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Received: 7 June 2016    Revised: 17 August 2016    Accepted: 27 October 2016    First published online: 16 November 2016

DOI: 10.1002/ijgo.12029


Association of biochemical markers with the severity of


Ahmed M. Maged* | Gamal Aid | Nehal Bassiouny | Doaa S. Eldin | Sherif Dahab | 

Nevein K. Ghamry

Department of Obstetrics and

Gynecology, Kasr AlAiny Hospital, Cairo Abstract
University, Cairo, Egypt Objective: To assess the association between pre-­eclampsia severity and biochemical
*Correspondence and ultrasonography markers.
Ahmed M. Maged, Haram, Giza, Egypt. Methods: A retrospective study was undertaken of women with severe pre-­eclampsia
(group 1, n=90), mild pre-­eclampsia (group 2, n=90), or a normal pregnancy (group 3,
n=90) who attended a hospital in Egypt in October 2013–April 2015. Associations
between pre-­eclampsia and biochemical, cardiotocography, and ultrasonography
markers were investigated.
Results: There were significant differences between the groups in C-­reactive protein
(331.44±112.38, 251.43±59.05, and 23.81±16.19 nmol/L; P≤0.05 for all), platelet
count (113.40±36.72, 172.93±57.60, and 212.68±70.00×109/L; P≤0.05 for group 1
comparisons), alanine transaminase (52.24±14.83, 38.34±13.12, and 23.11±6.92 U/L;
P≤0.05 for group 1 comparisons), and serum uric acid (600.80±117.19, 481.83±118.97,
and 243.89±53.54 μmol/L; P=0.050 for group 3 comparisons). Cardiotocography
score was worse among women with severe pre-­eclampsia than among those in the
other two groups (P=0.039 for both comparisons). Biophysical profile score and
­umbilical artery resistance index differed by group (P≤0.05 for all). Middle cerebral
artery resistance index was lower among women with severe pre-­eclampsia (P≤0.05).
Conclusion: The levels of C-­reactive protein, blood urea nitrogen, serum uric acid, and
alanine transaminase, and the platelet count were linked with the presence and severity
of pre-­eclampsia.

Biochemical markers; C-reactive protein; Maternal complications; Neonatal complications;
Severe pre-eclampsia

1 | INTRODUCTION a leading cause of perinatal mortality and morbidity worldwide.3 The

prevalence of pre-­eclampsia in nulliparous populations ranges from 3%
Pre-­eclampsia is a disorder of pregnancy that can affect nearly every to 10%.4 The frequency in multiparas is lower than that in nulliparas.4
organ system. Its pathogenesis is uncertain, but the initial step is The diagnosis of pre-­eclampsia is difficult. The symptoms in-
widely thought to be placental ischemia resulting from inadequate clude hypertension and signs of multiple organ disease.5 Severe pre-­
trophoblast invasion because of insufficiently remodeled uterine spiral eclampsia is characterized by any one of six signs: a systolic blood
arteries.2 The syndrome affects 2%–8% of pregnancies and remains pressure of 160 mm Hg or higher, or a diastolic blood pressure of

138  |

© 2016 International Federation of Int J Gynecol Obstet 2017; 136: 138–144
Gynecology and Obstetrics
Maged ET AL. |

