Combining Biochemical and Ultrasonographic Markers in Predicting Preeclampsia, A Systematic Review

Reviews
Clinical Chemistry 56:3

361374 (2010)
Combining Biochemical and Ultrasonographic Markers in

Predicting Preeclampsia:
A Systematic Review
Yves Gigue`re,1,2 Marc Charland,1 Emmanuel Bujold,1,3 Nathalie Bernard,1 Sonya Grenier,1
Francois Rousseau,1,2 Julie Lafond,4 France Legare,1,5 and Jean-Claude Forest1,2*
BACKGROUND: Early identification of pregnant women

at risk for preeclampsia is a priority to implement preventive measures. Some biochemical and ultrasonographic parameters have shown promising predictive
performance, but so far there is no clinically validated
screening procedure.
CONTENT:
Using a series of keywords, we reviewed electronic databases (Medline, Embase, all records to May
2009) reporting the performance of biological and ultrasonographic markers to predict preeclampsia, both
single markers and combinations of markers. We analyzed the data according to gestational age and risk
levels of the studied populations. We evaluated the
methodological quality of included publications using
QUADAS (quality assessment of diagnostic accuracy
studies). We identified 37 relevant studies that assessed
71 different combinations of biochemical and ultrasonographic markers. Most studies were performed
during the second trimester on small-scale high-risk
populations with few cases of preeclampsia. Combinations of markers generally led to an increase in sensitivity and/or specificity compared with single markers. In
low-risk populations, combinations including placental
protein 13 (PP13), pregnancy-associated plasma protein
A (PAPP-A), a disintegrin and metalloprotease-12
(ADAM12), activin A, or inhibin A measured in first or
early second trimester and uterine artery Doppler in
second trimester appear promising (sensitivity 60%
80%, specificity 80%). In high-risk populations, the
combination of PP13 and pulsatility index in first tri-
CHUQ Research Center/Hopital Saint-Francois dAssise, Quebec City, Quebec,

Canada; 2 Department of Medical Biology, 3 Department of Obstetrics and
Gynecology, and 5 Department of Family Medicine, Faculty of Medicine, Universite Laval, Quebec City, Quebec, Canada; 4 Department of Biological Sciences, BioMed Research Center, UQAM, Montreal, Quebec, Canada.
* Address correspondence to this author at: CHUQ Research Center/Hopital
Saint-Francois dAssise, 10, rue de lEspinay, Quebec City, Quebec, Canada, G1L
3L5. Fax 418-525-4481; e-mail jean-claude.forest@bcx.ulaval.ca.
Received July 31, 2009; accepted December 7, 2009.
Previously published online at DOI: 10.1373/clinchem.2009.134080
Parts of this manuscript have been presented as a poster at the 18th IFCC-EFCC
European Congress of Clinical Chemistry and Laboratory Medicine, Innsbruck,
Austria, June 711, 2009.
mester showed 90% sensitivity and 90% specificity in a

single study limited to severe preeclampsia.
SUMMARY:
Combinations of biochemical and ultrasonographic markers improved the performance of

early prediction of preeclampsia. From a perspective of
integrative medicine, large population-based studies
evaluating algorithms combining multiple markers are
needed, if screening approaches are to be eventually
implemented.
2009 American Association for Clinical Chemistry
Preeclampsia (PE),6 a leading cause of adverse pregnancy outcomes worldwide, remains a major cause of
maternal and perinatal mortality (13 ). It is defined as
de novo hypertension (140/90 mmHg) appearing after 20 weeks of gestation accompanied by proteinuria
(0.3 g/24 h) (4, 5 ). An increasing body of evidence
indicates that women affected by PE will be at higher
risk for cardiovascular disease later in life (6 9 ). WHO
has recognized the importance of PE by launching a
program specifically dedicated to the study and treatment of this syndrome (10 ).
PE is characterized by a complex pathophysiology
and heterogeneous clinical and laboratory findings
(1113 ). Numerous pathophysiological mechanisms,
alone or in combination, have been suggested to be
responsible for the diverse subsets of PE. They include
impaired vascular remodeling of the maternalfetal interface, excessive immune response to paternal antigens, systemic inflammatory response, and dysfunctional placental or endothelial response, all of these
processes being modulated by genetic and environmental parameters (1, 14 16 ). Such heterogeneity of
Nonstandard abbreviations: PE, preeclampsia; IUGR, intrauterine growth restriction; MeSH, medical subject heading; QUADAS, quality assessment of diagnostic accuracy studies; PPV, positive predictive value; NPV, negative predictive
value; hCG, human chorionic gonadotropin; AFP, -fetoprotein; PAPP-A,
pregnancy-associated plasma protein A; PlGF, placental growth factor; PI,
pulsatility index; ADAM12, a disintegrin and metalloproteinase 12; PP-13,
placental protein 13; MoM, multiple of the median; STARD, Standards for
Reporting Diagnostic Accuracy; sFlt1, soluble fms-like tyrosine kinase 1.
361
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potential processes leading to, or resulting from, PE has
contributed to the lack of diagnostic means for identification of women susceptible to developing PE, resulting in delayed recognition and severe complications
(17, 18 ) and impeding evaluation of new preventive
interventions. The latter problem holds particular consequences for high-risk women, in whom treatments
have shown potential protective effects (19 22 ). A recent metaanalysis suggests that, in high-risk women,
low-dose aspirin started before 16 weeks gestation
could prevent up to 50% of PE, severe PE, and intrauterine growth restriction (IUGR) (23 ). This reinforces the need for early identification of at-risk
women with the objective of implementing targeted
interventions for improving both perinatal and maternal outcomes.
In 2004, after performing a systematic review of
screening tests for PE, WHO reaffirmed that there is
no clinically useful screening test to predict the development of preeclampsia in either low-risk or high-risk
populations. Further prospective, longitudinal studies
are needed (24 ). Since this assertion, many groups
have identified or studied potential biochemical and/or
biophysical markers based on physiological mechanisms, some of which showing encouraging results.
Systematic reviews and/or metaanalyses assessing the
clinical utility of, most often, single markers, have recently been published (2528 ), but so far no marker
has demonstrated an appropriately high accuracy level
to justify its clinical application.
Because of the heterogeneous nature of PE, a
combination of 2 or more independent biomarkers,
each reflecting a different pathophysiological process,
should potentially increase the likelihood to derive
suitable predictive algorithms. So far, however, no systematic review has evaluated whether biochemical
markers improved the performance of ultrasonographic markers, and vice versa. In this study, we performed a systematic review of the available evidence
pertaining to the predictive characteristics of combinations of biochemical and ultrasonographic markers in
the first and second trimester. The development of efficient prediction algorithms would be a major step
toward the early identification of women destined to
suffer from PE, to classify them according to risk subsets and eventually to offer them appropriate surveillance and prophylactic interventions.
Materials and Methods
LITERATURE SEARCH AND STUDY SELECTION
We made electronic searches of Medline and Embase

