Ultrasound Obstet Gynecol 2014; 44: 419426

Published online 2 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.13313

Predictive value of ophthalmic artery Doppler velocimetry

in relation to development of pre-eclampsia
D. S. MATIAS*, R. F. COSTA, B. S. MATIAS, L. GORDIANO and L. C. L. CORREIA*
*Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil; Bahia Perinatology Institute, Salvador, Bahia, Brazil; Santo
Amaro Hospital, Jose Silveira Foundation, Salvador, Bahia, Brazil; Federal University of Bahia Salvador, Bahia, Brazil

K E Y W O R D S: Doppler velocimetry; ophthalmic artery; pre-eclampsia; pregnancy

ABSTRACT
Objective To test the hypothesis that ophthalmic artery
Doppler velocimetry is predictive of the development of
pre-eclampsia (PE).
Methods This was a prospective cohort study that
included pregnant women in the second trimester
who had risk factors for PE. Seven ophthalmic artery
Doppler parameters, in addition to uterine artery (UtA)
Doppler and clinical variables, were investigated for their
prognostic value with respect to PE.
Results A total of 347 women were recruited, of whom
40 developed PE. A comparison of the mean ophthalmic
artery Doppler parameter values between women with
and those without PE showed statistically significant differences in several parameters: peak systolic velocity,
end-diastolic velocity, mean velocity, peak mesodiastolic velocity (PMDV) and peak ratio. After adjusting
for confounding variables, only PMDV remained statistically significant (P < 0.001), with an area under the
receiveroperating characteristics curve (AUC) of 0.73.
The best cut-off for predicting PE was a PMDV of
> 22.11 cm/s, with sensitivity of 70%, specificity of 75%,
positive likelihood ratio of 2.8, negative likelihood ratio
of 0.4, positive predictive value of 28% and negative
predictive value of 95%. The AUC increased from 0.72
to 0.78 when the PMDV was incorporated into a prediction model based on clinical variables, demonstrating
that this marker increased the discriminatory capability of the model. The performance of ophthalmic artery
Doppler was similar to that of UtA Doppler for predicting PE. Additionally, the AUC increased significantly
from 0.82 to 0.88 when the PMDV was incorporated into
the model containing clinical variables and UtA Doppler
indices.
Conclusion A high ophthalmic artery PMDV in the
second trimester of pregnancy is an independent predictor

of PE that increases the discriminatory ability of clinical

markers, as well as of models that include clinical variables
and UtA Doppler indices. Copyright 2014 ISUOG.
Published by John Wiley & Sons Ltd.

INTRODUCTION
Pre-eclampsia (PE) is a multisystem disorder characterized
by hypertension and proteinuria that occurs after the
20th week of gestation and resolves after delivery1,2 .
The overall incidence is 514% of all pregnancies3 ,
and the disorder represents a major cause of maternal
deaths worldwide. PE involves endothelial dysfunction
along with generalized arterial constriction and decreased
intravascular volume including the ocular areas4 6 . An
ability to predict accurately this condition would be of
fundamental importance in clinical practice because it
would enable better surveillance of women at a high risk
of developing PE, thus allowing for the implementation
of prophylactic and therapeutic measures. Prediction of
PE has been based on environmental factors and the
detection of genetic, immunological and demographic risk
factors related to maternal diseases7 . However, these risk
factors have demonstrated poor accuracy in predicting
this condition, and therefore new biomarkers need to be
identified. Several recent studies have reported promising
new findings, particularly those that developed tests to
identify angiogenic factors in the maternal circulation;
however, these tests alone are not adequate for use in
screening8 10 .
Given that the ocular circulation reflects the status
of the hemodynamic cerebral circulation and because of
its embryological, anatomical and functional similarities,
Doppler studies of the ocular vessels have been used to
evaluate, treat and manage diseases that affect the cerebral
vasculature, including PE. However, no published studies
have evaluated the prognostic value of this test with regard
to the development of PE.

Correspondence to: Dr D. S. Matias, Av. Euclides da Cunha, 683/804, ZIP Code: 40150-122, Salvador, Bahia, Brazil (e-mail:
dmatias@ultradiag.com.br)
Accepted: 16 January 2014

Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.

ORIGINAL PAPER

Matias et al.

420

We aimed to test the prognostic value of ophthalmic

artery Doppler velocimetry in the second trimester of
pregnancy with respect to the occurrence of PE, and to
evaluate its incremental predictive value in combination
with data traditionally used in clinical practice, including
classical clinical risk factors and uterine artery (UtA)
Doppler indices.

