Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Early predictors of gestational hypertension in a

low-risk cohort. Results of a pilot study
Nieves Martell-Claros
a
, Fiona Blanco-Kelly
b
, Mara Abad-Cardiel
a
, Mara J. Torrejo n
b
,
Beatriz Alvarez-Alvarez
a
, Manuel E. Fuentes
c
, Dolores Ortega
b
, Manuel Arroyo
b
, and
Miguel A. Herraiz
d
Objective: To determine if the clinical or biochemical
markers used in pregnancy can be applied as early
predictors of gestational hypertension.
Design: Prospective cohort study. Population: 315
pregnant women referred from the Prenatal Diagnosis Unit
between weeks 1013 of pregnancy and followed up to
the childbirth.
Methods: Biomarkers were measured in serum specimens
in the first and second trimester of pregnancy. Blood
pressure (BP) was measured in the first, second and third
trimester.
Results: The cumulative incidence of gestational
hypertension was 6.01%. In the first trimester gestational
hypertension predictors were uric acid greater than
3.15mg/dl (P 0.01), BMI greater than 24kg/m
2
(P 0.003) SBP at least 120mmHg (P 0.02) and DBP at
least 71mmHg (P 0.007). After applied multivariate
analysis just uric acid and SBP were statistically significant.
Conclusion: In our cohort of healthy pregnant women
uric acid above 3.15mg/dl and SBP at least 120mmHg are
consistent predictors of gestational hypertension in the first
trimester. The most important implication of our study is
the possibility to identify in the first trimester women at
risk to develop gestational hypertension using available
markers.
Keywords: biochemical biomarkers, blood pressure,
Cystatin-C, gestational hypertension, uric acid
Abbreviations: MoM, multiple of the median; PAPP-A,
pregnancy-associated plasma protein A; PE, pre-eclampsia;
-HCG, free-b human chorionic gonadothrophin
INTRODUCTION
G
estational hypertension and pre-eclampsia are
multisystem and pregnancy-specific disorders.
The incidence is 210% of the pregnancies
depending on the population studied and contribute sub-
stantially to perinatal morbidity and mortality of both
mother and fetus [12]. Their origin is still unknown, but
it is accepted that it is caused by the presence of the
placentae [3]. Hypertension is a common first clinical pres-
entation of pre-eclampsia, appearing before the onset of
proteinuria in many cases [4].
Clinicians have traditionally relied on maternal risk
factors to determine which women are at risk, but there
are not biomarkers with high sensitivity and specificity for
pre-eclampsia; the problem being that many women have
these factors and do not develop gestational hypertension/
pre-eclampsia [57]. Signs and symptoms usually appear
late in pregnancy, even though the pathological mechan-
isms begin between the 8th and 18th week of pregnancy.
Since early prediction of gestational hypertension and
pre-eclampsia would allow close surveillance and preven-
tive strategies, many tests have been assessed until now.
However, no single test so far has met the clinical standards
for a predictive test and it is not clear whether routine
assessment of a range of haematological or biochemical
parameters in pregnant women would make it possible to
predict development of gestational hypertension [8].
Gestational hypertension has been recognised as a risk
factor for pre-eclampsia, its early detection and treatment
would allow a decrease in the incidence of pre-eclampsia.
Furthermore, hyperuricaemia in women with gestational
hypertension without proteinuria has been associated with
adverse fetal outcomes including small for gestational age
infant (SGA) and preterm birth [9]. Few studies have
focused their objectives in looking for specifically gesta-
tional hypertension predictors. We designed a prospective
study, which looks for markers of gestational hypertension
in healthy pregnant women.
We focus our study in classical biomarkers previously
