Clinica Chimica Acta 464 (2017) 218222

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Clinica Chimica Acta

journal homepage: www.elsevier.com/locate/clinchim

Hematocrit and plasma albumin levels difference may be a potential

biomarker to discriminate preeclampsia and eclampsia in patients with
hypertensive disorders of pregnancy
Dong-Mei Dai a, Jing Cao a, Hong-Mei Yang b, Hai-Mei Sun a, Yu Su a, Yuan-Yuan Chen a,
Xiao Fang a, Wang-Bin Xu a,
a
Department of Intensive Medicine, The First Afliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
b
Department of Gynecology, The Geriatrics Hospital of Yunnan Province, Kunming, Yunnan 650041, China

a r t i c l e i n f o a b s t r a c t

Article history: Background: We evaluated whether alterations of hemoglobin (HB), hematocrit (HCT), serum albumin level
Received 19 October 2016 (ALB), and the difference of HCT and ALB can be used in the diagnosis of preeclampsia and eclampsia in patients
Received in revised form 21 November 2016 with hypertensive disorders of pregnancy (HDP).
Accepted 1 December 2016 Methods: A total of 509 individuals were recruited and divided into 4 groups: Group 1, 170 healthy nonpregnant
Available online 3 December 2016
women; Group 2, 125 normal pregnant women; Group 3, 105 pregnant women diagnosed with gestational and
chronic hypertension; Group 4, 109 pregnant women diagnosed as having preeclampsia and eclampsia. Data of
Keywords:
Hypertensive disorders of pregnancy (HDP)
HB, HCT, ALB, globulin (GLB) were collected at the time of a prenatal examination during the third trimester.
Eclampsia Results: Alterations in the HCT and the ALB levels in these groups were signicantly different. Group 4 had a
Preeclampsia higher mean HCT-ALB value (P b 0.01), but lower ALB and GLB values compared with the other three groups.
Hematocrit (HCT) We used Groups 2 and 3 as the respective reference to draw the receiver operating characteristic (ROC) curves
Albumin (ALB) of HCT-ALB in Group 4, and found that the threshold values of maximum index corresponding were 12.95 and
12.65 (sensitivity N 57.0%, specicity N 98.9%), respectively.
Conclusions: The value of HCT-ALB N 12.65 might be used as a potential biomarker for the auxiliary diagnosis of
preeclampsia and eclampsia in HDP.
2016 Elsevier B.V. All rights reserved.

1. Introduction to increased vascular permeability and in turn to hemoconcentration,

The hypertensive disorders of pregnancy (HDP) remain a major
cause of maternal and fetal morbidity and mortality. Preeclampsia, by it-
self, is a complication in 5% to 10% of pregnancies worldwide [13]. The
clinical characteristics of HDP are high blood pressure affecting the func-
tion and causing physical damage to multiple organs, such as heart,
lung, kidney, blood and nervous system. The American College of Obste-
tricians and Gynecologists has classied hypertension during pregnancy
into 4 categories: 1) Gestational hypertension, 2) Preeclampsia and
eclampsia, 3) Chronic hypertension, and 4) Preeclampsia superimposed
on chronic hypertension [4]. At the present time, the clinical diagnosis of
preeclampsia is dened by nding an elevated blood pressure and/or
the severity of 24-h urine protein [5]. However, proteinuria is a poor
predictor of either maternal or fetal complications in women with pre-
eclampsia [6].
The pathophysiological basis of preeclampsia and eclampsia is the in-
jury to systemic small arteries and capillary endothelial cells, which leads
Corresponding author at: Department of Intensive Medicine, The First Afliated
Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
E-mail address: xwbyn@126.com (W.-B. Xu).
hypoalbuminemia and edema [7,8]. Therefore, there may be an increase
of hematocrit (HCT), a reduction of serum albumin (ALB), and an in-
crease in the HCT and ALB difference in patients with preeclampsia and
eclampsia. The physiological increase of plasma volume would cause
changes of maternal blood components during pregnancy [9], such as a
decreased hemoglobin (HB) and ALB, and an increased HCT [10]. The ef-
fects of the pregnancy-related changes in maternal HB, ALB and HCT
levels on the outcome of pregnancies have been widely studied
[1114]. It was proposed that the increased HCT, HB and red cell mass
in early pregnancy can be considered as a risk factor for preeclampsia
[15], and the changes in HCT levels between the rst half and the second
half of pregnancy might suggest preeclampsia [12].
2. Materials and methods
2.1. Study subjects and ethics statement
All the subjects were enrolled in the First Afliated Hospital of Kun-
ming Medical University (KMU) from January 2013 to October 2015.
We collected the related data of HB, HCT, ALB, GLB, height, weight and
gestational situation of each participant. The diagnostic criteria of HDP