METHODS
Sample selection
Pregnant women who visited the ultrasound department
of the Institute of Perinatology of Bahia for obstetric
ultrasonography between 20 and 28 weeks gestation
were evaluated consecutively for study admission. We
selected pregnant women at high risk for PE, based on
at least one of the following criteria: first pregnancy
at 18 years of age or 40 years of age, a personal
or family history of PE, primipaternity or new father,
multiple gestation, hypertension prior to pregnancy,
diabetes prior to pregnancy, obesity (body mass index
(BMI) > 30 kg/m2 ), thrombophilia and autoimmune
disease. Patients who smoked and those who used local
or systemic antihypertensive drugs were excluded. Each
patient was examined only once. After inclusion, each
woman was followed prospectively until delivery or until
the identification of an outcome. The cohort was established over a period of 2 years and 3 months (March 2010
to June 2012), beginning with the inclusion of the first
patient and ending with the delivery of the last patient.
The study was approved by the Committee for Ethics
in Research of the Bahia School of Medicine and Public

Health (Escola Bahiana de Medicina e Saude

Publica).
All patients were informed about the study objectives and
gave their informed consent.

Doppler velocimetry
Upon study admission, subjects underwent ophthalmic
artery Doppler velocimetry. Only the right eye was
examined because previous studies have shown no
statistically significant differences in blood flow between
the eyes11 13 . The angle of insonation between the ultrasound beam and the vessel orientation was set at less than
20 , and the gain was adjusted for each individual examination and kept constant throughout. The pulse repetition
frequency of the equipment was set at 5208 Hz to avoid
aliasing, and the volume sample size was set at 2 mm.
A single operator (D.S.M.) performed all the ophthalmic artery Doppler velocimetry examinations using
high-resolution equipment (Medison SonoAce 8000
Ultrasound System, Seoul, South Korea) with an electronic linear transducer with frequency of 7.5 MHz.
The technique used in this study has been described
previously14 16 . In brief, patients were examined while
in a supine position with a head tilt of approximately 15
after a rest period of at least 10 min. After placing a small
amount of methylcellulose gel on the closed eyelid, the
transducer was positioned horizontally without pressing

Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.

the orbit, and up-and-down tipping movements were performed to identify the ophthalmic artery at approximately
15 mm from the ocular globe via color mapping. Using
pulsed Doppler ultrasound, five consecutive flow-velocity
waveforms similar in size and shape were obtained,
and measurements of the Doppler parameters were then
performed on a single flow-velocity waveform. The analyzed variables included peak systolic velocity (PSV),
end-diastolic velocity (EDV), peak mesodiastolic velocity (PMDV), mean velocity (MV), resistance index (RI),
pulsatility index (PI) and peak ratio (PR). All parameters
were automatically calculated by the ultrasound equipment, except for the PMDV and PR values, with the latter
calculated as the ratio between the PMDV and PSV17 .
The women also underwent transabdominal ultrasound
examination with color-flow/pulsed Doppler of both
UtAs at their apparent intersection with the internal iliac
artery. The sample volume was placed to occupy the
entire diameter of the UtA at 1 cm distal from that site.
The same operator (D.S.M.) performed all examinations.
The analyzed variables included mean UtA-RI, mean
UtA-PI, mean UtA-RI > 0.60, mean UtA-PI > 0.96, the
presence of unilateral and bilateral diastolic notches and
the bilateral notch combined with mean UtA-RI > 0.60
and mean UtA-PI > 0.96.

End-point definition
The main outcome was defined as the occurrence of PE,
according to the criteria adopted in the latest revision of
the Report of the National High Blood Pressure Education
Program Working Group on High Blood Pressure in
Pregnancy in 20001 : i.e. hypertension and proteinuria
in previously normotensive patients beyond 20 weeks
gestation.
The women were followed prospectively through to
delivery according to the following protocol: monthly
visits until 32 weeks gestation, biweekly visits until 36
weeks and then weekly visits until delivery, or whenever
complications indicated the need to return. For cases
of suspected or confirmed hypertensive disorders during
the peripartum period, the patients medical records
were reviewed to obtain better clinical and laboratory
characterizations and confirmation of the outcomes.