110 mm Hg or higher on two occasions at least 4 hours apart (with level, total leukocyte count, platelet count) had been obtained using
the woman on bed rest and before the initiation of antihypertensive a CELL-­Dyn 3700 analyzer (Abbott, St Paul, MN, USA) and kits sup-
therapy); thrombocytopenia; impaired liver function; progressive plied by Spectra Group (Mannheim, Germany). The prothrombin time,
renal insufficiency; pulmonary edema; or new-­onset cerebral or visual prothrombin concentration, and international normalized ratio (INR)
disturbances.6 had been assayed on an STA Compact CT analyzer (Diagnostica Stago,
The pathophysiology of pre-­eclampsia involves endothelial Parsippany, NJ, USA) using kits supplied by Etico (Dokki, Giza, Egypt).
cell dysfunction and inflammation. For example, pre-­eclampsia is Blood urea nitrogen, creatinine, aspartate transaminase (AST), alanine
­associated with generalized activation of circulating leukocytes and transaminase (ALT), alkaline phosphatase (ALP), electrolytes (sodium,
­increased concentrations of C-­reactive protein (CRP).7 Therefore, the potassium), uric acid, and CRP had been assayed on an Dimension
current study was designed to assess the association between serum Xpand Plus system (Siemens Healthcare, Erlangen, Germany) using
biochemical markers and the severity of pre-­eclampsia. kits supplied by Siemens Medical Solutions Diagnostics (Los Angeles,
CA, USA). The results were compared between the three groups for
the present study.
2 | MATERIALS AND METHODS All women had also undergone transabdominal obstetric ultra-
sonography examination using a SonoAce X6 machine (Samsung
The present retrospective study included 270 women with a singleton Medison, Seoul, South Korea) equipped with a 4–7-­MHz transabdom-
pregnancy of 34–40 weeks and a viable fetus who were seen at the inal 3D4-­7EK probe (also from Samsung Medison). The examination
outpatient clinic, casualty department, or high-­risk department at Kasr was performed in the supine position with a slight left lateral tilt to
AlAiny Hospital in Cairo, Egypt, between October 1, 2013, and April avoid supine hypotension. The aims of the examination were to con-
30, 2015. The study included 90 women with severe pre-­eclampsia (as firm the pregnancy duration (originally estimated by matching the
defined by the American College of Obstetricians and Gynecologists6), dates obtained from the last menstrual period and the first-­trimester
90 with mild pre-­eclampsia, and 90 who were normotensive and had ultrasonography scan), to evaluate the fetal viability, to estimate the
no medical disorders (control group). Pre-­eclampsia was diagnosed fetal weight, to assess for placental separation, to measure the volume
as the development of hypertension—defined as a persistent systolic and turbidity of the amniotic fluid, to perform a detailed anomaly scan,
blood pressure of 140 mm Hg or higher or a diastolic blood pressure and to assess fetal well-­being (biophysical profile test; measurement of
of 90 mm Hg or higher—after 20 weeks of pregnancy in a woman the resistance indices of the umbilical artery [UA] and middle cerebral
with previously normal blood pressure, alongside additional diagnostic artery [MCA]).8
signs such as new-­onset proteinuria. Women with a multiple preg- Doppler studies of the UA and MCA had been conducted in color
nancy, chronic hypertension, diabetes mellitus, or a history of cardiac, mode with a curvilinear transabdominal probe and at a Doppler angle
liver, or renal disease were excluded from the study. Further exclusion close to 0 degrees (with the Doppler ultrasound beam being parallel to
criteria were intrauterine fetal death, an apparent congenital anomaly, the direction of blood flow). The UA was visualized in a segment of the
and a history of rupture of membranes. The study was approved by cord where it was possible to keep the beam parallel to the blood flow;
the local ethics committee. All participants had provided consent for the MCA was visualized near its separation from the ­internal ­carotid
the inclusion of their data. artery. The measurements were obtained during periods of fetal
The 90 women in each group were randomly selected from the ­inactivity and apnea. Average readings from at least three ­consecutive
overall pool of eligible women who attended the study center in the waveforms were used to calculate the resistance index of the UA and
study period. Random numbers in sealed envelopes were used for ran- the resistance index of the MCA.
dom selection. Cardiotocography (CTG) had been performed to assess the fetal
Data were recorded for age, gravidity, parity, date of the last nor- heart rate; the tracings were classified as normal, suspicious, of
mal menstrual period (to estimate the pregnancy duration), medical pathologic as per Royal College of Obstetricians and Gynecologists
history, and symptoms such as headache and visual disturbances. All criteria.9 Normal tracings indicated good fetal well-­being and led to
women had undergone a general and obstetric physical examination. a conservative approach to delivery; suspicious tracings resulted in
Blood pressure had been measured in a semi-­sitting position with the continuous observation and additional tests including vibroacoustic
woman’s arm supported and positioned at the level of the heart using stimulation; and pathological tracings were an indication for urgent
the first (systolic) and fifth (diastolic) Korotkoff sounds. Urine samples delivery.
were tested for proteinuria by the dipstick method. Mild proteinuria The primary outcomes were the associations between the pres-
was defined as a dipstick reading of 1+ or more in at least two mid- ence and severity of pre-­eclampsia and abnormal serum CRP, hemo-
stream samples 6 hours apart, and severe proteinuria was defined as globin, platelet count, blood urea nitrogen, creatinine, AST, ALT, and
a dipstick reading of 2+ on at least two midstream samples 6 hours ALP.
apart. The sample size was calculated on the basis of the assumption of a
Additionally, 5-­mL venous blood samples had been drawn on type-­1 error of 5%, a power of 90%, and a prevalence of pre-­eclampsia
­admission (before any magnesium sulfate administration) and analyzed of 3%–10%,4 and was estimated to be 87 women per group using an
at Kasr AlAini Hospital laboratory. A complete blood count (hemoglobin uncorrected χ2 test.
140       Maged ET AL.

