Objective: Pre-eclampsia (PE) is a serious disease of pregnancy and one of the major causes of morbidity and mortality for both the mother and baby. This systematic review aims to detect the role of high-sensitivity C-reactive protein (CRP) in the detection of PE. Methods: Thirty-four articles published between 2001 and 2019 were included in this review. The articles were extracted from OVID Medline and Embase. The study designs of these articles are randomized controlled, cohort, case-control, and cross-sectional studies evaluating CRP as a marker to predict or early diagnose PE. The quality assessment of these articles is made by the modified Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis was not done because of clinical and statistical heterogeneity. Results: A positive association between CRP levels and the development of PE was confirmed in 18 studies. This positive effect was addressed in patients with normal BMI (<25 kg/m2) in 3 studies and in overweight patients in 2 studies. One study addressed this positive association in patients with a BMI ranging between 28 and 31 kg/m2. Three studies determined a cutoff level of CRP above which a significant risk of PE development should be suspected. These levels ranged between 7 and 15 mg/L. Conclusion: CRP is a promising cost-effective biomarker that may be used in the prediction of PE. A CRP level higher than 15 mg/L may suggest initiation of low-dose aspirin in low-risk pregnancies.

1.
Hypertension
G
.
Preeclampsia. ACOG practice bulletin no. 202. American college of obstetricians and gynecologists
.
Obstet Gynecol
.
2019
;
133
(
1
):
e1
e25
.
2.
Ghulmiyyah
L
,
Sibai
B
.
Maternal mortality from preeclampsia/eclampsia
.
Semin Perinatol
.
2012
;
36
(
1
):
56
9
. .
3.
Roberge
S
,
Nicolaides
KH
,
Demers
S
,
Villa
P
,
Bujold
E
.
Prevention of perinatal death and adverse perinatal outcome using low dose aspirin: a meta analysis
.
Ultrasound Obstet Gynecol
.
2013
;
41
(
5
):
491
9
.
4.
Duley
L
,
Meher
S
,
Hunter
KE
,
Seidler
AL
,
Askie
LM
.
Antiplatelet agents for preventing pre-eclampsia and its complications
.
Cochrane Database Syst Rev
.
2019
;
2019
(
10
):
CD004659
. .
5.
Hofmeyr
GJ
,
Lawrie
TA
,
Atallah
ÁN
,
Torloni
MR
.
Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems
.
Cochrane Database Syst Rev
.
2018
;
10
(
10
):
CD001059
. .
6.
Staff
AC
.
The two-stage placental model of preeclampsia: an update
.
J Reprod Immunol
.
2019 Sep
;
134–135
:
1
10
.
7.
Liu
J
,
Zhao
G
,
Xie
J
,
Wu
S
,
Li
B
,
Yao
J
.
There is a strong association between early preeclampsia and congenital heart defects: a large population-based, retrospective study
.
Gynecol Obstet Invest
.
2020
.
8.
Zhou
J
,
Zhang
D
,
Bai
J
,
Li
Z
,
Chen
Y
.
Altered expressions of AQP3 and ADP are closely related with the risk of preeclampsia occurrence
.
Gynecol Obstet Invest
.
2020
;
85
(
4
):
362
70
. .
9.
Severens-Rijvers
CAH
,
Al-Nasiry
S
,
Vincken
A
,
Haenen
G
,
Winkens
B
,
Ghossein-Doha
C
, et al.
Early-pregnancy circulating antioxidant capacity and hemodynamic adaptation in recurrent placental syndrome: an exploratory study
.
Gynecol Obstet Invest
.
2019
;
84
(
6
):
616
22
. .
10.
Valencia-Ortega
J
,
Zárate
A
,
Saucedo
R
,
Hernández-Valencia
M
,
Cruz
JG
,
Puello
E
.
Placental proinflammatory state and maternal endothelial dysfunction in preeclampsia
.
Gynecol Obstet Invest
.
2019
;
84
(
1
):
12
9
. .
11.
Zhang
P
,
Yang
H
,
Feng
Y
,
Wu
W
,
Li
S
,
Thompson
B
, et al.
Polymorphisms in sex hormone metabolism genes and risk of preeclampsia in Taiyuan, China
.
Gynecol Obstet Invest
.
2018
;
83
(
2
):
179
86
. .
12.
Webster
K
,
Fishburn
S
,
Maresh
M
,
Findlay
SC
,
Chappell
LC
.
Diagnosis and management of hypertension in pregnancy: summary of updated NICE guidance
.
BMJ
.
2019
;
366
:
l5119
. .
13.
Leslie
K
,
Thilaganathan
B
,
Papageorghiou
A
.