bibliographic databases from inception to May 2009. The
search strategy consisted of MeSH (medical subject heading) terms, Emtree terms, and keywords related to the
362 Clinical Chemistry 56:3 (2010)
disease (hypertensive disorders of pregnancy, preeclampsia, gestosis, eclampsia, pregnancy-induced hypertension, etc.) combined with biochemical and biophysical
(ultrasonographic, Doppler, etc.) markers. We developed the search strategy through an iterative and collaborative process in close collaboration with information specialists and clinical experts in laboratory
medicine and obstetrics, particularly for the development of the biochemistry-marker search strategy. Special care was taken to include proper synonyms, abbreviations, and spelling differences of biochemical
markers, as well as to look for and to select more general MeSH terms when necessary (for example, the
marker IL-10 is linked to the MeSH interleukin-10,
which is included within the MeSH Interleukins,
which, in turn, is part of Cytokines; we thus selected
cytokines as an encompassing MeSH term). Overall,
this strategy produced 68 MESH terms that were combined with 303 keywords, which represented more
than 118 different molecules to produce the search
strategy in Medline (for Embase, we used 311 keywords). Supplemental Table 1 (which accompanies
the online version of this article at www.clinchem.org/
content/vol56/issue3) presents the research strategy
used for Medline searching. The search strategy used
for Embase is available on request from the authors.
Bibliographies of selected publications were manually
screened to include potential articles not captured by
electronic searches. We initially included all original
studies reporting any ultrasound methodology for assessment of either maternal or fetal health and any biochemical marker (from blood, urine, or any biological
fluid) in any healthcare setting, in any population level
of PE risk, performed before the diagnosis of the disease and reported in either English or French. Studies
allowing development of 2 2 tables for combined test
accuracy were included.
DATA EXTRACTION AND QUALITY ASSESSMENT
Titles and abstracts of citations were first screened by 2

independent reviewers (N. Bernard, S. Grenier, or M.
Charland) for their relevance. Citations without abstracts were rejected. Screened articles for which there
were disagreements between the assessments of 2 independent reviewers were resolved by the third reviewer.
After agreement, the full-text article was assessed by 2
reviewers for inclusion and data extraction. For multiple publications of the same data set, only the most
relevant study was included.
Methodological quality of the publications was
evaluated by two independent reviewers (N. Bernard
and M. Charland) using the QUADAS (quality assessment of diagnostic accuracy studies) tool, a questionnaire that uses 14 criteria for evaluating the avoidance
of different types of bias (29 31 ). Disagreements were
Early Prediction of Preeclampsia with Biomarkers
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resolved by consensus. Because the QUADAS tool requires a clear definition of a reference standard, the
definition of the International Society for the Study of
Hypertension in Pregnancy was selected: PE is diagnosed in women with persistent high systolic (140
mmHg) or diastolic (90 mmHg) blood pressure and
proteinuria (0.3 g/24 h or dipstick test result 1)
arising after the 20th week of pregnancy (4 ).
DATA SYNTHESIS: ANALYSIS
We were able to build 2 2 tables for combinations of