Reproducibility
Ophthalmic artery examinations of 48 patients (14% of
the sample) were performed by two operators (D.S.M.
and R.F.C.) in order to evaluate the interobserver
agreement according to the BlandAltman method18,19 .
The mean SD of absolute differences and the 95% limits
of agreement (LoA) values of the Doppler parameters
showed good reproducibility, and were as follows:
PSV 5.6 5.6 cm/s (LoA, 16.8 to 14.2 cm/s); EDV
2.2 2.5 cm/s (LoA, 6.8 to 6.2 cm/s); MV 2.9 2.8 cm/s
(LoA, 8.4 to 7.4 cm/s); PMDV 3.2 3.0 cm/s (LoA, 8.6
to 8.7 cm/s); RI 0.04 0.04 (LoA, 0.10 to 0.11); PI
0.3 0.2 (LoA, 0.81 to 0.81); and PR 0.06 0.04 (LoA,
0.13 to 0.16).

Ultrasound Obstet Gynecol 2014; 44: 419426.

Ophthalmic artery Doppler and PE

Statistical analysis
Assuming an incidence of PE of 14% in patients with risk
factors, a minimum sample size of 300 pregnant women
would be required to obtain the 40 outcomes of interest
necessary for the inclusion of four covariates in a logistic
regression model (10 outcomes for each covariate)20 .
Continuous variables were expressed as mean SD,
and comparisons between groups were analyzed with
Students t-test. Comparisons of dichotomous variable
data were performed with the chi-square test. Univariate
associations were identified by comparing the Doppler
parameter values for the ophthalmic artery and uterine
arteries between women with and without PE (level of
significance, P < 0.05). Once identified as risk predictors,
these parameters were evaluated for their independent
predictive value in multivariate logistic regression models,
in which the occurrence of PE was defined as a
dichotomous outcome and the markers were adjusted
for clinical covariates (a level of significance of P < 0.20
and/or biological plausibility were considered).
Logistic regression was performed to create five models;
initially, two separate models were constructed for UtA
and ophthalmic artery Doppler parameters and another
for clinical parameters. Subsequently, a further model
was developed to include the UtA Doppler parameters
and clinical variables that were associated with PE in
the first three models and a final model was developed
to also include significant ophthalmic artery Doppler
variables (level of significance, P < 0.05). The odds
ratio (OR) was used as the measure of association.
The HosmerLemeshow test was used to evaluate the
goodness-of-fit (calibration) of the logistic regression
models21 .
The predictive ability of the ophthalmic artery and
UtA Doppler parameters relative to the occurrence of PE
was assessed using the area under the receiveroperating
characteristics (ROC) curve (AUC). Optimal cut-offs were
chosen, thus allowing sensitivity and specificity values to
be calculated.
The incremental values of ophthalmic artery Doppler
parameters were evaluated by comparing the AUC of the
model that included the clinical and Doppler variables
with the clinical model alone, using the method developed
by DeLong et al.22 . In addition, the AUC relating to use
of the ophthalmic artery data and that for the UtA data
were compared, and the sensitivity and specificity were
compared with McNemars test. Finally, the incremental
value of ophthalmic artery Doppler indices was evaluated
by comparing the AUC for the model that included the
clinical and UtA Doppler variables with the AUC for the
model that included those variables plus the ophthalmic
artery Doppler variables, using the method developed by
DeLong et al.22 .
Statistical analyses were performed with the SPSS
version 17.0 software package for Windows (SPSS Inc.,
Chicago, IL, USA) and MedCalc version 12.3.0 (MedCalc
Software, Mariakerke, Belgium).

Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.

421
Table 1 Demographic characteristics and risk factors of study
population (n = 347)
Characteristic

Value

Age (years)
Gestational age (weeks)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Mean arterial pressure (mmHg)
Body mass index (kg/m2 )
Self-reported race*
White
Brown
Black
Number of current pregnancy
1
2
3
>3
Parity
0
1
2
3
>3
Risk factor
Body mass index > 30 kg/m2
Primigravida 18 years
Primigravida 40 years
Primipaternity
Hypertension upon admission
Personal history of pre-eclampsia
Family history of pre-eclampsia
Prior hypertension
Prior diabetes
Multiple pregnancy

25 9.3
23.2 1.7
107.7 12.9
67.3 10.4
80.8 10.5
25.3 6.3
16/333 (5)
187/333 (56)
130/333 (39)
186 (54)
69 (20)
46 (13)
46 (13)
223 (64)
73 (21)
28 (8)
16 (5)
7 (2)
77 (22)
142 (41)
18 (5)
138 (40)
25 (7)
42 (12)
83 (24)
42 (12)
13 (4)
23 (7)

Data are given as mean SD or n (%). *In 14 patients, selfreported race was not recorded.