http://dx.doi.org/10.1016/j.cca.2016.12.001
0009-8981/ 2016 Elsevier B.V. All rights reserved.
 D.-M. Dai et al. / Clinica Chimica Acta 464 (2017) 218222 219

were based on the clinical characteristics as previously reported [16]
and were listed in Table 1. The subjects were divided into 4 groups:
Group 1 has 170 healthy nonpregnant women who attended for a
physical examination in the First Afliated Hospital of KMU, with an
age ranging from 20 to 40 y. Group 2 has 125 normal pregnant
women who delivered a baby in the same hospital, with an age from
21 to 37 y. Group 3 has 105 patients who were diagnosed as having
HDP, but without preeclampsia/eclampsia. These patients aged from
26 to 36 y, including 70 patients with gestational hypertension and 35
patients with chronic hypertension. Group 4 has 109 patients who
were diagnosed as already having preeclampsia and eclampsia
(including 6 preeclampsia, 86 severe preeclampsia and 17 eclampsia
patients), with an age from 17 to 43 y (Table 2). The value of the HCT-
ALB difference was calculated for each group. Pregnant women who
had received blood or protein products by infusion, developed gesta-
tional moderate to severe anemia, gestational severe bacterial infection
disease, intrauterine fetal death or severe liver and kidney diseases were
excluded from this study.
The Ethics Committee of the First Afliated Hospital of KMU ap-
proved the study protocol for the collection of blood samples. Written
informed consent was obtained from each subject. The procedures
were carried out in accordance with the approved guidelines.