associated with pre-eclampsia risk as a higher level of
cystacin-C [10], an abnormal lipid profile [11,12] or its shift
towards a dyslipidemic profile [13], the proinflammatory
marker C-reactive protein (CRP) [1416], and the presence
of obesity and overweight. We explore also other
Journal of Hypertension 2013, 31:23802385
a
Hypertension Unit. Hospital Clnico San Carlos,
b
Department of Clinical Chemistry,
c
Department of Epidemiology and Preventive Medicine and
d
Department of Gyne-
cology and Obstetrics, Hospital Clnico San Carlos. Instituto de Investigacio n Sanitaria
del Hospital Clnico San Carlos (IdISSC), Madrid, Spain
Correspondence to Nieves Martell-Claros, Hypertension Unit. Hospital Clnico San
Carlos. Instituto de Investigacio n Sanitaria del Hospital Clnico San Carlos (IdISSC),
C/Prof. Martn Lagos s/n. 28040 Madrid, Spain. Tel: +34629112113/34913303395;
fax: +34913303280; e-mail: nmartellc@uhta.es, nieves.martell@salud.madrid.org
Received 30 January 2013 Revised 1 July 2013 Accepted 16 July 2013
J Hypertens 31:23802385 2013 Wolters Kluwer Health | Lippincott Williams &
Wilkins.
DOI:10.1097/HJH.0b013e32836523f6
2380 www.jhypertension.com Volume 31 Number 12 December 2013
Original Article
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
biomarkers of pre-eclampsia, such as pregnancy-associated
plasma protein A (PAPP-A) and free-b human chorionic
gonadothrophin (b-HCG) [1720].
We also studied uric acid levels because in pregnancy
they have been proposed not only as a biomarker but also
to have a pathogenic role in the development of pre-
eclampsia in chronic hypertension settings [21,22].
The aim of the present study was to identify early
prognostic factors of gestational hypertension, and the
blood pressure (BP) levels evolution along pregnancy.
METHODS
Population sample studied
We designed a prospective study. We enrolled a total of 315
pregnant women referred from the Prenatal Diagnosis Unit
of Hospital Cl nico San Carlos in Madrid between weeks 10
and 13 of pregnancy. Participants were included the day of
the first trimester chromosomopathies screening (offered to
all pregnant women in Spanish national health system).
They were informed about the aim of the study and
provided written informed consent. Exclusion criteria were:
multiple gestation, chronic hypertension, previous cardio-
vascular events, and creatinine more than 1.3 mg/dl, hypo-
thyroidism, autoimmune diseases, diabetes mellitus,
morbid obesity, previous gestational diabetes, treatment
with methotrexate or antiepileptic drugs, previous gesta-
tional hypertension or pre-eclampsia and maternal age over
40 years.
During follow-up women were excluded if any of the
following conditions appeared: chromosomopathies, fetal
major morphological alterations, positive result in the 100 g
oral glucose tolerance test (ADA recommendations) [23],
spontaneous abortion, intrauterine growth restriction
(IUGR), intrauterine fetal death, or noncomplete obstetric
follow-up of the pregnancy.
The protocol was approved by the ethical committee of
the Hospital Cl nico San Carlos, Madrid, Spain. The pro-
cedures followed were in accordance with institutional
guidelines.
Measurements
We measured BP, height, and weight in the first (weeks
10th13th), second (weeks 20th22nd) and in the third
trimester (weeks 30th32nd). BP was measured with a
semiautomatic device with the women in a sitting position,
with the arm at the level of the heart, based on the average
of at least two measurements taken using the same arm [24].
The follow-up protocol consisted of obtaining each
trimester, on the same day as the obstetric routine echog-
raphy, a blood sampling after an overnight fast to measured
lipid profile (total cholesterol, HDL-cholesterol, triglycer-
ides); uric acid, creatinine, cystatin-C, uCRP. 24-h urine
collection was recovered to quantify proteinuria. The
PAPP-A and free-bHCG were measured only in the first
