The diagnostic accuracy of the usage of the <i>Fetal Medicine Foundation</i>’s (FMF) on-line risk calculator with first-trimester ultrasound for screening for preeclampsia in high-risk pregnant Brazilian population

doi:10.4236/ojog.2012.23063

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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

Email: *[email protected]

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.

OPEN ACCESS

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-

OPEN ACCESS

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

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

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

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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