All statistical calculations were performed using SPSS version 17 With regard to the biochemical variables, there were no significant
(SPSS Inc, Chicago, IL, USA) for Microsoft Windows. One-­way ANOVA differences between the three study groups in the hemoglobin level,
was used to compare the three study groups. Spearman rank correla- the total leukocyte count, the creatinine level, the prothrombin time
tion was used to evaluate the correlation between serum levels of CRP and concentration, the INR, and the levels of AST, ALP, total bilirubin,
and blood pressure. P≤0.05 was considered statistically significant. and serum sodium and potassium (Table 2). The platelet count was sig-
nificantly lower and the ALT level significantly higher among women
with severe pre-­eclampsia compared with the other two groups,
3 |  RESULTS whereas blood urea nitrogen and serum uric acid were significantly
lower in the control group than among women with mild or severe pre-­
The three study groups did not differ significantly in terms of age eclampsia. There were also significant differences between the three
and body mass index (Table 1). Nulliparity was more common among study groups regarding the CRP level.
women with severe or mild pre-­eclampsia than among ­controls Ultrasonography revealed differences between the three study
(Table 1). The pregnancy duration at delivery among women with groups regarding the biophysical profile, the UA resistance index,
­severe pre-­eclampsia was significantly shorter than that among and the MCA resistance index; the differences were significant for
women with mild pre-­eclampsia or controls (Table 1). The mode of all comparisons between the two pre-­eclampsia groups and between
­delivery also differed significantly between the three study groups: the group with severe pre-­eclampsia and the control group (Table 3).
vaginal delivery was most common in the control group and least Cardiotocography scores were significantly higher among women with
­common among women with severe pre-­eclampsia (Table 1). There severe pre-­eclampsia than among those with mild disease or healthy
were also significant differences in the indication for cesarean controls (Table 3).
­delivery, with ­deterioration of the general condition being the most The CRP level was significantly correlated with the systolic blood
­common ­indication among women with severe or mild pre-­eclampsia, pressure among women with severe pre-­eclampsia, but not in any of
but not in the control group (Table 1). the other groups (Table 4).

T A B L E   1   Characteristics of the study population.a

P values
Group 1: severe Group 2: mild Group 3:
Characteristic pre-­eclampsia (n=90) ­pre-­eclampsia (n=90) control (n=90) 1 vs 2 1 vs 3 2 vs 3

Age, y 26.1±51.0 26.2±4.4 25.4±4.7 0.132 0.173 0.451

Body mass indexb 32.9±2.8 31.8±2.9 29.4±2.1 0.942 0.361 0.122
c c
Pregnancy duration at delivery, wk 35.5±1 37.4±1 38.3±1.6 0.050 0.040 0.364
Parity 0.443 0.018c 0.026c
Nulliparous 54 (60.0) 53 (58.9) 40 (44.4)
Multiparous 36 (40.0) 37 (41.1) 50 (55.6)
Mode of delivery 0.007c 0.001c 0.001c
Normal vaginal 20 (22.2) 35 (38.9) 58 (64.4)
Cesarean 70 (77.8) 55 (61.1) 32 (35.6)
Deterioration of 38 (54.3) 22 (40.0) 6 (18.8) 0.263 0.004c 0.020c
maternal conditiond
Abnormal BPP scoree 18 (25.7) 12 (21.8) 2 (6.3) 0.311 0.010c 0.029c
Previous cesarean 10 (14.3) 15 (27.3) 12 (37.5) 0.036c 0.004c 0.162
f c
Other 4 (5.7) 6 (10.9) 12 (37.5) 0.145 0.001 0.173
Blood pressure, mm Hg
Systolic 175±14 143±6 120±3 0.030c <0.001c 0.030c
Diastolic 116±14 92±5 70±4 0.021c <0.001c 0.030c

Abbreviation: BPP, biophysical profile.

Values are given as mean±SD or number (percentage), unless indicated otherwise.
Calculated as weight in kilograms divided by the square of height in meters.
Statistically significant (P≤0.05).
Worsening of the signs and symptoms of pre-­eclampsia.
Malpresentation or infertility.
Maged ET AL. |

T A B L E   2   Hematological, biochemical, and coagulation measures.a

P values
Group 1: severe Group 2: mild Group 3: control
Measure pre-­eclampsia (n=90) pre-­eclampsia (n=90) (n=90) 1 vs 2 1 vs 3 2 vs 3