2.2. Statistical analysis

Table 1
Diagnostic criteria of with the hypertensive disorders of pregnancy.
Hypertensive disorders of
pregnancy
Gestational hypertension
Chronic hypertension
Preeclampsia/eclampsia
Preeclampsia superimposed
on chronic hypertension
a
Mainly based on the previously reported criteria [16].
Clinical characteristicsa
Onset of hypertension after gestational week 20,
blood pressure 140 mmHg systolic or 90
mmHg diastolic, and 12 weeks postpartum
returns to normal, and the urinary protein test
negative; patient with blood pressure 160
mmHg systolic or 110 mmHg diastolic was
diagnosed as having severe gestational
hypertension.
Presence or history of hypertension
preconception or in the rst half period of
pregnancy, blood pressure 140 mmHg systolic
or 90 mmHg diastolic, and no aggravation
during the gestation period; Or patient diagnosed
as hypertension from 20 weeks of pregnancy and
continuing past 12 weeks postpartum. Urine
protein test negative.
Preeclampsia. De novo hypertension (blood
pressure 140/90 mmHg) after gestational week
20, and new onset of one or more of the
following: proteinuria 0.3 g/24 h or urinary
protein/creatinine ratio 0.3 or random urinary
protein (+) when it unable to carry out urinary
protein quantitation; Urine protein test negative,
but with any of the organs (heart, lung, liver,
kidney etc.) or systems (blood system, digestive
system, nervous system) involved. Blood pressure
and/or urinary protein levels continue to rise.
Severe preeclampsia. Patient with preeclampsia
appear with any of the following: (1) blood
pressure 160 mmHg systolic or 110 mmHg
diastolic; (2) persistent headache, visual
disturbances or other central nervous system
abnormalities; (3) persistent pain of epigastrium
and liver subcapsular hematoma or rupture of the
liver; (4) elevated blood alanine
aminotransferase (ALT) or aspartate
aminotransferase (AST) levels; (5) impaired
renal function: proteinuria 0.3 g/24 h; oliguria
(24 h urine output b 400 ml, or hourly urine
output b17 ml) or serum creatinine N 106 mol/l;
(6) hypoalbuminemia with ascites, pleural or
pericardial effusion; (7) hematological disorders,
like platelet count was persistent decline and b
100 109/l. and microvascular hemolysis
(anemia, jaundice or elevated blood lactate
dehydrogenase (LDH) levels); (8) heart failure;
(9) pulmonary edema; (10) fetal growth
restriction or oligohydramnios, fetal death and
placental abruption.
Eclampsia. Other signs that cannot be explained
on the basis of preeclampsia, convulsions
Patients with proteinuria 0.3 g/24 h or random
urinary protein (+) after gestational week 20;
proteinuria before 20 weeks of pregnancy and
signicantly increased urinary protein excretion
after gestational week 20; further increase in
blood pressure and with any other feature of
severe preeclampsia.
The values of HB, HCT, ALB, GLB and HCT-ALB were presented as the
mean SEM. The difference between two groups was compared by
using the Student's t-test, whereas differences between three or more
groups were evaluated by one-way analysis of variance (ANOVA). The
ROC curves of HCT-ALB of Group 4 were prepared by using Groups 2
and 3 as the reference standard, respectively. We calculated AUC and
the right index, and took the largest right index corresponding indica-
tors to calculate the diagnostic threshold. All statistical analyses were
performed by using SPSS (ver 21.0). A P b 0.05 was regarded as statisti-
cally signicant.
3. Results and discussion
The subjects in the 4 groups under study had a similar age (P N 0.05;
Table 2) and were from the same geographical region. There was also no
statistically signicant difference in the gestational age at enrolment in
the subjects of Groups 2, 3 and 4 (P N 0.05 data not shown). Therefore,
potential differences of HB, HCT and ALB among the groups might re-
ect the different nature of their diseases, leaving aside any genetic ef-
fect. All tested variables (HB, HCT, ALB, GLB and HCT-ALB) were
normally distributed according to the Kolmogorov-Smirnov test
(P N 0.05), except for HB level in Group 1 (P = 0.005). Compared with
Group 1, the levels of HB, HCT and ALB were decreased and the levels
of HCT-ALB were increased in Groups 2 and 3 (P b 0.01; Table 3). The
level of HCT-ALB was also increased (P b 0.01; Table 3) in Group 4,
which had a decreased levels of ALB. Group 4 had an increase of HB,
HCT and HCT-ALB levels and a decreased ALB and GLB levels in compar-
ison with those of Group 2 and Group 3 (P b 0.01; Table 3). Note that
most of eclampsia patients (13/17) had a high HCT-ALB level (N12) in
Group 4. When we took Group 2 and Group 3 as the respective reference
to draw the ROC curves of HCT-ALB of Group 4 (See Fig. 1), we found
that the AUC were 0.786 and 0.804, respectively. The cut-point of
HCT-ALB values were 12.95 (with sensitivity of 57% and specicity of
99.2%) and 12.65 (with sensitivity of 58.1% and specicity of 98.9%)
base on Youden index (Table 4), respectively. These results suggested
that HCT-ALB levels difference might be of reasonably good sensitivity
and high specicity for the diagnosis of preeclampsia and eclampsia.
During pregnancy, the maternal vascular tone is decreased and both
cardiac output and blood volume are increased to supply enough oxy-
gen and nutrients to the fetus and placenta [17]. Long before the forma-
tion of the placenta, the reactivity of blood vessels against angiotensin II
and catecholamine is reduced. Meanwhile, the increase in endothelial
prostacyclin and nitric oxide production causes a decrease in systemic
vascular tone, vasodilation, a decrease of cardiac afterload and barore-
ceptor activation, thereby resulting in an increase in the heart rate, car-
diac output, cardiac contractility and increased systemic vein transfer to
artery. At the same time, changes in the renin-angiotensin-aldosterone
system and the increase in secretion of cortisol and antidiuretic hor-
mone cause an increase of blood volume to restore cardiac preload.
The decreased vascular reactivity also inhibits the release of atrial natri-
uretic peptide [18]. As the pregnancy progresses, increased estrogen
levels promote sodium retention by increasing the hepatic synthesis
220 D.-M. Dai et al. / Clinica Chimica Acta 464 (2017) 218222

Table 2
Clinical characteristics of the subjects enrolled in this study.