RESULTS
Sample characteristics
A total of 347 women with a mean age of 25 9.3 years
(range, 1348 years) and at a mean gestational age of
23 1.7 weeks were included in the study, 54% of whom
were primigravid and 64% of whom were nulliparous.
The most common risk factors for PE were an early
first pregnancy, primipaternity, family history of PE
and obesity. Less frequent risk factors included diabetes
mellitus before pregnancy and a late first pregnancy
(Table 1). Ophthalmic artery Doppler parameter values
observed in the patient sample are described in Table 2
and are higher than reference values in the general
population.
During pregnancy 40 women developed PE, corresponding to an incidence of 12%. The average time
between the Doppler examination (inclusion of patients
in the study) and development of PE was 14 1.1 weeks.
The disease occurred at an average of 37 2.9 weeks
gestation; 70% of the cases were late onset (> 36 weeks)
and 10% were early onset (< 32 weeks).

Ultrasound Obstet Gynecol 2014; 44: 419426.

Matias et al.

422
P < 0.001

Table 2 Ophthalmic artery Doppler parameters of study

population (n = 347)

Peak systolic velocity (cm/s)

End-diastolic velocity (cm/s)
Mean velocity (cm/s)
Peak mesodiastolic velocity (cm/s)
Resistance index
Pulsatility index
Peak ratio

Value

Peak mesodiastolic velocity (cm/s)

Doppler parameter

50.0

38.94 11.12 (17.3086.75)

7.17 3.23 (2.1320.84)
14.89 5.08 (4.8637.30)
20.14 7.09 (6.9648.02)
0.82 0.14 (0.483.02)
2.22 0.55 (0.874.24)
0.52 0.12 (0.210.87)

Data are given as mean SD (range).

Doppler velocimetry and PE: univariate analysis

40.0

30.0

20.0

10.0

0.0
No

Yes

Of the seven ophthalmic artery Doppler parameters

tested, the following five had significantly higher values in
patients who eventually developed PE than in those who
did not (P < 0.05): PSV, EDV, MV, PMDV and PR. Of
these, PMDV exhibited the greatest difference between
the groups, with values of 24 6.5 cm/s vs 19 6.7 cm/s
(P < 0.001) (Table 3, Figure 1).
The following seven of eight uterine artery Doppler
parameters were associated with PE (P < 0.05): mean
UtA-RI, mean UtA-PI, mean UtA-RI > 0.60, mean
UtA-PI > 0.96, bilateral notch, bilateral notch combined
with mean UtA-RI > 0.60 and bilateral notch combined
with mean UtA-PI > 0.96 (Table 3).

Regarding the number of risk factors identified per

patient, 23% of patients had only one risk factor, 41%
had two, 30% had three and 6% had four or more. There
was no association between the number of risk factors
and the occurrence of PE (P = 0.77).

Clinical predictors of PE: univariate analysis

Multivariate analysis

The age of the patients who developed PE was significantly

higher than that of those who did not. Similarly, the mean
arterial pressure, hypertension upon admission, BMI,
obesity, hypertension before pregnancy, diabetes before
pregnancy and multiple gestation were associated with PE.
The other analyzed variables showed no associations with
PE. There was also a trend towards statistical significance
in patients with a history of PE (P = 0.05) (Table 4).

Initially, three separate multivariate models were created

for the clinical data, ophthalmic artery Doppler data
and UtA Doppler data. Variables with P < 0.05 in the
univariate analysis were included in these models.
In the clinical model, first pregnancy (OR = 2.19 (95%
CI, 0.994.86); P = 0.05) and obesity (OR = 1.91 (95%
CI, 0.904.06); P = 0.09) were the only variables that
showed a trend toward a positive association with PE,

Pre-elcampsia

Figure 1 Box plots showing distribution of ophthalmic artery peak

mesodiastolic velocity in women who did and those who did not
subsequently develop pre-eclampsia. Boxes and whiskers indicate
median, interquartile range and range excluding outliers. Black
dots represent outliers and the star is an extreme value.