Early prediction and prevention of pre-eclampsia
.
Best Pract Res Clin Obstet Gynaecol
.
2011
;
25
(
3
):
343
54
. .
14.
O'Gorman
N
,
Wright
D
,
Poon
LC
,
Rolnik
DL
,
Syngelaki
A
,
de Alvarado
M
, et al.
Multicenter screening for pre‐eclampsia by maternal factors and biomarkers at 11–13 weeks’ gestation: comparison with NICE guidelines and ACOG recommendations
.
Ultrasound Obstet Gynecol
.
2017
;
49
(
6
):
756
60
.
15.
Liberati
A
,
Altman
DG
,
Tetzlaff
J
,
Mulrow
C
,
Gøtzsche
PC
,
Ioannidis
JP
, et al.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration
.
PLoS Med
.
2009
;
6
(
7
):
e100010065
. .)
16.
Young
B
,
Gleeson
M
,
Cripps
AW
.
C-reactive protein: a critical review
.
Pathology
.
1991
;
23
(
2
):
118
24
. .
17.
World Health Organization
.
C-reactive protein concentrations as a marker of inflammation or infection for interpreting biomarkers of micronutrient status
.
World Health Organization
;
2014
.
18.
Ledue
TB
,
Rifai
N
.
Preanalytic and analytic sources of variations in C-reactive protein measurement
.
Springer
;
2003
. p.
305
17
.
19.
Whiting
PF
,
Rutjes
AW
,
Westwood
ME
,
Mallett
S
,
Deeks
JJ
,
Reitsma
JB
, et al.
QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies
.
Ann Intern Med
.
2011
;
155
(
8
):
529
36
. .
20.
Ruma
M
,
Boggess
K
,
Moss
K
,
Jared
H
,
Murtha
A
,
Beck
J
, et al.
Maternal periodontal disease, systemic inflammation, and risk for PE
.
Am J Obstet Gynecol
.
2008
;
198
(
4
):
389
5
. .
21.
de Jonge
LL
,
Steegers
EA
,
Ernst
GD
,
Lindemans
J
,
Russcher
H
,
Hofman
A
, et al.
C-reactive protein levels, blood pressure and the risks of gestational hypertensive complications: the generation R Study
.
J Hypertens
.
2011
;
29
(
12
):
2413
21
. .
22.
Barden
A
,
Singh
R
,
Walters
BN
,
Ritchie
J
,
Roberman
B
,
Beilin
LJ
.
Factors predisposing to pre-eclampsia in women with gestational diabetes
.
J Hypertens
.
2004
;
22
(
12
):
2371
8
. .
23.
Beigi
A
,
Saeedi
L
,
Samiei
H
,
Zarrinkoub
F
,
Zarrinkoub
H
.
Elevated CRP levels during first trimester of pregnancy and subsequent preeclampsia: a prospective study
.
Tehran Univ Med J
.
2008
;
66
(
1
):
25
8
.
24.
Behboudi-Gandevani
S
,
Moghadam
NA
,
Mogadam-Banaem
L
,
Mohamadi
B
,
Asghari
M
.
Association of high-sensitivity C-reactive protein serum levels in early pregnancy with the severity of preeclampsia and fetal birth weight
.
J Perinat Med
.
2012
;
40
(
6
):
601
5
.
25.
Kashanian
M
,
Aghbali
F
,
Mahali
N
.
Evaluation of the diagnostic value of the first-trimester maternal serum high-sensitivity C-reactive protein level for prediction of pre-eclampsia
.
J Obstet Gynaecol Res
.
2013
;
39
(
12
):
1549
54
. .
26.
Rasanen
J
,
Girsen
A
,
Lu
X
,
Lapidus
JA
,
Standley
M
,
Reddy
A
, et al.
Comprehensive maternal serum proteomic profiles of preclinical and clinical preeclampsia
.
J Proteome Res
.
2010
;
9
(
8
):
4274
81
. .
27.
Scholl
TO
,
Chen
X
,
Goldberg
GS
,
Khusial
PR
,
Stein
TP
.
Maternal diet, C-reactive protein, and the outcome of pregnancy
.
J Am Coll Nutr
.
2011
;
30
(
4
):
233
40
. .
28.
Talcott
K
,
Christensen
A
,
Tyler
E
,
Hamilton
W
,
Boese
B
,
Santillan
D
, et al.
The effect of obesity on C-reactive protein levels and poor pregnancy outcomes
.
Reprod Sci
.
2013
;
20
(
3
):
310A
1A
.
29.