markers from 24 of the included studies in relation to
PE. Data related to the predictive performance (sensitivity, specificity, predictive values, and likelihood ratios) of studied combinations were either directly extracted or calculated from retrieved raw data. Using the
classical equations for calculation of these parameters,
the prevalence of the disease is taken into account as it
influences the rate of false positives and false negatives;
that is, the calculated positive predictive value (PPV)
and negative predictive value (NPV) will vary according to the prevalence of the disease under study. Unfortunately, the large diversity of combinations, the variability related to study characteristics (cutoffs, risklevel of studied populations, etc.) and the small
number of included studies for a given combination of
biochemical and ultrasonographic markers did not
permit meta-analyses to be performed.
Results
The initial electronic search strategy led to screen titles
and abstracts of 394 citations. Fig. 1 shows the screening and selection process that was followed for the
identification and inclusion of studies combining biochemical and ultrasonographic markers to predict PE.
We retrieved 92 potentially eligible primary studies for
detailed evaluation and inclusion in the systematic review, and an additional 15 potentially eligible publications from the bibliographies of included studies. Detailed evaluation led to the exclusion of 70 publications
that did not meet the selection criteria. Overall, 37
studies were considered relevant and were included in
the systematic review; their characteristics are shown in
online Supplemental Table 2.
Included studies were conducted in 12 different
countries; among them, 19 were from the U.K.,
whereas 3 each were from Italy and Turkey. Most selected studies were performed using a prospective design including nested case-control studies that were
carried out as part of larger prospective studies, consistent with our inclusion criterion that the tests had to be
performed before the occurrence of PE. More than
60% (23 of 37) of included studies were conducted on
high-risk populations, a characteristic that was either
Fig. 1. Study selection process for systematic review

of combining biochemical and ultrasonographic
markers for predicting preeclampsia.
directly stated by the authors or deduced from the

study data. For example, a study including women after
an abnormal test result (either biochemical or ultrasonographic) was considered to be performed on a
high-risk population. Almost half of included studies
(17 of 37) were based on fewer than 25 preeclamptic
women as cases, whereas only 5 studies investigated
more than 100 PE women (see online Supplemental
Table 2).
Of the 37 included studies, biochemical and ultrasonographic markers were simultaneously evaluated
(same gestational age) in 23 studies, whereas they were
performed sequentially in the remaining 14, the biochemical marker always being assessed before the ultrasonographic one. For studies with simultaneously
evaluated markers, 8 combinations of tests were conducted during first trimester, 1 in the early second trimester (before 20 weeks), and 14 after 20 weeks of gestation. For studies in which markers were sequentially
evaluated, the biochemical markers were sampled during the first trimester of pregnancy in 5 studies and
during the second trimester in 9; ultrasonographic
markers were assessed during the second trimester in
all but 1 study. The most frequently studied biochemical markers were human chorionic gonadotropin
(hCG, 8 studies), inhibin A, and soluble fms-like tyrosine kinase 1 (sFlt-1) in 6 studies and -fetoprotein
(AFP), activin A, pregnancy-associated plasma protein
A (PAPP-A), and placental growth factor (PlGF) in 5
studies. The uterine artery Doppler pulsatility index
Clinical Chemistry 56:3 (2010) 363
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Fig. 2. Proportion of studies rated as compliant, noncompliant, or unclear for each of the QUADAS items.
(PI) was studied in 20 studies (in 14 as the sole ultrasonographic marker and in 6 as a component of a suite
of ultrasonographic markers). Few studies (n 9) simultaneously combined more than 1 biochemical
marker with ultrasonographic measurements to evaluate the predictive capability of a combination of tests
for predicting PE.
The methodological quality of selected studies as
assessed by their compliance with the 14 items included
within QUADAS is shown in Fig. 2. More than 75% of
studies met the following criteria: clear description of
patient selection criteria, avoidance of partial and differential verification bias, use of an independent reference test, adequate description of index test, blind assessment of both index and reference tests, and
explanation of withdrawals. However, fewer than 50%
of studies met the following criteria: appropriate patient spectrum, availability of clinical data, and reporting of uninterpretable results.
Data extraction from the 37 studies allowed us to
build 2 2 tables and calculate the performance characteristics of combinations drawn from 24 studies (Table 1). Performance characteristics of the test combinations were expressed as sensitivity, specificity, PPV,
and NPV. When this was not possible (13 studies),
we used the major conclusions given by the study
authors to qualify the predictive ability of the combinations (Table 2).
Plotting test sensitivity as a function of falsepositive rate (1 specificity) (Figs. 3 and 4) allowed
comparison of the performance characteristics of
markers taken alone or in combination. The data plotted were stratified according to the risk level of the population (high vs low risk) and the time of marker sampling or measurement (first, early second, or late
second trimester). Overall, combinations of markers
generally led to an increase in sensitivity and/or speci364 Clinical Chemistry 56:3 (2010)
ficity compared with single markers. In low-risk

populations, several combinations, including PP13,
PAPP-A, a disintegrin and metalloproteinase 12
(ADAM12), activin A, or inhibin A measured early in
first or early second trimester combined with uterine
artery Doppler (pulsatility index or resistance index
and/or presence of a notch) showed reasonable accuracy (sensitivity 60% 80% for specificity 80%). In 1
high-risk population, placental protein 13 (PP13) and
PI measured in the first trimester showed 90% sensitivity and 90% specificity when limited to the diagnosis of
severe preeclampsia.
Discussion
We evaluated the performance characteristics of 71
combinations of ultrasonographic and biological
markers in identifying women susceptible to development of PE. Although 65 combinations of markers included at least 1 marker that was assessed during the
second trimester, only 6 combinations included both
biological and ultrasonographic markers measured
during the first trimester (3237 ). No given combination was assessed more than once. The large variety of
marker combinations observed across studies reflects
the complexity and heterogeneity of the pathophysiology of PE or the lack, at this point, of powerful individual candidate markers. Such heterogeneity and the
limited number of published studies for each combination precluded any further comparative analyses such
as meta-analyses.
Among the numerous marker combinations studied during the second trimester, several appeared to
have promising predictive characteristics (sensitivity
60%90%, specificity 90%). Overall, the addition of
uterine artery Doppler data to biochemical marker
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Table 1. Performance characteristics of studies combining biochemical and ultrasonographic markers in

preeclampsia prediction.
Study
Markers studied,
cutoffs applied
Time of testing,
week or trimester
Sensitivity,
%
Specificity,
%
PPV,
%
NPV,
%
hCG 2.5 MoM and PI 95th%

or bilateral UtA notchesa
2nd, 2024
72.7
90.0
72.7
90.0
2nd, 2428
54.6
93.3
75.0
84.9
2nd, 2024
NS
NS
NS
NS
2nd, 2428
63.6
76.7
50.0
85.2
Studies combining 1 biochemical

marker and 1
ultrasonographic marker
Studies with high-risk
populations
Jauniaux et al. (43 )
hCG 2.5 MoM and PI