Characteristics Group 1 Group 2 Group 3 Group 4

Number, n 171 125 105 109

Maternal age, year 32.89 8.83 26.78 4.54 31.77 4.95 31.40 5.59
BMI, kg/m2 21.38 3.38 27.20 6.11a 28.75 5.29a 28.56 4.40a
Gestational week at delivery, week 38.3 1.78 36.94 5.20 33.27 4.12

Group 1: healthy nonpregnant women; Group 2: women with normal pregnancies; Group 3: women with gestational hypertension and chronic hypertension; Group 4: women with
preeclampsia and eclampsia.
a
Compared with Group 1, P b 0.01.

Table 3
Comparison of the values of HB, HCT, ALB, GLB and HCT-ALB in the 4 groups of subjects.

Characteristics Group 1 (n = 170) Group 2 (n = 125) Group 3 (n = 105) Group 4 (n = 109)

a a
HB, g/l 138.81 7.80 130.08 11.7 129.46 11.9 137.90 20.90b,c
HCT, % 41.97 2.21 39.50 3.06a 39.04 3.32a 41.45 6.15b,c
ALB, g/l 42.48 2.16 31.48 2.41a 31.32 3.18a 26.79 4.68a,b,c
GLB, g/l 31.38 2.81 32.95 3.15a 32.97 4.13a 30.50 6.33b,c
HCT-ALB 0.51 2.56 8.02 3.08a 7.53 3.10a 14.65 6.97a,b,c

HB - Hemoglobin concentration; HCT - Hematocrit; ALB - Serum albumin; GLB - Globulin.

a
Compared with Group 1, P b 0.01.
b
Compared with Group 2, P b 0.01.
c
Compared with Group 3, P b 0.01.

of angiotensinogen [19]. In addition, the uterine placental circulation (a
low resistance physiological arteriovenous shunt) also stimulates the
increase in blood volume [20]. These effects contribute to an increase
of blood volume by 40%47% [21], cardiac output by 3040% [22], and
uterine blood ow by about 8 fold [23] in the late stages of a normal
pregnancy. Any disease that changes these normal physiological mech-
anisms can be expected to adversely affect a pregnancy.
Maternal blood volume begins to increase in the rst trimester of
pregnancy, and 12 weeks after menelipsis, the expansion of the blood
volume is about 15% as compared to a non-pregnant woman [24]. The
rate of increase of blood volume is fastest in gestational week 12, signif-
icantly slows after gestational week 12, and then maintains a constant
level until the last weeks of pregnancy. The increase of plasma and red
blood cells leads to an increase in blood volume. Normally, plasma
increases more than red blood cells, and the body is therefore in a rela-
tively anemic state in pregnancy, so that hemoglobin and hematocrit
levels are reduced in pregnant women. The average hematocrit is
about 37.5% at delivery [25]. Due to the increase of blood volume, albu-
min is diluted and becomes relatively lower. In this study, we conrmed
the decreased levels of hemoglobin, hematocrit, and albumin in healthy
pregnant women as compared to the levels found in healthy non-
pregnant women.
Previous studies of pregnant women who had gestational hyperten-
sion without proteinuria showed an inconsistent result of blood volume
changes when compared to non-pregnant women. For instance, Gallery
et al. [26] reported that the plasma volume was reduced, while Brown
et al. [27] found that there was no change of plasma volume in gesta-
tional hypertension. The difference of baseline and the measurement