trimester. The measurement of urine proteins was per-
formed using the pyrogallol red methodology.
Gestational hypertension was defined as SBP at least
140 mmHg and/or DBP at least 90 mmHg in at least two
occasions with more than 6-h time interval, after the 20th
week of pregnancy. Pre-eclampsia was considered as
gestational hypertension and proteinuria (protein in urine
300 mg/24 h). The study was approved by our Hospital
Ethics Committee.
Statistical analysis
Qualitative variables were summarized by their frequency
distribution as well as quantitative variables by their mean
and SD. The continuous nonnormally distributed variables
were summarized by the median and interquartile range
(IQR: P
25
P
75
). For PAPP-A and free-bHCG was employed
as multiple of the median (MoM).
In the case of qualitative variables the comparison
between the gestational hypertension and non-gestational
hypertension groups was calculated by x
2
test, or by Fisher
exact test in case more than 25% of the expected values
were less than 5. For quantitative variables the Students
t-test or nonparametric median test (where appropriate)
was used to compare between the two groups.
The study has a 72% of power in uric acid for difference
detection in the first trimester. The study has a 92%of power
in SBP for the difference detection in the firs trimester.
ANOVA repeated measures analysis was used to study
the change in the levels of SBP and DBP between the two
groups.
Receiver operator characteristics (ROC) analysis was
calculated to assess the utility of the independent variables
(biomarkers) to distinguish gestational hypertension and
non-gestational hypertension group in the first trimester;
the area under curve (AUC) and its 95%confidence intervals
(95% CI) were calculated. For the biomarker variables that
showed a statistically significant AUC and based on the
optimal discriminatory point with the best combination of
sensitivity and specificity values, the cutoff points of the
biomarker variables were determined and new variables
were generated. Sensitivity, specificity and a 95% CI for the
new variables were determined.
In order to evaluate the role of the different new bio-
marker variables in the first trimester in the association with
gestational hypertension, a multiple logistic regression
analysis were performed. The model is based on stepwise
forward algorism with the P value set at 0.05 for entering
and 0.1 for exclusion. All results of the regression models
were presented using the odds ratio (OR) and its 95% CI.
For all determinations a P value less than 0.05 was
considered significant.
Statistical analysis was performed using SPSS V.15 stat-
istical package (SPSS, Chicago, Illinois, USA).
RESULTS
We enrolled 315 pregnant women on the same day as
obstetric routine echography. Out of them, 10% (n 32)
were not included in the statistical analysis (21 did not
complete the obstetric follow-up, three had intrauterine
deaths, three had a voluntary pregnancy interruption, three
were spontaneous abortions and two presented IUGR). In
the second and third visit, 8% (25) and 19% (60) of the total
enrolled pregnant women did not undergo blood sampling.
Mean age of our cohort was 30.25 4.71 years, and BMI
23.97 4.3 kg/m
2
. The clinical and biochemical character-
istics of the total group are shown in Table 1. The
Early predictors of gestational hypertension
Journal of Hypertension www.jhypertension.com 2381
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
cumulative incidence of gestational hypertension (followed
or not by pre-eclampsia) was 6.01% (95%, CI: 3.068.90).
From the 17 women who developed gestational hyperten-
sion, six also developed pre-eclampsia (2.1%).
We divided the sample in two subgroups, those with and
without gestational hypertension. The univariate analysis of
the first trimester and gestational hypertension status of the
measured biomarkers, clinical characteristics and BP