95th% or bilateral UtA
notches
Merviel et al. (44 )
hCG 2 MoM and UtA notch

and D/S ratio decreased 0.2
2nd
54.5
93.5
50.0
98.9
AFP 2.5 MoM and PI 95th%

or bilateral UtA notches
2nd, 2024
72.7
70.0
47.0
88.0
2nd, 2428
46.0
86.7
56.0
81.0
Chung et al. (45 )
AFP 2.5 MoM and UtA notch

or RI 0.6
2nd
88.5
88.9
57.5
NA
Kuo et al. (46 )
AFP 2.5 MoM and ultrasound

sonolucencies
2nd
61.5
47.3
6.9
95.1
Williams et al. (47 )
AFP 2.0 MoM and placental

ultrasound abnormalities
2nd
7.9
91.7
8.8
90.7
Aquilina et al. (48 )
Inhibin A 2.0 MoM (2nd) and

bilateral notches and RI
0.55 (50th%) or unilateral
UtA notch and RI 0.65
(80th%) (all PE cases)
2nd
42.9
97.9
53.6
96.7
Early PE cases, 37 weeks
2nd
60.0
97.0
32.0
99.0
Inhibin A, 1st or 2nd;

PI, 2nd
68.0
95.0
NA
NA
Inhibin A 1.8 MoM and 1

UtA notch
2nd
38.9
92.5
70.0
77.1
Florio et al. (50 )
Activin A 1.7 MoM and 1

UtA notch
2nd
61.1
77.5
55.0
81.6
Spencer et al. (72 )
Activin A, cutoff unspecified, and

PI, cutoff unspecified
Activin A, 1st; PI,

2nd
63.0
95.0
NA
NA
Nicolaides et al. (34 )
PP-13, cutoff unspecified, and PI,

cutoff unspecified (data from
ROC curves)
1st
90.0
90.0
NA
NA
Stepan et al. (51 )
PlGF 118.0 pg/mL and
2nd
PI 1.46 (all PE)
2nd
77.0
68.0
45.0
NA
PI 1.64 (early PE)
2nd
83.0
76.0
36.0
NA
PI 1.45 and/or bilateral

notches and
2nd
PlGF 144 pg/mL (all PE)
2nd
88.0
81.0
67.0
94.0
PlGF 134 pg/mL (early PE)
2nd
100.0
76.0
25.0
100.0
Inhibin A, cutoff unspecified, and

PI, cutoff unspecified
Florio et al. (50 )
Diab et al. (52 )
Continued on page 366
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preeclampsia prediction. (Continued from page 365)
Markers studied,
cutoffs applied
Time of testing,
week or trimester
Sensitivity,
%
Specificity,
%
PPV,
%
NPV,
%
sFlt1 567.2 pg/mL and PI

2.31 (all PE)
2nd
77.0
73.0
50.0
NA
sFlt1 631.3 pg/mL and PI

2.79 (early PE, 34 weeks)
2nd
83.0
89.0
56.0
NA
PI 1.45 and/or bilateral

notches and
2nd
sFlt1 614 pg/mL (all PE)
2nd
96.0
87.0
76.0
98.0
sFlt1 978 pg/mL (early PE,

34 weeks)
2nd
100.0
87.0
38.0 100.0
Soluble endoglin 4.15 ng/mL

and PI 1.64
2nd
All PE
2nd
66.7
72.7
Study
Stepan et al. (51 )
Diab et al. (52 )
Stepan et al. (53 )
NA
NA
NA
NA
Early PE, 34 weeks
2nd
100.0
72.7
NA
NA
Florio et al. (54 )
Factor IIC activity 136.5% and

RI 0.57
2nd
66.7
95.1
66.7
80.5
Anastasakis et al. (55 )
Malondialdehyde 1.68 mol/L

and PI 1.6 or bilateral
notches
2nd
100.0
50.0
NA
NA
ADAM12, cutoff unspecified, and

mean PI, cutoff unspecified
ADAM12, 1st;
PI, 2nd
66.0
95.0
NA
NA
Uric acid 4 mg/dL and PI

95th% or bilateral
notches
2nd, 2024
NS
NS
NS
NS
2nd, 2428
63.6
86.7
63.6
86.7
Studies with low-risk

populations
Audibert et al. (56 )
Total hCG 2 MoM and 1

UtA notch or PI 95th%
2nd
7.8
99.5
25.0
98.2
Audibert et al. (56 )
AFP 1.5 MoM and 1 UtA

notch or PI 95th%
2nd
7.8
99.0
13.8
98.2
AFP 1.5 MoM and bilateral

UtA notches
2nd
5.9
99.6
21.4
98.2
Inhibin A 2.79 MoM and 1

UtA notch
2nd
71.0
100.0
100.0
97.6
Inhibin A 2.79 MoM and RI

0.62
2nd
71.0
100.0
100.0
97.6

PI, cutoff unspecified (data
from ROC curves)
2nd
67.0
95.0
NA
NA
Ay et al. (57 )
Activin A 6.58 MoM and 1