Hemoglobin, g/L 130.30±19.10 123.01±13.10 112.01±11.10 0.372 0.171 0.501
9 b b
Platelets, ×10 /L 113.40±36.72 172.93±57.60 212.68±70.00 0.050 0.001 0.061
Total leukocyte count, ×109/L 6.96±1.82 6.85±1.43 6.61±1.29 0.562 0.442 0.521
Creatinine, μmol/L 97.24±35.36 97.24±35.36 79.56±17.68 >0.99 0.891 0.891
Blood urea nitrogen, mmol/L 9.25±3.75 7.71±3.96 5.68±2.31 0.124 0.001 0.050b
Aspartate transaminase, U/L 45.62±14.43 35.54±13.03 28.31±11.02 0.061 0.050 0.071
b b
Alanine transaminase, U/L 52.24±14.83 38.34±13.12 23.11±6.92 0.050 0.001 0.062
C-­reactive protein, nmol/L 331.44±112.38 251.43±59.05 23.81±16.19 0.050b 0.001b 0.001b
Alkaline phosphatase, U/L 280.21±96.60 255.41±73.22 245.50±48.01 0.122 0.091 0.343
Total bilirubin, μmol/L 5.34±2.74 5.64±1.71 5.13±1.71 0.873 0.562 0.882
Uric acid, μmol/L 600.80±117.19 481.83±118.97 243.89±53.54 0.453 0.050 0.050b
Sodium, mEq/L 135.00±3.52 137.11±3.02 139.41±3.74 0.782 0.664 0.673
Potassium, mmol/L 2.91±0.28 3.42±0.72 4.22±0.44 0.442 0.062 0.091
Coagulation profile
Prothrombin time, s 20.23±6.14 15.31±3.01 12.53±0.53 0.063 0.050b 0.542
Prothrombin concentration, % 72.24±10.04 86.12±6.12 98.34±4.03 0.114 0.050b 0.492
International normalized ratio 1.81±0.62 1.22±0.38 0.96±0.14 0.062 0.050 0.323
Values are given as mean±SD unless indicated otherwise.
Statistically significant (P≤0.05).

There were significant differences between women with se-

vere pre-­eclampsia and women in the other two groups in terms 4 | DISCUSSION
of maternal complications such as HELLP syndrome (hemolysis,
elevated liver enzyme levels, and low platelet levels) and eclamp- Increasing evidence indicates that pre-­eclampsia is primarily caused
sia than women in the other two groups, but not in terms of intra- by a disturbance of normal endothelial cell function10 that results
cranial hemorrhage (Table 5). Regarding neonatal complications, from persistent systemic inflammation during early pregnancy.11
the pre-­eclampsia groups had significantly lower Apgar scores Consistent with this hypothesis, the present study found a significant
than the control group, and admission to the neonatal intensive positive correlation between the level of CRP and the presence and
care unit was more likely than in the control group (Table 5). severity of pre-­eclampsia.
Moreover, severe pre-­e clampsia was associated with perinatal Previously, a US study12 found that women with a CRP level
death (Table 5). of more than 4.1 mg/L had a three-­ to five-­times higher risk of

T A B L E   3   Ultrasonography assessment of fetal well-­being, and Doppler measures.a

P values
Group 1: severe Group 2: mild Group 3: control
Parameter pre-­eclampsia (n=90) pre-­eclampsia (n=90) (n=90) 1 vs 2 1 vs 3 2 vs 3
b c c
Cardiotocography score 2 (1–3) 1 (1–3) 1 (1–2) 0.039 0.039 0.925
d c c
Biophysical profile score 6 (10–4) 8 (10–6) 10 (10–6) 0.050 0.001 0.050c
c c
Umbilical artery resistance index 0.87±0.10 0.71±0.14 0.66±0.11 0.039 0.010 0.050c
Middle cerebral artery resistance 0.77±0.07 0.81±0.08 0.90±0.07 0.050c 0.021c 0.061
Values are given as median (range) or mean±SD.
1=normal; 2=suspicious; 3=pathologic.
Statistically significant (P≤0.05).
0–4=fetal asphyxia; 6=possible fetal asphyxia; 8–10=normal.
142       Maged ET AL.

T A B L E   4   Correlation between C-­reactive protein level and blood pressure.

