Open Journal of Obstetrics and Gynecology, 2012, 2, 298-303 OJOG
http://dx.doi.org/10.4236/ojog.2012.23063 Published Online September 2012 (http://www.SciRP.org/journal/ojog/)
The diagnostic accuracy of the usage of the Fetal Medicine
Foundation’s (FMF) on-line risk calculator with
first-trimester ultrasound for screening for pre-eclampsia
in high-risk pregnant Brazilian population
Ernesto Antonio Figueiró-Filho*, Maithe Vendas Galhardo, Bruno Areco de Souza
Faculty of Medicine, University Hospital, Federal University of Mato Grosso do Sul, Campo Grande, Brazil
Received 28 July 2012; revised 25 August 2012; accepted 9 September 2012
ABSTRACT
To evaluate the sensitivity and specificity of the usage
of the FMF On-Line Risk Calculator with first-tri-
mester ultrasound, in screening assessment for pre-
eclampsia (PE), without serum markers. To define
the best risk cut-off values for early, intermediate and
late pre-eclampsia. Diagnostic accuracy study of preg-
nant women who had first-trimester ultrasounds be-
tween 11 and 13 weeks. The index test was the first-
trimester ultrasound scan plus the FMF On-Line
Risk Calculator to assess the risk for PE. The refer-
ence standard was the confirmation of actual deve-
lopment of early, intermediate or late PE. For calcu-
lations of sensitivity and specificity to determine the
best cut-off values for early, intermediate and late PE,
all the information were processed into ROC curves.
The assessment of pre-eclampsia risk in the first tri-
mester using an ultrasound plus the FMF On-Line
Risk Calculator demonstrated a significant (p < 0.05)
area under the ROC curve for early, intermediate
and late pre-eclampsia. The best risk cut-off values
were defined as 2.1% for early, 2.5% for intermediate
and 3.5% for late pre-eclampsia. The first trimester
US plus the FMF On-Line Risk Calculator tool was
useful and applicable when assessing the risk for
pre-eclampsia in a specific pregnant Brazilian popu-
lation.
Keywords: Accuracy; Sensitivity; Specificity;
Pre-Eclampsia; First Trimester; Risk
1. INTRODUCTION
Pre-Eclampsia (PE) is a multisystem disorder exclusive
to pregnancy characterized by hypertension and protein-
uria that develops after 20 weeks of gestation [1-4]. PE
affects 2% - 10% of all pregnancies and is an important
cause of morbidity and maternal and perinatal mortality
[1-3,5,6]. Early screening of women with a potential risk
of developing pre-eclampsia is justified because it allows
the possibility of early intensiv e maternal and fetal moni-
toring, thereby avoiding adverse outcomes. Furthermore,
there is evidence that prophylactic usage of aspirin may
reduce the incidence of PE in 50% of women when the
treatment is starte d bef o re 16 week s [7, 8] .
Advances in fetal medicine and ultrasound imaging
techniques have allowed extensive research on the role
of first-trimester screening for several maternal and fetal
conditions [4,9-14]. This new assessment of risk factors
using fetal, maternal and biochemical markers suggests
new approaches for prenatal care that are more focused
on the first rather than third trimester [14,15].
Many current studies have demonstrated the possibi-
lity of pre-eclampsia screening be tween 11 and 13 weeks
with promising results [4,13,16-22]. This screening fo-
cuses on the multivariate analysis of risk associatin g ma-
ternal data, clinical, obstetric, ultrasound and serum ma rker
measurements [19,20].
It was recently demonstrated that first-trimester ultra-
sound scanning can predict early PE by identifying wo-
men who will require delivery before 34 weeks’ gesta-
tion, intermediate PE by identifying women requiring
delivery at 34 - 37 weeks and late PE by identifying
women requiring delivery after 37 weeks. This study
conclude d t hat effe ct ive prediction of PE can be achieved
at 11 - 13 weeks’ gestation [4]. Based on these results,
the Fetal Medicine Foundation (FMF) provides an on-
line risk calculator for the assessment of risk for early,
inter-mediate and late PE using information from the
ultrasound scan as well as clinical and serum biochemi-
cal markers.