UtA notch
2nd
78.6
100.0
98.2

PI, cutoff unspecified (data
from ROC curves)
2nd
57.0
95.0
NA
NA
PP-13, cutoff unspecified and PI,

cutoff unspecified (all PE)
PP-13, 1st; PI, 2nd
74.0
80.0
NA
NA
Early PE, 35 weeks
79.0
80.0
NA
NA
Late PE, 35 weeks
70.0
80.0
NA
NA
Ay et al. (57 )
100
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Study
Poon et al. (36 )
Markers studied,
cutoffs applied
Time of testing,
week or trimester
Sensitivity,
%
Specificity,
%
PPV,
%
NPV,
%
PP-13, cutoff unspecified, and PI,

cutoff unspecified (all PE)
2nd
75.0
80.0
NA
NA
Early PE, 35 weeks
100.0
80.0
NA
NA
Late PE, 35 weeks
29.0
80.0
NA
NA
1st
20.5
95.0
NA
NA
PAPP-A, cutoff unspecified, and

PI, cutoff unspecified (all PE)
Early PE, 34 weeks
46.9
95.0
NA
NA
PAPP-A, cutoff unspecified,

and PI, cutoff unspecified
PAPP-A, 1st; PI, 2nd
62.1
95.0
NA
NA

(all PE)
PAPP-A, 1st; PI, 2nd
76.0
80.0
NA
NA
Early PE, 35 weeks
76.0
80.0
NA
NA
Late PE, 35 weeks
70.0
80.0
NA
NA
58.0
80.0
NA
NA
Early PE, 35 weeks
60.0
80.0
NA
NA
Late PE, 35 weeks
43.0
80.0
NA
NA
27.3
96.4
21.4
97.3
Early PE, 34 weeks
64.0
96.5
12.7
99.7
Severe PE
63.6
96.3
15.0
99.6
Espinoza et al. (61 )

(all PE)
PlGF 280 pg/mL and PI

95th% and/or bilateral UtA
notches (all PE)
2nd
2nd
Homocysteine 6.3 mol/L

(95th%) and bilateral UtA
notches with RI 0.55
(50th%) or unilateral UtA
notch with RI 0.85 (80th%)
or absence UtA notch with RI
0.70 (95th%)
2nd
61.3
98.1
53.3
97.5
Florio et al. (50 )
Activin A 1.7 MoM and inhibin

A 1.8 MoM and 1 UtA
notch
2nd
33.3
97.5
85.7
76.5
AFP 2.5 MoM and hCG 2.5

MoM and UtA PI 95th% or
bilateral UtA notches
2nd, 2024
63.6
96.7
87.5
89.7
Liu et al. (63 )
hCG and PAPP-A and nuchal

translucency (Down syndrome
risk 1/270)
1st
6.0
91.8
2.1
97.0

inhibin A, cutoff unspecified,
2nd
75.0
95.0
NA
NA
Onalan et al. (62 )

markers and 1
ultrasonographic marker
Studies with high-risk
populations

populations
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Markers studied,
cutoffs applied
Time of testing,
week or trimester
Sensitivity,
%
Specificity,
%
PPV,
%
NPV,
%
PP-13 and PAPP-A,

1st; PI, 2nd
74.0
80.0
NA
NA
Early PE, 35 weeks
70.0
80.0
NA
NA
Late PE, 35 weeks
73.0
80.0
NA
NA
67.0
80.0
NA
NA
Early PE, 35 weeks
80.0
80.0
NA
NA
Late PE, 35 weeks
43.0
80.0
NA
NA
83.0
80.0
NA
NA
100.0
80.0
NA
NA
71.0
80.0
NA
NA
67.0
80.0
NA
NA
Early PE, 35 weeks
100.0
80.0
NA
NA
Late PE, 35 weeks
14.0
80.0
NA
NA
67.0
80.0
NA
NA
Early PE, 35 weeks
100.0
80.0
NA
NA
Late PE, 35 weeks
29.0
80.0
NA
NA
Early PE, 35 weeks
84.6
95.0
NA
NA
Late PE, 35 weeks
33.7
95.0
NA
NA
Study
PP-13, cutoff unspecified, and

(all PE)

PI, cutoff unspecified (all PE)

activin A, cutoff unspecified,
(all PE)
2nd
2nd
Early PE, 35 weeks

Late PE, 35 weeks

free hCG, cutoff unspecified,
(all PE)

Inhibin A, cutoff unspecified,
(all PE)
2nd
2nd

marker, 1 ultrasonographic
marker, and another type of
marker
populations
Akolekar (32 )