measurements are shown in Table 1.
The gestational hypertension group showed higher
levels of BMI, uric acid, SBP and DBP to be statistically
significant.
We also performed univariate analysis in the second
trimester variables. Only HDL-cholesterol was significantly
different (nongestational hypertension: 69.7 13.6; gesta-
tional hypertension: 61.8 14.9, P0.02).
We observed from the first trimester higher BP levels in
those who developed gestational hypertension, statistically
different compared with nongestational hypertension
(P<0.001). These differences were steady during preg-
nancy evolution (P<0.001) (Fig. 1).
The AUC values for the biomarkers and clinical variables
in the first trimester that showed statistically significant
differences between the two groups were calculated. All
variables showed a statistically significant AUC (Table 2,
Fig. 2).
According to the selection procedure previously
described a multiple logistic regression model was applied,
introducing the variables according to the cutoff points
selected. The multivariate analysis showed that for the first
trimester only uric acid and SBP were statistically significant
and independently associated to gestational hypertension
(Table 3). The sensitivity and specificity index in the uni-
variate analysis were similar for uric acid (>3.15 mmol/l and
SBP (>120 mmHg), as we showed previously. When both
these variables were combined the prediction value
improved the specificity (84.2) but reduced the sensitivity
(50%); AUC 0.75 (CI: 0.632-0.873) for the two-variable
combination.
DISCUSSION
In our cohort of healthy pregnant women we have ident-
ified a cut off level in BP and uric acid during the first
trimester as predictors of gestational hypertension.
The incidence of gestational hypertension and pre-
eclampsia in our prospective study is in concordance with
that previously reported in the general population [25].
Wilson et al. [26] reported in 1980 on 69 pregnant
women that in normal pregnancy the mean BP decreases
early in pregnancy, and by mid trimester diastolic levels are
often 10 mmHg lower than postpartum measurements,
approaching prepregnancy values near term.. In our cohort
(n285), we did not find any changes in BP across preg-
nancy in both groups. SBP and DBP levels were steady
higher in the gestational hypertension group than in the
nongestational hypertension. We found in the first trimester
that SBP at least 120 mmHg increased the risk of develop-
ment of gestational hypertension by 3.6-fold. Kenny et al.
[27] described the same SBP level in a cohort of pregesta-
tional women, as predictor of pre-eclampsia. Moreover,
Tranquilli et al. [28] concluded, with results of 24-h ambu-
latory BP monitoring registers, that a DBP more than
68 mmHg is a predictor of gestational hypertension in the
second trimester.
By identifying a set of biomarkers we may achieve the
appropriate predictive values to help in daily clinical prac-
tice, not having to rely on several conditions with low
prediction value for gestational hypertension.
During uncomplicated pregnancies, uric acid concen-
trations decrease by 2530% in early pregnancy but then
increase throughout pregnancy until the end of it, when
they approach nonpregnant values [29]. In our cohort, we
observed that uric acid was significantly higher in the first
trimester in women who developed gestational hyperten-
sion, with an increase of 4.02-fold (P0.01) in the risk of
developing gestational hypertension compared with non-
gestational hypertension pregnant women. Uric acid levels
higher than 5.2 mg/dl [25] or 4.7 mg/dl [4] have been
TABLE 1. Clinical and biochemical characteristics in total group and subgroups. Univariate analysis from1st trimester
Total Non-GH GH
P
(N283) (N266) (N17)
Mean, (SD) Mean, (SD) Mean, (SD)
T. cholesterol (mg/dl) 193.7 (31.2) 193.9 (31.2) 190.53 (31) 0.67
Triglycerides (mg/dl)