Group 1: severe pre-­eclampsia (n=90) Group 2: mild pre-­eclampsia (n=90) Group 3: control (n=90)


r value 0.352 0.612 0.593 0.563 0.053 0.193

P value 0.001 0.021 0.042 0.332 0.617 0.072

Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.

pre-­eclampsia than did women whose CRP level was lower than developed pre-­eclampsia had significantly higher concentrations of
1.1 mg/L. Hwang et al. reported that the serum CRP level was CRP than did normotensive women (8.7±5.5 mg/L vs 5.3±4.3 mg/L;
higher in women with pre-­eclampsia than in healthy pregnant women, P=0.02).
and both the systolic and the diastolic blood pressure were positively The platelet count in the present study was significantly lower
correlated with the serum CRP level in the group with pre-­eclampsia. among women with severe pre-­eclampsia than in the other two
Another study14 of 506 pregnant women found that women who groups. Mohapatra et al.15 reported an inverse relationship ­between

T A B L E   5   Maternal and neonatal outcomes.a

P values
Group 1: severe Group 2: mild Group 3: control
Outcome pre-­eclampsia (n=90) pre-­eclampsia (n=90) (n=90) 1 vs 2 1 vs 3 2 vs 3

Maternal complications
Eclampsia 12 (13.3) 0 0 <0.001b 0.001b NA
c b b
HELLP syndrome 8 (8.9) 0 0 <0.001 0.001 NA
Intracranial hemorrhage 1 (1.1) 0 0 0.159 0.159 NA
Neonatal outcomes
Apgar score
1 min 4 (2–6) 6 (4–8) 8 (4–8) 0.041b 0.001b 0.040b
5 min 6 (2–10) 8 (4–10) 10 (4–10) 0.051b 0.001b 0.050b
Admission to neonatal intensive care unit 16 (17.8) 9 (10.0) 2 (22.2) 0.062 0.001 0.010b
Reason for admission
Low birth weight 11 (68.8) 6 (66.7) 0 0.451 0.031b 0.050b
Infection 2 (12.5) 1 (11.1) 1 (50.0) 0.114 0.174 0.315
Prematurity 2 (12.5) 1 (11.1) 0 0.324 0.267 0.336
Other 1 (6.3) 1 (11.1) 1 (50.0) 0.465 0.101 0.124
>24 h 11 (68.8) 2 (22.2) 0 0.012b 0.031b 0.254
b b
Perinatal death 7 (7.8) 2 (2.2) 2 (22.2) 0.044 0.044 0.511
Prematurity 5 (71.4) 1 (50.0) 0 0.313 0.044b 0.213
Stillbirth 1 (14.3) 0 1 (50.0) 0.314 0.174 0.213
Other 1 (14.3) 1 (50.0) 1 (50.0) 0.173 0.174 0.501
Stillbirth 1 (14.3) 1 (50.0) 0 0.175 0.314 0.215
First day 2 (28.6) 1 (50.0) 0 0.316 0.235 0.216
First 3 days 3 (42.9) 0 1 (50.0) 0.237 0.316 0.213
First week 1 (14.3) 0 1 (50.0) 0.316 0.177 0.213

Abbreviation: NA, not available.

Values are given as number (percentage) or median (range), unless indicated otherwise.
Statistically significant (P<0.05).
Hemolysis, elevated liver enzymes, low platelets.
Meconium aspiration syndrome, asphyxia, jaundice.
Congenital anomaly, birth asphyxia.
Maged ET AL. |

the ­platelet count and the severity of pregnancy-­induced hyperten- In conclusion, the present study has shown that the plate-
sion. The present findings agree with a study of 100 women with se- let count and levels of CRP, blood urea nitrogen, serum uric acid,
vere pre-­eclampsia,16 in which 50 women had a platelet count below and ALT are linked with the development and severity of pre-­
150 000/μL, and 13 of these women had a prolonged prothrombin eclampsia. Therefore, these markers could be used to assess the
or activated partial thromboplastin time. No patient had an abnormal risk of the ­disease and its severity. CTG monitoring, and UA and
fibrinogen level or a prolonged prothrombin time ­partial thrombo- MCA Doppler assessments should be done for all patients with
plastin time in the absence of thrombocytopenia. The ­authors con- pre-­eclampsia to detect changes that could be associated with fetal
cluded that thrombocytopenia is a strong indicator of the severity of compromise.
There was no significant difference between the three study
groups for the hemoglobin level, the total leukocyte count, the serum
levels of creatinine, AST, ALP, total bilirubin, sodium, and potassium, GA and NB developed the study protocol. NB, DSE, and NKG col-
the prothrombin time and concentration, and the INR. However, the lected data. DSE and NKG managed data. AMM, DSE, and SD ana-
ALT level was significantly higher among women with severe pre-­ lyzed the data. All authors participated in the writing and editing of
eclampsia than in the other two groups, and blood urea nitrogen and the manuscript.
serum uric acid were significantly higher in the two groups of women
with pre-­eclampsia. In a previous study,17 women in the pre-­eclampsia
group (n=50) had significantly higher levels of liver enzymes (ALT,
AST, and ALP) than did women in the control group (n=50). However, The authors have no conflict of interest.
the difference in total bilirubin between these two groups was not
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