PI, cutoff unspecified, and
maternal factorsb
1st
Akolekar et al. (32 )

maternal factorsb (early PE,
35 weeks)
1st
61.5
95.0
NA
NA
Akolekar et al. (32 )

and PI, cutoff unspecified, and
maternal factorsb (early PE,
35 weeks)
1st
80.8
95.0
NA
NA
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Study
Poon et al. (35 )
Poon et al. (36 )
Markers studied,
cutoffs applied
Time of testing,
week or trimester
Sensitivity,
%
Specificity,
%
PPV,
%
PlGF, cutoff unspecified, and

and PI, cutoff unspecified, and
MAP, cutoff unspecified, and
maternal factorsc (logistic
regression)
1st
Early PE, 34 weeks
93.1
95.0
21.1
NA
Late PE, 34 weeks
35.7
95.0
NA
NA
32.1
95.0
NA
NA
62.5
95.0
NA
NA

maternal factorsd (all PE)
1st
Early PE, 34 weeks
NPV,
%
Poon et al. (37 )
MMP-9, cutoff unspecified, and

maternal factorse (logistic
regression) (late PE,
34 weeks)
1st
34.3
95.0
NA
NA
Poon et al. (37 )

maternal factorse (logistic
regression) (early PE,
34 weeks)
1st
69.0
95.0
NA
NA
95th%, 95th percentile; UtA, uterine artery; hCG, hCG; NS, not significant; D/S, diastolic/systolic; RI, resistance index; NA, not applicable; MAP, mean arterial
pressure; MMP-9, matrix metalloproteinase 9.
b
Maternal factors included ethnicity, body mass index, and history of PE.
c
Maternal factors included ethnicity, parity, and history of PE or chronic hypertension.
d
Maternal factors included ethnicity, parity, body mass index, and history of PE.
e
Maternal factors included ethnicity, parity, body mass index, weight, and history of PE.
a
data improved the predictive performance of biochemical markers alone to a greater extent than did the addition of biochemical markers to uterine artery Doppler data alone. In 1 study (the only first-trimester study
of high-risk populations), however, the addition of
PP-13 to uterine artery PI increased sensitivity from
40% to 90% (at a specificity of 90%) (34 ). This study
was limited to only 10 cases of early-onset PE. However, the results are in agreement with data from Romero et al. (38 ), who observed that PP-13 appears to be
an interesting marker for risk assessment of preterm PE
but a weak marker for severe PE at term, and ineffective
for identifying mild PE at term. Also, data from Spencer et
al. (39 ) suggested that first trimester serum PP-13 as a
single marker in a low-risk population showed poor predictive performance. We were unable to find published
data on first trimester PP-13 in combination with Doppler parameters in a low-risk population.
We observed that first trimester or early second
trimester PAPP-A, inhibin A, and activin A in combination with uterine artery Doppler measurements may
provide good predictive performance for PE in both

low- and high-risk populations. Data from recent publications have indicated that these biochemical markers, taken individually, can predict up to 42% of early
PE, but up to 89% when combined with maternal characteristics (race, body mass index, parity) and uterine
artery PI (at a false-positive rate of 10%) in a low-risk
population (32 ). PAPP-A and PlGF were recently
found to be significantly decreased during first trimester [0.53 multiple of the median (MoM) and 0.61 MoM
respectively] in women destined to experience earlyonset PE, whereas they were only mildly diminished in
women who developed late PE. When these variables
were combined in logistic regression algorithms for
early PE, a predictive rate of 94% at a false-positive rate
of 5% was observed (35 ). Therefore, a growing body of
evidence suggests that combination of first-trimester
biochemical and ultrasonographic markers may be
useful in prediction of early PE; the addition of maternal characteristics to the prediction algorithms might
further improve their performance (33, 3537 ).
Reviews
Table 2. Qualitative performance characteristics of combined biochemical and ultrasonographic markers in

preeclampsia prediction.
Study
sFlt1, cutoff unspecified, and UtA bilateral notches
Parra et al. (65 )
sFlt1, cutoff unspecified, and PI 95th percentile
Espinoza et al. (61 )
sVEGFR-1, cutoff unspecified, and PI 95th percentile

and/or bilateral UtA notchesa
Homocysteine, cutoff unspecified, and PI 95th
percentile (1.6)
Yu et al. (66 )
Markers studied and cutoff points
Savvidou et al. (64 )
Parra et al. (65 )
PlGF, cutoff unspecified, and PI 95th percentile
PAI-1/PAI-2, cutoff unspecified, and PI 95th

percentile
F2-isoprostane, cutoff unspecified, and PI 95th
percentile
PlGF, cutoff unspecified, and bilateral UtA notches
Soluble endoglin, cutoff unspecified, and bilateral UtA

notches
sFlt1/PlGF ratio and bilateral UtA notches
(sFlt1 soluble endoglin):PlGF ratio and bilateral
UtA notches
VEGF, cutoff unspecified, and bilateral UtA notches
Prefumo et al. (68 )
ADMA, cutoff unspecified, and RI 95th percentile

and bilateral UtA notches
Diab et al. (52 )
Malondialdehyde, cutoff unspecified, and PI 1.6
CRP, cutoff unspecified, and bilateral UtA notches
Adiponectin and leptin, cutoffs unspecified, and

bilateral UtA notches
Tommaselli et al. (71 )
Leptin, cutoff unspecified, and RI 0.68 or 1 UtA

notch
Leal et al. (33 )
TNF-R1, cutoff unspecified (1st trimester), and PI,

cutoff unspecified (1st trimester), and maternal
factors (race, body mass index, method of
conception)
Results or conclusions
No significant difference was found in sFlt1 levels at 2325
weeks between women with normal Doppler who will
deliver normally and women with abnormal Doppler who
subsequently develop preeclampsia.
No biochemical marker, although level significantly changed
between 23 and 25 weeks, significantly improved the
UtA Doppler capacity to predict PE.
sVEGFR-1 was of limited use in the prediction of earlyonset and/or severe preeclampsia.
No significant difference was found in homocysteine levels
2224 weeks between women with normal Doppler who
will deliver normally and women with abnormal Doppler
who subsequently develop preelampsia.
No biochemical marker, although level significantly changed
between 23 and 25 weeks, significantly improved the
UtA Doppler capacity to predict PE.
The combinations are not significantly altered in women

with abnormal Doppler parameters destined to develop
PE (without SGA) vs women with normal Doppler
parameters and normal outcome and with women with
abnormal Doppler and normal outcomes, although they
significantly are in women destined to develop PE and
SGA.
A small but significant (P 0.02) decrease of VEGF at