Fig. 1. The ROC curves of HCT-ALB difference in Group 4 with Group 2 (A) or Group 3 (B) as the reference standard.
 D.-M. Dai et al. / Clinica Chimica Acta 464 (2017) 218222
Table 4
The characteristics of the ROC curves of the HCT-ALB differences in Group 4.
Item Reference AUCa Threshold Sensitivity Specicity
standard
HCT-ALB Group 2 0.786 12.95 57.0% 99.2%
Group 3 0.804 12.65 58.1% 98.9%
a
AUC: the area under curve.
methods may account for the differences between these two studies.
Silver et al. [28] measured blood volumes of 15 pregnant women with
hypertension at late pregnancy and found that there was no statistically
signicant difference of plasma and red blood cell volume between nor-
motensive pregnant women and women with gestational hypertension
in late pregnancy. The pregnancy-induced hypertension in pregnant
women is also in a relatively anemic state and the levels of hemoglobin
and hematocrit are reduced, which is consistent with that of normoten-
sive pregnant women. We conrmed this observation in this study and
found that the levels of hemoglobin, hematocrit and albumin are de-
creased in women affected by gestational hypertension and chronic hy-
pertension in pregnancy.
The expected increase in blood volume has been found to be signif-
icantly limited in preeclampsia and eclampsia patients. Pritchard et al.
[29] reported that on average the blood volume increases by 47% during
normal pregnancy, however, the change in blood volume of women
with eclampsia in late pregnancy was limited, and increased by only
16%. Similarly, Zeeman et al. [30] reported that 44 pregnant women in
the third trimester had an increase of about 47% of blood volume as
compared to their non-pregnant level. However, in 29 cases of pre-
eclampsia, the blood volume was only increased by about 9%. Salas
et al. [21] monitored the plasma volume of 17 patients with preeclamp-
sia and 95 normotensive pregnant women, and demonstrated that the
plasma volume of women who developed preeclampsia (about
2290 ml) was different from normal pregnant women (about
2460 ml) by gestational week 12. This difference reached a peak at the
gestational weeks 1417 (2325 ml for patients with preeclampsia and
2609 ml for normal pregnant women) and continued into the third tri-
mester. Therefore, the difference in plasma volume between women
who develop preeclampsia and normotensive pregnant women occurs
in early pregnancy. Dysfunction of the renin-angiotensin-aldosterone
system and vasodilator system, resulted in an increase of peripheral vas-
cular resistance, decline of cardiac output, limitation of blood volume
expansion, and elevation of blood pressure in preeclampsia patients
[25]. The dysfunction of vasomotor and endothelial damage in pre-
eclampsia patients caused an increased vascular permeability which
accounted for the limited blood volume amplication, and this was ag-
gravated when the patients had hypoalbuminemia. In preeclampsia pa-
tients, capillary endothelial cell damage and albumin leakage into the
interstitial space caused hemoconcentration, hypoalbuminemia and
edema [16,31], resulting in HCT elevation and ALB reduction, nally
lead to a higher HCT-ALB difference. We conrmed this speculation in
our study. We showed that the levels of HB and ALB, except for HCT,
were signicantly decreased in our preeclampsia patients as compared
to women with normal pregnancies, gestational hypertension, or chron-
ic hypertension in pregnancy. The HCT-ALB value increased in normal
pregnancy (mean SEM, 8.02 3.08), gestational hypertension and
chronic hypertension with pregnancy (mean SEM, 7.53 3.10) com-
pared with healthy nonpregnant women (mean SEM, 0.51
2.56). In particular, the HCT-ALB value of patients with preeclampsia
and eclampsia (mean SEM, 14.65 6.97) was much higher than
any of the other groups under study, suggesting that the HCT-ALB differ-
ence could be used as a potential biomarker, albeit arbitrary, in the diag-
nosis of preeclampsia and eclampsia patients in HDP. It is to be noted
that we collected the data of HB, HCT, ALB, GLB from all the pregnant
women at the time of a prenatal examination during the third trimester,
but a patient with preeclampsia can be dened as having the condition
221
after 20 weeks of gestation by measuring the blood pressure and detect-
ing proteinuria. Future study with a large sample size is needed to show
Youden whether the value of HCT-ALB is raised from 20 weeks of gestation. In
index addition, we did not analyze patients with preeclampsia and patients
0.562 with eclampsia separately in this study, as the sample size of eclampsia
0.570 patients was relatively small and probably had no sufcient statistical
power, albeit that most of eclampsia patients (13/17) had a high HCT-
ALB value (N 12).
In short, we used the ROC analysis to estimate the predictive ability
of HCT-ALB levels difference for discriminating preeclampsia and
eclampsia in patients with HDP. We found that HCT-ALB difference (es-
pecially N 12.65) might be a potential biomarker in pregnant women
who are developing preeclampsia or eclampsia.
Acknowledgments
We thank Ian Logan for language editing. This study was supported
by the Science Research Project of Yunnan Province Education Depart-
ment (2014C050Y).
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