94 (73116.8) 94 (74116) 96 (66123) 0.76

HDL-Chol (mg/dl) 66.64 (12.6) 66.8 (12.4) 63.6 (15.5) 0.31
Creatinine (mg/dl) 0.69 (0.08) 0.69 (0.07) 0.75 (0.14) 0.08
Cystatin-C (mg/l) 0.52 (0.08) 0.51 (0.08) 0.54 (0.12) 0.34
Uric acid (mg/dl) 3.04 (0.67) 3.01 (0.67) 3.45 (0.62) 0.01
uCRP (mg/dl)

0.30 (0.140.78) 0.30 (0.140.76) 0.48 (0.151.20) 0.41

MoM bHCG

1.07 (0.71.5) 1.1 (0.71.5) 1.1 (0.71.9) 0.80

MoM Papp-A

1.1 (0.81.6) 1.4 (0.81.6) 0.9 (0.81.9) 0.18

BMI 23.97 (4.30) 23.7 (3.94) 28.1 (7.0) 0.02
SBP (mmHg) 115.8 (11.3) 115.2 (11) 125.4 (11) 0.001
DBP (mmHg) 69.2 (8.1) 69 (8) 77.3 (7.4) <0.001
Age at pregnancy 30.3 (4.7) 30.3 (4.8) 29.6 (3.5) 0.55
GH, gestational hypertension; HDL-Chol, HDL-cholesterol; uCRP, ultrasensitive C-reactive protein; Significant values in bold lettering. Values expressed as mean (SD).

Median [Interquartile range (IQR, p

25
p
75
)].
Martell-Claros et al.
2382 www.jhypertension.com Volume 31 Number 12 December 2013
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
NON-GH
GH
135
125.4
121.7
115.2
114.6
114.1
126.4
M
e
a
n

S
B
P

(
m
m
H
g
)

9
5
%

C
I
1 trimester 2 trimester 3 trimester
130
125
120
115
110
(a)
NON-GH
GH
85
77.3
75.9
68.7
67.4
69.7
78.6
M
e
a
n

D
B
P

(
m
m
H
g
)

9
5
%

C
I
1 trimester 2 trimester 3 trimester
80
75
70
65
(b)
FIGURE 1 Evolution of SBP in both groups. P <0.001 for the three quarters.
TABLE 2. Receiver operator characteristics analysis and individual discriminative capacity
First Trimester
AUC P Sensitivity Specificity
P

RR

(CI 95%) (CI 95%) (AUC) (%) (%)

BMI >24 0.70 (0.550.84) 0.006 64.7 61.2 0.03 2.70 (1.037.09)
Uric acid (mg/dl) >3.15 0.69 (0.570.82) 0.008 76.5 65.8 <0.001 5.59 (1.8716.68)
SBP (mmHg) 120 0.74 (0.620.87) 0.002 71.4 62.5 0.02 3.83 (1.2311.86
DBP (mmHg) 71 0.78 (0.680.87) 0.000 71.4 66.8 0.007 4.57 (1.4714.2)