2325 weeks is present in women with abnormal
Doppler who will subsequently develop preeclampsia vs
women with normal Doppler/outcome.
No significant difference was found in maternal serum
ADMA between pregnancies with 1st-trimester highresistance UtA blood flow and controls.
Malondialdehyde is significantly increased in women
destined to develop PE compared with in normal
women, both having abnormal Doppler parameters at
2023 weeks.
No significant difference in CRP levels at 2325 weeks
between women with normal Doppler/outcome and
women with abnormal Doppler who will subsequently
develop PE.
2nd-trimester levels of maternal plasma adiponectin and
leptin in pregnancies (initially abnormal for Doppler UtA
parameters) that subsequently develop PE and/or IUGR
are not significantly different from those in pregnancies
without adverse pregnancy outcomes.
At 3rd trimester, but not at 2nd trimester, leptin levels
were significantly different between women with normal
Doppler/outcome and women with abnormal Doppler
who will subsequently develop PE.
Although regression analysis demonstrated significant
contribution to the detection or PE from maternal
factors, TNF-R1, and PI, in multiple regression analysis,
there was no significant contribution of TNF-R1 (P
0.07) to the prediction provided by maternal factors and
PI (sensitivity 32%, specificity 95%).
sVEGFR-1, soluble vascular endothelial growth factor receptor 1; PAI, plasminogen activator inhibitor; ADMA, asymmetric dimethylarginine; CRP, C-reactive
protein; TNF-R1, tumor necrosis factor receptor 1; SGA, small for gestational age.
Reviews
Fig. 3. Performance characteristics of biochemical and ultrasonographic markers taken alone or in combinations in
predicting preeclampsia in high-risk populations.
Superscript numbers are reference citations: Nicolaides et al. (34 ), Spencer et al. (49 ), Spencer et al. (72 ), Aquilina et al. (48 ),
Kuo et al. (46 ), Merviel et al. (44 ), Anastasakis et al. (55 ), Diab et al. (52 ), Florio et al. (50 ), Florio et al. (54 ), Stepan et al.
(51 ), Stepan et al. (53 ), Williams et al. (47 ).
This systematic review has several strengths: (a) an

exhaustive coverage of existing literature from sound
and highly recognized databases, (b) an assessment of
articles not limited to those written in English, and (c) a
quality assessment of studies based on recognized criteria (30, 31 ). On the other hand, we also recognize
several limitations: (a) the definition of PE has changed
over time and between studies using different national
guidelines, introducing heterogeneity in the classification of the syndrome; (b) variability in the inclusion
criteria, further increasing the heterogeneity between
studies; (c) study-to-study variation in the criteria defining level of risk of a given population: some studies
on low-risk populations showed incidence rates of
PE that were higher than high-risk populations included in other studies, (d) a multiplicity of potential
Reviews
Fig. 4. Performance characteristics of biochemical and ultrasonographic markers taken alone or in combination in
predicting preeclampsia in low-risk populations.
Superscript numbers are reference citations: Poon et al. (36 ), Spencer et al. (60 ), Spencer et al. (39 ), Audibert et al. (56 ), Ay
et al. (57 ), Onalan et al. (62 ), Espinoza et al. (61 ), Spencer et al. (58 ), Spencer et al. (59 ).
tests, test combinations, and timings of sampling during pregnancy, which hampered detailed analysis; and
(e) a lack of precise information in several studies,
flawed study design and/or conduct, although it is unclear how such flaws may have affected the results of a
systematic review or a metaanalysis of diagnostic accuracy (40, 41 ). For each given study on a combination of
markers, it would have been beneficial to have ready
access to the screening performance characteristics of
the markers, either individually or in combination. The

absence of such data led us to remove numerous studies from the core analysis. Extraction of data from ROC
curves and provision of sensitivity data based on a
given level of specificity (e.g., 80% or 95%) limit the
ability to fully evaluate test accuracy. Among the greatest weaknesses of the included studies, affecting the
interpretation of accuracy data, were the lack of a systematic approach in the reporting of performance as-
Reviews
sessment of markers, alone or in combination, and the