Considering the paucity of studies using ultrasound
*Corresponding author.

E. A. Figueiró-Filho et al. / Open Journal of Obstetrics and Gynecology 2 (2012) 298-303 299
screening to assess the risk of pre-eclampsia in pregnant
women in Brazil, the objective of this study was to
evaluate the sensitiv ity and specificity o f th e usage of the
FMF On-Line Risk Calculator and first trimester ultra-
sound scan in assessment of risk for pre-eclampsia, but
not serum markers. The actual development of pre-
eclampsia was the reference standard. This study also
aimed to define the best risk cut-off values for early, in-
termediate and late pre-eclampsia, using the FMF on-line
risk calculator.
2. METHODS
We followed the STARD (Standards for Reporting of
Diagnostic Accuracy) recommendations for reporting the
accuracy of a diagnostic procedure [23]. This involved
completing a checklist of items to ensure that all perti-
nent information was present in the text, thus allowing
the reader to detect the potential for bias and to judge the
applicability of the results.
This was a study of diagnostic accuracy among preg-
nant women who had first-trimester ultrasound between
11 and 13 weeks at the High Risk Pregnancy Service,
University Hospital (UH), School of Medicine (FAMED),
Federal University of Mato Grosso do Sul (UFMS) be-
tween October 2010 and May 2011. All pregnant women
who had first-trimester ultrasound examinations during
the study period and whose obstetric and perinatal clini-
cal information were available in the medical records
were includ ed. We excluded patients w ho were under 18
years of age or who had indigenous heritage and twin
pregnancies. All patients included in study signed an
informed consent. The study and its informed consent
were approved by the Ethics Committee on Human Re-
search, Protocol 1859, on September 30, 2010.
The index test considered in this series was the first-
trimester ultrasound scan plus the FMF On-Line Risk
Calculator
(https://courses.fetalmedicine.com/calculator/pe?locale=en).
Together, they were used to assess the risk for early, in-
termediate and late PE. The theoretical 3.0% cut-off risk
for pre-eclampsia was defined for the index test (the ul-
trasound scan + the FMF On-Line Risk Calculator),
based upon previous pre-eclampsia prevalence studies in
different populations [1-3], before confirmation using the
reference standard.
The reference standard was the confirmation of actual
development of early, intermediate or late PE after pa-
tient delivery. This study was planned after the patients
had performed the index test and after they had delivered;
therefore, this was a retrospective analysis of diagnostic
accuracy.
For the confirmation of maternal pre-eclampsia deve-
lopment (reference standard), we considered women who
presented with the diagnostic criteria of two or more
blood pressure measurements exceeding 140/100 mmHg
and proteinuria exceeding 300 mg/24 h [2,3], as reco rded
in the medical record during prenatal care. If PE deve-
loped and required delivery before 34 weeks, this was
defined as early PE. If PE developed and required termi-
nation of pregnancy between 34 - 37 weeks, we consid-
ered this intermediate PE. Finally, patients that deve-
loped late PE were those whose diagnosis required de-
livery after 37 weeks [4].
To calculate the risk of pre-eclampsia, we used the
FMF On-Line Risk Calculator for Pre-eclampsia, avail-
able on the FMF web site. We also considered maternal
clinical variables (e.g., age, ethnicity, weight, height,
body mass index, mode of conception, smoking history,
illicit drug us e, history of hypertension, histor y of diabe-
tes and history of systemic lupus erythematous), obstet-
rical variables (e.g., parity, history of PE in the woman’s
mother, history of previous PE, history of miscarriages
and stillbirths), ultrasound data (e.g., fetal crown-rump
length and pulsatility ind ex of uterine arteries) and blood
pressure (BP) measured at the time of examination [13,
17-22]. No maternal serum biochemical markers were
used in the risk assessment for pre-eclampsia; only the
clinical information, obstetric ultrasound and BP mea-
surements were used. Blood pressure was measured
twice in each arm, and the mean BP was calculated ac-
cording to the criteria establishe d for the implementation
of this examination by FMF [21,22]. All the ultrasound
scanning data were collected by FMF-certified sonogra-
phers. The Ultrasound used to acquire the images were
Nemio 17, TOSHIBA, with preset of first trimester scan
default.
