severity of preeclampsia. Eur. J. Obstet. Gynecol. Reprod. Biol., 121: 154-158.Direct Link |
Vickers, M., I. Ford and R. Morrison, 2003.
Markers of endothelial activation and atherotrombosis in women with history of preeclampsia or gestational hypertension. Thromb. Haemost., 90: 1192-1197.Direct Link |
Yoshimura, A., T. Ideura, S. Iwasakis and S. Koshikawa, 1990.
Significance of uric acid clearance in pre-eclampsia. Am. J. Obstet. Gynecol., 162: 1639-1640.PubMed |