Chaparro
A
,
Sanz
A
,
Quintero
A
,
Inostroza
C
,
Ramirez
V
,
Carrion
F
, et al.
Increased inflammatory biomarkers in early pregnancy is associated with the development of pre-eclampsia in patients with periodontitis: a case control study
.
J Periodont Res
.
2013
;
48
(
3
):
302
7
. .
30.
Bodnar
LM
,
Ness
RB
,
Harger
GF
,
Roberts
JM
.
Inflammation and triglycerides partially mediate the effect of prepregnancy body mass index on the risk of preeclampsia
.
Am J Epidemiol
.
2005
;
162
(
12
):
1198
206
. .
31.
Cetin
I
,
Cozzi
V
,
Papageorghiou
AT
,
Maina
V
,
Montanelli
A
,
Garlanda
C
, et al.
First trimester PTX3 levels in women who subsequently develop preeclampsia and fetal growth restriction
.
Acta Obstet Gynecol Scand
.
2009
;
88
(
7
):
846
9
. .
32.
Cheng
PJ
,
Huang
SY
,
Su
SY
,
Hsiao
CH
,
Peng
HH
,
Duan
T
.
Prognostic value of cardiovascular disease risk factors measured in the first-trimester on the severity of preeclampsia
.
Medicine
.
2016
;
95
(
5
):
e2653
. .
33.
Djurovic
S
,
Clausen
T
,
Wergeland
R
,
Brosstad
F
,
Berg
K
,
Henriksen
T
.
Absence of enhanced systemic inflammatory response at 18 weeks of gestation in women with subsequent pre-eclampsia
.
BJOG
.
2002
;
109
(
7
):
759
64
. .
34.
Du
M
,
Basu
A
,
Fu
D
,
Wu
M
,
Centola
M
,
Jenkins
AJ
, et al.
Serum inflammatory markers and preeclampsia in type 1 diabetes: a prospective study
.
Diabetes Care
.
2013
;
36
(
7
):
2054
61
. .
35.
Ferguson
KK
,
Meeker
JD
,
McElrath
TF
,
Mukherjee
B
,
Cantonwine
DE
.
Repeated measures of inflammation and oxidative stress biomarkers in preeclamptic and normotensive pregnancies
.
Am J Obstet Gynecol
.
2017
;
216
(
5
):
527
e9
. .
36.
Garcia
RG
,
Celedon
J
,
Sierra-Laguado
J
,
Alarcon
MA
,
Luengas
C
,
Silva
F
, et al.
Raised C-reactive protein and impaired flow-mediated vasodilation precede the development of preeclampsia
.
Am J Hypertens
.
2007
;
20
(
1
):
98
103
.
37.
Kronborg
CS
,
Knudsen
UB
,
Moestrup
SK
,
Allen
J
,
Vittinghus
E
,
Møller
HJ
.
Serum markers of macrophage activation in preeclampsia: no predictive value of soluble CD163 and neopterin
.
Acta Obstet Gynecol Scand
.
2007
;
86
(
9
):
1041
6
. .
38.
Freeman
DJ
,
McManus
F
,
Brown
EA
,
Cherry
L
,
Norrie
J
,
Ramsay
JE
, et al.
Short- and long-term changes in plasma inflammatory markers associated with preeclampsia
.
Hypertension
.
2004
;
44
(
5
):
708
14
. .
39.
Haedersdal
S
,
Salvig
JD
,
Aabye
M
,
Thorball
CW
,
Ruhwald
M
,
Ladelund
S
, et al.
Inflammatory markers in the second trimester prior to clinical onset of preeclampsia, intrauterine growth restriction, and spontaneous preterm birth
.
Inflammation
.
2013
;
36
(
4
):
907
13
. .
40.
Jääskeläinen
T
,
Heinonen
S
,
Heinonen
S
,
Hämäläinen
E
,
Pulkki
K
,
Romppanen
J
, et al.
Impact of obesity on angiogenic and inflammatory markers in the finnish genetics of pre-eclampsia consortium (FINNPEC) cohort
.
Int J Obes
.
2019
;
43
(
5
):
1070
81
. .
41.
Levine
RJ
,
Qian
C
,
LeShane
ES
,
Yu
KF
,
England
LJ
,
Schisterman
EF
, et al.
Two-stage elevation of cell-free fetal DNA in maternal sera before onset of preeclampsia
.
Am J Obstet Gynecol
.
2004
;
190
(
3
):
707
13
. .
42.
Karinen
L
,
Leinonen
M
,
Bloigu
A
,
Paldanius
M
,
Koskela
P
,
Saikku
P
, et al.
Maternal serum Chlamydia pneumoniae antibodies and CRP levels in women with preeclampsia and gestational hypertension
.