Clinical and obstetrical information, as well as ultra-
sound data and blood pressure values, were included in
the respective fields requested on the online risk calcula-
tor homepage from the FMF website. The risks were
registered on the patient’s record in the same format in
which they were presented as percentages values for the
following: risk for early, intermediate and late pre-
eclampsia. The assessment risks from the index test were
acquired blindly, without knowledge of the patient’s ac-
tual development of pre-eclampsia; th e latter information
was only available after delivery. Because each patient
could have more than one risk factor according to the
screening test, indicating their elevated risk for early,
intermediate or late PE, they were grouped by the earliest
possibility of developing PE. For example, if a patient
was assessed to have a risk higher than 3.0% for early,
intermediate and late PE, this patient was considered
only in the early PE group.
The design of the study is outlined in a flowchart
(Figure 1). For calculations of sensitivity and specificity
nd to determine the best cut-off values for early, inter- a

E. A. Figueiró-Filho et al. / Open Journal of Obstetrics and Gynecology 2 (2012) 298-303 300
Eligible Patients
n=200
Ultrasound Scan (11-13 weeks)
+
Risk Assessment On-Line (FMF Web Site)
n=195
Excluded Patients
Age < 18, indigenous,
twins
n=5
Risk for Preeclampsia
> 3.0%
n=64 (33%)
Risk for Preeclampsia
< 3.0%
n=131 (67%)
Early
(< 34 sem)
n=12 (6%)
Intermediate
(34-37 sem)
n=17 (9%)
Late
(> 37 sem)
n=35 (18%)
Early
(<34sem)
n=12 (6%)
Preeclampsia Development
(Blood press ure > 140 x10 0mmHg + Proteinuria > 300mg/24h)
n=195
Intermediate
(34-37sem)
n=5 (2.5%)
Late
(>37sem)
n=7 (3.5%)
Not Co nfir me d
n=171 (88%)
Confirmed
n=24 (12%)
Index
Test
Reference
Standard
Figure 1. Flowchart diagram of the design of the study.
mediate and late PE, all the information was processed
into ROC curves. To create the ROC curves, the risk
values from patients with unconfirmed PE (n = 171)
were compared to the risk values from patients with con-
firmed early (n = 12), intermediate (n = 5) and late (n = 7)
PE. For statistical calculations, we used the area under
the ROC curve and considered a significant p value to be
less than 0.05. The calculated Odds Ratio (OR) an d con-

E. A. Figueiró-Filho et al. / Open Journal of Obstetrics and Gynecology 2 (2012) 298-303 301
fidence intervals (CI) greater than 95% were also pre-
sented. The calculations were processed with Prism 5
software for Windows (GraphPad Software Inc., 1992-
2007©).
3. RESULTS
Initially, the eligible patients included 200 pregnant
women who underwent ultrasound screen ing in their first
trimester from October 2010 to May 2011. Five patients
were excluded because they had not met the inclusion
criteria. The final sample studied (n = 195) corresponded
to 97.5% of pregnant women who submitted to ultra-
sound screening during the study period (Figure 1).
The patients’ mean age was 32 ± 4.5 years, and most
of the subjects were Caucasian (62.5%). The average
weight of the pregnant women studied was 64.7 ± 12.2
kg, and the mean height was 163 ± 0.6 cm. The mean
parity was 1.69 ± 0.9 ch ildren. The mean gestational age
at examination was 12 ± 0.6 weeks, and the mean fetal
crown-rump length (CRL) was 60.2 ± 9.5 mm. The mean
gestational age at delivery was 37.4 ± 2.4 weeks, with
newborns having a mean weight of 3046 ± 515 g and a
mean height of 47. 7 ± 3. 17 c m.
Of the 195 pregnant women screened for PE by the
index test (first-trimester US + FMF On-Line Risk Cal-
culator, considering the theoretical cut-off risk of 3.0%,
131 (67%) were selected not to developed PE, consider-
ing their risk lower than 3.0%. Alternatively, 64 (33%)
were identified to developed PE when their risk was
greater than or equal to 3.0%. Among these screened
patients with a positive risk for PE (n = 64), 12 (6%)
were high-risk for early PE, 17 (9%) were high-risk for
intermediate PE, and 35 (18%) were high-risk for late
PE.