Unadjusted values. AUC, area under the curve. Significant values in bold lettering.
1.0
0.8
0.6
0.4
0.2
0.0
S
e
n
s
i
t
i
v
i
t
y
0.0 0.2 0.4 0.6 0.8 1.0
1specificity
(a)
1.0
0.8
0.6
0.4
0.2
0.0
0.0 0.2 0.4 0.6 0.8 1.0
S
e
n
s
i
t
i
v
i
t
y
1specificity
(b)
FIGURE 2 Receiver operator characteristics (ROC) curves uric acid 1st trimester.
Early predictors of gestational hypertension
Journal of Hypertension www.jhypertension.com 2383
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
described in pregnancies with gestational hypertension
associated with 2.3-fold higher odds of progression to
pre-eclampsia [25]. Early detection of gestational hyperten-
sion is important in order to reduce the progression to pre-
eclampsia, furthermore each week of delay in the onset of
gestational hypertension was associated with about 50%
reduction in the odds of progression to pre-eclampsia [4].
The relevance of our results is the finding of a threshold
level of uric acid in the first trimester as predictor of gesta-
tional hypertension. As an external validation, if we applied
our threshold of 3.15 mg/dl in the first trimester to the
Bellomos gestational hypertension cohort all the women
could be detected before gestational hypertension was
established.
Nevertheless, Laughon et al. [30], in her study found no
risk of development gestational hypertension with higher
uric concentration in the first trimester. But when the
authors compared women who remained normotensive
to those who developed hypertensive disease by the pres-
ence or absence of hiperuricemia, the mean first trimester
uric acid concentration was significantly lower in normo-
tensive women compared with women who developed
the hiperuricemic forms of gestational hypertension and
pre-eclampsia. The elevated uric acid in the first trimester
may represent concentrations before pregnancy, such as
from metabolic syndrome or prehypertension, reported
increases in xanthine oxidase, a synthetic enzyme for uric
acid, in pre-eclamptic women [30]. Uric acid increased may
be induce by reduced renal clearance, and increased plan-
cental production due to placental ischemia and increased
trophoblast shedding, leading to further purine availability
[25].
Kidney biomarkers as creatinine or more sensitive
marker for subtle changes of glomerular filtration rate in
pregnancy as cystatin C [31] have been used as variables for
the gestational hypertension severity, but not as early
predictors. Also, we did not find relationship of creatinine
or cystatin C levels with the presence of gestational hyper-
tension.
Regarding lipid profile, hypertriglyceridemia and total
cholesterol have been positively correlated with the devel-
opment of pre-eclampsia [1113]. Nevertheless these cor-
relations may be confounded by the presence of diabetes
mellitus, obesity, nonfasting sampling or ethnic differences.
We did not find association between the levels of trigly-
cerides in gestational hypertension compared with non-
gestational hypertension pregnant women.
The uCRP did not show discriminative capacity between
groups in our cohort; neither did it seem to have a role in
prediction of gestational hypertension. Also we did not find
any association between MoM bHCG and PAPP-A with
gestational hypertension. Poon et al. [32] described a
specific algorithm for the calculation of patients specific
risks for early and late pre-eclampsia and gestational
hypertension, based in a combination of factors in the
maternal history, the measurement of MAP and uterine
artery pulsatility index and maternal serum levels of
placental growth factor including PAPP-A that only pre-
dicted 18% of gestational hypertension. So, this protein
does not seem to be a specific marker for development
of gestational hypertension.
Due to the low frequency of gestational hypertension in
pregnancy in healthy women, the results of our study are
underpowered and should be replicated/proved in larger
studies.
In conclusion, in our cohort of healthy pregnant women
SBP more than 120 mmHg and uric acid above 3.15 mg/dl
are consistent predictors of gestational hypertension in the
first trimester. The most important implication of this study
is the possibility to identify in the first trimester women at
risk to develop gestational hypertension using available
markers.
ACKNOWLEDGEMENTS
Conflicts of interest
The authors do not have any conflict of interest.
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Reviewers Summary Evaluations
Reviewer 1
Gestational hypertension is the most common medical com-
plication of pregnancy and is associated with increased
maternal, fetal, and neonatal morbidity and mortality. In a
cohort of 315 healthy pregnant women, uric acid 3.15 mg/
dl and systolic BP 120 mmHg in the first trimester were
found to be predictive of gestational hypertension.
The results have to be interpreted with caution as the
incidence of gestational hypertension was low, and there-
fore error of small numbers cannot be excluded. The results
are applicable only to low-risk populations, as females with
known and widely accepted risk factors for developing
preeclampsia were excluded: multiple gestation, chronic
hypertension, chronic kidney disease, autoimmune dis-
ease, diabetes mellitus, morbid obesity, previous gesta-
tional hypertension or preeclampsia, and maternal age
over 40.
Reviewer 2
The search for predictive markers of gestational hyperten-
sion (and preeclampsia) is still a puzzling open question. To
date there is no marker to predict with sufficient certainty
the subsequent development of gestational hypertension in
normotensive pregnant women. The research here pre-
sented by Martell-Claros and co workers tries to give an
answer to the problem. In a well designed prospective
study and with a multivariate analysis the authors identified
two simple markers which were altered by the first trimester
in women who subsequently developed gestational hyper-
tension: increased uric acid and SBP over 120 mmHg. If
these results are confirmed in a larger series of women this
would offer a simple prognostic tool. A limitation of this
nice piece of work is the relatively small series, and the
possibility that a BP over the normal pregnancy range
would rather be the expression of a general tendency to
hypertension rather than to true gestational hypertension,
which is a condition due to impaired placentation.
Early predictors of gestational hypertension
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