Hypertens Pregnancy
.
2008
;
27
(
2
):
143
58
. .
43.
Qiu
C
,
Luthy
DA
,
Zhang
C
,
Walsh
SW
,
Leisenring
WM
,
Williams
MA
.
A prospective study of maternal serum C-reactive protein concentrations and risk of preeclampsia
.
Am J Hypertens
.
2004
;
17
(
2
):
154
60
. .
44.
Myatt
L
.
Relationship of inflammatory biomarkers in preeclampsia to BMI
.
Reprod Sci
.
2013
;
20
(
3
):
266A
7A
.
45.
Nikolić
A
,
Čabarkapa
V
,
Spasojević
Z
,
Milošević-Tošić
M
,
Radišić-Bosić
J
.
Biochemical markers in prediction of pre-eclampsia
.
Clinica Chimica Acta
.
2019
;
493
:
S587
.
46.
Tuuri
AL
,
Jauhiainen
MS
,
Tikkanen
MJ
,
Kaaja
RJ
.
Systolic blood pressure and fatty acid-binding protein 4 predict pregnancy-induced hypertension in overweight nulliparous women
.
Placenta
.
2014
;
35
(
10
):
797
801
. .
47.
Thilaganathan
B
,
Wormald
B
,
Zanardini
C
,
Sheldon
J
,
Ralph
E
,
Papageorghiou
AT
.
Early-pregnancy multiple serum markers and second-trimester uterine artery doppler in predicting preeclampsia
.
Obstet Gynecol
.
2010
;
115
(
6
):
1233
8
. .
48.
Tjoa
ML
,
Van Vugt
JM
,
Go
AT
,
Blankenstein
MA
,
Oudejans
CB
,
Van Wijk
IJ
.
Elevated C-reactive protein levels during first trimester of pregnancy are indicative of preeclampsia and intrauterine growth restriction
.
J Reprod Immunol
.
2003
;
59
(
1
):
29
37
. .
49.
Teran
E
,
Escudero
C
,
Calle
A
.
C-reactive protein during normal pregnancy and preeclampsia
.
Int J Gynaecol Obstet
.
2005
;
89
(
3
):
299
300
. .
50.
Wolf
M
,
Kettyle
E
,
Sandler
L
,
Ecker
JL
,
Roberts
J
,
Thadhani
R
.
Obesity and preeclampsia: the potential role of inflammation
.
Obstet Gynecol
.
2001
;
98
(
5 Pt 1
):
757
62
. .
51.
Zwahlen
M
,
Gerber
S
,
Bersinger
NA
.
First trimester markers for pre-eclampsia: placental versus. non-placental protein serum levels
.
Gynecol Obstet Invest
.
2007
;
63
(
1
):
15
21
. .
52.
Savvidou
MD
,
Lees
CC
,
Parra
M
,
Hingorani
AD
,
Nicolaides
KH
.
Levels of C-reactive protein in pregnant women who subsequently develop pre-eclampsia
.
BJOG
.
2002
;
109
(
3
):
297
301
. .
53.
Gammill
HS
,
Powers
RW
,
Clifton
RG
,
Van Dorsten
JP
,
Klebanoff
MA
,
Lindheimer
MD
, et al.
Does C-reactive protein predict recurrent preeclampsia?
Hypertens Pregnancy
.
2010
;
29
(
4
):
399
409
. .
54.
Kao
TW
,
Lu
IS
,
Liao
KC
,
Lai
HY
,
Loh
CH
,
Kuo
HK
.
Associations between body mass index and serum levels of C-reactive protein
.
S Afr Med J
.
2009
;
99
(
5
):
326
.
55.
Ford
ES
.
Body mass index, diabetes, and C-reactive protein among U.S. adults
.
Diabetes care
.
1999
;
22
(
12
):
1971
7
. .
56.
O'Brien
TE
,
Ray
JG
,
Chan
WS
.
Maternal body mass index and the risk of preeclampsia: a systematic overview
.
Epidemiology
.
2003
;
14
(
3
):
368
74
. .
57.
Rebelo
F
,
Schlüssel
MM
,
Vaz
JS
,
Franco-Sena
AB
,
Pinto
TJ
,
Bastos
FI
, et al.
C-reactive protein and later preeclampsia: systematic review and meta-analysis taking into account the weight status
.
J Hypertens
.
2013
;
31
(
1
):
16
26
. .
58.
Black
KD
,
Horowitz
JA
.
Inflammatory markers and preeclampsia: a systematic review
.
Nurs Res
.
2018 May
;
67
(
3
):
242
51
. .
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