Pre-eclampsia was really confirmed in 12% of the
study population (24/195): 6% (12/195) with early pre-
eclampsia, 2.5% (5/195) with intermediate pre-eclampsia
and 3.5% (7/195) with late pre-eclampsia. These data are
presented in a flow chart (Figure 1).
The assessment of risk for pre-eclampsia in the first
trimester, with an ultrasound scan plus the FMF On-Line
Risk Calculator, demonstrated a significant (p < 0.05)
area under the ROC curve for early (area = 0.84 95% IC:
0.67 - 1.0), intermediate (area = 0.89 95% IC: 0.72 - 1.0)
and late (area = 0.88 95% IC: 0.73 - 1.0) pre-eclampsia,
as presented in Figures 2-4 and in Table 1.
For women for whom PE was not confirmed, the me-
dian and 25th - 75th percentile risks are as follows: early
PE, 0.04% (0.01% - 0.14%); intermediate PE, 0.49%
(0.1% - 1.0%) and late PE, 1.0% (0.54% - 3.0%). For
patients for whom PE was confirmed, the median and
25th - 75th percentile risks are as follows: early PE, 5.0%
(0.95% - 22.0%); intermediate PE, 12.0% (2.2% - 16.0%)
and late PE, 12.0% (4.0% - 25.0%). These data are pre-
sented in Table 1.
After the statistical calculations of specificity and sen-
sitivity, the best risk cut-off risk values were defined as
greater than 2.1% for early, greater than 2.5% for inter-
mediate and greater than 3.5% for late pre-eclampsia.
The sensitivity, specificity and likelihood ratio for each
cut-off value a re p r es ented in Table 1.
4. DISCUSSION
The assessment of pre-eclampsia risk using mater-
nal-fetal parameters is a novel topic in prenatal diagnosis.
Most of the studies concerning this subject are dated af-
ter 2009 [4,18-20,24]. Maternal characteristics associated
with biochemical and biophysical tests at 11 - 13 weeks’
gestation can iden tify 90%, 80% and 60% of pregn ancies
that will result in early, intermed iate and late PE, respec-
tively [4]. Based on these results, the Fetal Medicine
Foundation website gives free access to research materi-
als and online tools that facilitate the assessment of the
PE risk factors [4]. The question raised was if this as-
sessment of calculated risks could be useful and applica-
ble in different populations of pregnant women.
Our results demonstrate that the reference test studied
(assessment of risk for PE with a first-trimester ultra-
sound + the FMF On-Line Risk Calculator ) could accu-
rately screen for early (cut-off risk value: >2.1%, 75%
Ta ble 1. The median risk values, best risk cut-off values, sensitivity, specificity, likelihood ratio and area under the ROC curve for
the assessment of risk for pre-eclampsia with a first-trimester ultrasound in pregnant women.
Assessment of risk for
pre-eclampsia in
first-trimester
(ultrasound + FMF on-line
risk calculator)
Median risk values
(25th - 75th percentile)
of patients without
PE (%)
Median risk
values (P25 - P75)
of confirmed PE
patients (%)
Best risk
cut-off
value (%)
Sensitivity
(95% CI)Specificity (95% CI)Likelihood ratio
Area under
ROC curve
(95% CI)p value
Early
(<34 weeks) 0.04
(0.01 - 0.14) 5.0 (0.95 - 22.0) >2.1 75.0% (42.8 - 94.5)98.2% (94.9 - 99.6)43.0 0.84 (0.67 - 1.0)<0.0001
Intermediate
(34 - 37 weeks) 0.49 (0.1 - 1.0) 12.0 (2.2 - 16.0) >2.5 80.0% (28.3 - 99.4)91.2% (85.9 - 95.0)9.12 0.89 (0.72 - 1.0)0.002
Late
(>37 weeks) 1.0
(0.54 - 3.0) 12.0 (4.0 - 25.0) >3.5 85.7% (42.1 - 99.6)82.4% (75.9 - 87.8)4.89 0.88 (0.73 - 1.0)0.0005

E. A. Figueiró-Filho et al. / Open Journal of Obstetrics and Gynecology 2 (2012) 298-303 302
ROC curv e: Screening for Early PE (<34sem) with First Trimester
Ultrasound (11-13 sem)
020 40 60 80
0
20
40
60
80
100
100% - Specificity%
Sensitivity%
Figure 2. ROC curve: screening for early PE (<34 weeks) with
first-trimester ultrasound (11 - 13 weeks).