absence of a standardized definition of the syndrome.
Our systematic review reveals a real need to develop experimental approaches that would allow comparison of candidate biomarker combinations. Such
information would likely improve statistical power and
our capability for finding a screening procedure that
can better identify at-risk women. Larger prospective
studies including more patients with clearly specified
outcomes would likely lead to more meaningful conclusions. Of importance, studies performed during the
first trimester could guide the assessment of new prophylactic interventions (such as acetylsalicylic acid) in
at-risk women (23 ). In such studies, specific care
should be taken to (1) describe the population (including risk level, means of recruitment, follow-up) and
methodological aspects (including a clear and recognized definition of PE, adequate identification of outcomes in accordance with internationally recognized
guidelines, and thorough description of the tests); (2)
differentiate between mild and severe disease as well as
early and late onset, as these factors confer differences
in terms of maternal and fetal morbidity and mortality;
and (3) report all data related to single markers and
report all data with similar cutoffs to facilitate betweenstudy comparisons. The above criteria should be fulfilled, as stated by WHO in their systematic review on
screening tests for PE (24 ) and by the Standards for
Reporting Diagnostic Accuracy (STARD) initiative
(42 ), on reporting studies of test diagnostic accuracy.
Furthermore, it has been shown recently that the
inclusion of maternal parameters, namely body mass
index, ethnicity, and previous maternal medical and
obstetrical history, in prediction algorithms further
improves predictive accuracy of combinations of biochemical and ultrasonographic markers (3537 ). The
addition of such easily accessible variables that increase
sensitivity, and thus decrease false-negative results, is
of great value. Numerous papers have been published
on potential biomarkers for identifying women predisposed to development of PE before the onset of clinical
symptoms. As our understanding of PE improves, new
tests that will contribute to better predictive perfor-
mance characteristics of a PE-risk model need to be

developed. In addition, this systematic review underscores the need for well-conducted investigations that
integrate various candidate parameters (clinical, biochemical, ultrasonographic) into algorithms capable of
identifying women at risk of PE early in pregnancy so
that early preventive measures can be instituted.
From the perspective of integrative medicine,
there is a clear need for prospective large-scale studies
with rigorous study design criteria to determine the
clinical usefulness of combinations of biomarkers in
different geographic and healthcare environments. In
conducting such studies, it will be essential to incorporate a universally agreed-on definition of hypertensive
disorders of pregnancy. The ultimate outcome of research efforts like these will be the development of an
efficient screening procedure that is evidence based
and that uses a multivariate algorithm of selected maternal characteristics and measurements of biochemical and ultrasonographic markers to identify women at
risk for PE who would benefit from early targeted preventive interventions.
Author Contributions: All authors confirmed they have contributed to

the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design,
acquisition of data, or analysis and interpretation of data; (b) drafting
or revising the article for intellectual content; and (c) final approval of
the published article.
Authors Disclosures of Potential Conflicts of Interest: Upon
manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: The project Healthy Pregnancy is supported by
a grant from the Canadian Institutes for Health Research [Institute of
Human Development, Child and Youth Health (IHDCYH)].
Expert Testimony: None declared.
Role of Sponsor: The funding organizations played no role in the
design of study, choice of enrolled patients, review and interpretation
of data, or preparation or approval of manuscript.
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Combining Biochemical and Ultrasonographic Markers in Predicting Preeclampsia, A Systematic Review

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Combining Biochemical and Ultrasonographic Markers in Predicting Preeclampsia, A Systematic Review

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Clinical Chemistry 56:3

Combining Biochemical and Ultrasonographic Markers in

BACKGROUND: Early identification of pregnant women

CHUQ Research Center/Hopital Saint-Francois dAssise, Quebec City, Quebec,

mester showed 90% sensitivity and 90% specificity in a

Combinations of biochemical and ultrasonographic markers improved the performance of

2009 American Association for Clinical Chemistry

We made electronic searches of Medline and Embase

Titles and abstracts of citations were first screened by 2

Early Prediction of Preeclampsia with Biomarkers

We were able to build 2 2 tables for combinations of

Fig. 1. Study selection process for systematic review

directly stated by the authors or deduced from the

ficity compared with single markers. In low-risk

Early Prediction of Preeclampsia with Biomarkers

Table 1. Performance characteristics of studies combining biochemical and ultrasonographic markers in

hCG 2.5 MoM and PI 95th%

Studies combining 1 biochemical

hCG 2.5 MoM and PI

hCG 2 MoM and UtA notch

Jauniaux et al. (43 )

AFP 2.5 MoM and PI 95th%

Chung et al. (45 )

AFP 2.5 MoM and UtA notch

Kuo et al. (46 )

AFP 2.5 MoM and ultrasound

Williams et al. (47 )

AFP 2.0 MoM and placental

Aquilina et al. (48 )

Inhibin A 2.0 MoM (2nd) and

Early PE cases, 37 weeks

Inhibin A, 1st or 2nd;

Inhibin A 1.8 MoM and 1

Florio et al. (50 )

Activin A 1.7 MoM and 1

Spencer et al. (72 )

Activin A, cutoff unspecified, and

Activin A, 1st; PI,

Nicolaides et al. (34 )

PP-13, cutoff unspecified, and PI,

Stepan et al. (51 )

PlGF 118.0 pg/mL and

PI 1.46 (all PE)

PI 1.64 (early PE)

PI 1.45 and/or bilateral

PlGF 144 pg/mL (all PE)

PlGF 134 pg/mL (early PE)

Spencer et al. (72 )

Inhibin A, cutoff unspecified, and

Florio et al. (50 )

Diab et al. (52 )

Continued on page 366

Clinical Chemistry 56:3 (2010) 365

Table 1. Performance characteristics of studies combining biochemical and ultrasonographic markers in

sFlt1 567.2 pg/mL and PI

sFlt1 631.3 pg/mL and PI

PI 1.45 and/or bilateral

sFlt1 614 pg/mL (all PE)

sFlt1 978 pg/mL (early PE,

Soluble endoglin 4.15 ng/mL

Stepan et al. (51 )

Diab et al. (52 )

Stepan et al. (53 )