ROC curve: Screening for Intermediate PE (34-37sem) with First
Trimester Ultrasound (11-13 sem)
050 100 150
0
50
100
150
100%-Specificity%
Sensitivity%
Figure 3. ROC curve: screening for intermediate early PE (34 -
37 weeks) with first-trimester ultrasound (11 - 13 weeks).
ROC curve: Screening for Late PE (>37sem) with First Trimester
Ultras ound (11-13 s em)
050100 150
0
50
100
150
100%-Specificity%
Sensitivity%
Figure 4. ROC curve: screening for late PE (>37 weeks) with
first-trimester ultrasound (11 - 13 weeks).
sensitivity, 98.2% specificity); intermediate (cut-off risk
value: >2.5%, 80.0% sensitivity, 91.2% specificity) and
late (cut-off risk value: >3.5%, 85.7% sensitivity, 82.4%
specificity) PE. The advantage of this method is th at it is
low-cost and applicable to daily clinical practice. The
free provision of FMF On-Line Risk Calculator and the
ease of acquiring an ultrasound scan and maternal clini-
cal data give this method good reproducibility. Moreover,
because maternal biochemical serum markers were not
used, this method is applicable in developing countries
like Brazil.
Our results also demonstrate a high frequency (12%;
24/195) of confirmed pre-eclampsia diagnoses among
the pregnant patients studied: 6.0% (12/195) early PE,
2.5% (5/195) intermediate PE and 3.5% (7/195) late PE.
These rates are elevated when compared to other studies.
Among the 35,000 singleton pregnancies included in a
recent study [4], it was reported the prevalence of early,
intermediate and late PE at 0.3%, 0.6% and 1.3%, re-
spectively. In our study, the assessed risk using the first-
trimester ultrasound scan plus the FMF On-Line Risk
Calculator for patients who did not have confirmed pre-
eclampsia showed median risk values of 0.04%, 0.49%
and 1.0% for early, intermediate and late PE, respectively.
This finding is in agreement with the Akolekar et al.
2011 study [4].
The most probable explanation for the high frequency
of PE development in our population was that we re-
cruited from a High Risk Pregnancy Referral Center.
This supports the accuracy rates of the first-trimester
screening for PE demonstrated herein, considering that
assessed risk rates for early, intermediate and late PE >
3.0% was calculated for 6% (12/195), 9% (17/195) and
18% (35/195) of patients, respectively, according to the
index test before confirmation with the reference stan-
dard. After confirmation, the rates of early, intermediate
and late pre-eclampsia were 6% (12/195), 2.5% (5/195)
and 3.5% (7/195).
The accuracy of the index test presented in this retro-
spective study was not 100%, as we failed to identify all
patients that developed PE [25]. However, retrospective
accuracy tests may reflect routine clinical practice better
than a prospective study [23,25], as demonstrated in the
flowchart (Figure 1). We have demonstrated the applica-
bility of this PE screening technique, which relies on
first-trimester ultrasound and the FMF On-Line Risk
Calculator, but not on maternal serum biochemical
markers, for use in daily practice.
Despite the short period of evaluation, our results
suggest that the FMF On-Line Risk Calculator tool is
useful and applicable for PE risk assessment in a high-
risk pregnant Brazilian population. These results, how-
ever, demonstrate that new research should be conducted
on the early assessment of patient-specific risk factors
for pre-eclampsia to prevent complications and improve
pregnancy outcomes by shifting prenatal care from a
series of routine visits to a more individualized approach
[4]. In the case of PE, the assessment of risk by first-
trimester ultrasound requires future studies to determine
the role of pharmacological intervention, such as starting
an aspirin regimen during the first trimester, to decrease
subsequent development of the disease [4].
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