Table 3 Ophthalmic artery and uterine artery Doppler parameters in pregnant women who subsequently developed pre-eclampsia (PE)
compared with those in women who did not (n = 330)*
Doppler parameter
Ophthalmic artery
Peak systolic velocity (cm/s)
End-diastolic velocity (cm/s)
Mean velocity (cm/s)
Peak mesodiastolic velocity (cm/s)
RI
PI
Peak ratio
Uterine artery
Unilateral notch
Bilateral notch
Bilateral notch + mean RI > 0.60
Bilateral notch + mean PI > 0.96
Mean RI > 0.60
Mean PI > 0.96

No PE (n = 290)

PE (n = 40)

38.19 11.13
6.94 3.12
14.46 4.90
19.29 6.72
0.82 0.14
2.23 0.57
0.51 0.12

42.67 9.13
8.32 3.12
17.00 4.71
24.27 6.46
0.80 0.07
2.10 0.48
0.57 0.11

0.01
0.01
0.002
< 0.001
0.28
0.15
0.003

27 (9)
58 (20)
33 (11)
42 (14)
65 (22)
89 (31)

5 (13)
18 (45)
18 (45)
18 (45)
25 (63)
29 (73)

0.52
< 0.001
< 0.001
< 0.001
< 0.001
< 0.001

Data shown as mean SD or n (%). *17 patients were lost to follow-up. PI, pulsatility index; RI, resistance index.

Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.

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Ophthalmic artery Doppler and PE

423

Table 4 Comparison of clinical characteristics between women with and without subsequent development of pre-eclampsia (PE) (n = 330)*
Clinical characteristic
Age (years)
Gestational age (weeks)
Mean arterial pressure (mmHg)
Body mass index (kg/m2 )
Self-reported race
White
Brown or black
Number of current pregnancy
Primigravida
Not primigravida
Risk factor
Body mass index > 30 kg/m2
Primigravida 18 years
Primigravida 40 years
Primipaternity
Hypertension upon admission
Personal history of PE
Family history of PE
Prior hypertension
Prior diabetes
Multiple pregnancy

No PE (n = 290)

PE (n = 40)

24 9.3
23.2 1.7
80.2 10.1
25.0 6.2

29 7.7
22.9 1.8
84.7 11.3
27.7 6.4

0.001
0.32
0.009
0.01
0.37

12/279 (4)
267/279 (96)

3 (8)
37 (93)

158 (54)
132 (46)

17 (42)
23 (58)

60 (21)
130 (45)
15 (5)
117 (40)
20 (7)
33 (11)
68 (23)
30 (10)
9 (3)
16 (6)

16 (40)
4 (10)
3 (8)
11 (28)
4 (10)
9 (23)
10 (25)
9 (23)
4 (10)
6 (15)

0.15

0.007
< 0.001
0.54
0.12
0.04
0.05
0.85
0.03
0.03
0.02

Data shown as mean SD or n (%). *17 patients were lost to follow-up. In 11 patients, all in the No-PE group, self-reported race was not
recorded.

Incremental predictive value

The ROC-AUC of the clinical model was 0.72 (95%
CI, 0.670.77), and there was an increase to 0.78
(95% CI, 0.730.82) when PMDV was included, with

Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.

100

80

Sensitivity (%)

whereas early first pregnancy was identified as a protective

factor for the disease (OR = 0.10 (95% CI, 0.030.32);
P < 0.001). These three variables were selected for the
final model (Table S1).
In the ophthalmic artery Doppler model, only PMDV
remained statistically significant (OR = 1.15 (95% CI,
1.051.26); P = 0.002) in the multivariate model that
contained the Doppler variables (Table S2).
In the UtA Doppler model, mean UtA-PI (OR = 3.17
(95% CI, 1.039.71); P = 0.04) and mean UtA-PI > 0.96
(OR = 2.96 (95% CI, 1.078.20); P = 0.04) were the
only variables associated with PE (Table S3). The model
including significant clinical and UtA Doppler variables is
illustrated in Table S4.
The significant variables in the first three models were
included in the final multivariate model that contained
the clinical, UtA Doppler and ophthalmic artery Doppler
data. The following factors were identified as independent
predictors of PE: first pregnancy (OR = 3.10 (95% CI,
1.227.83); P = 0.02), mean UtA-PI > 0.96 (OR = 6.81
(95% CI, 2.9615.69); P < 0.001) and ophthalmic artery
PMDV > 22.11 cm/s (OR = 6.24 (95% CI, 2.8013.90);
P < 0.001). Early first pregnancy remained a protective
factor against the development of PE (OR = 0.10 (95% CI,
0.030.35); P < 0.001). The model showed an excellent
goodness-of-fit (calibration) according to the Hosmer
Lemeshow test (P = 0.97); in other words, this model is
able to predict the outcome probability (Table S5).

60

40

20

0
0

20

40
60
100 Specificity (%)

80

100

Figure 2 Receiveroperating characteristics curves showing

increase in prognostic value with respect to pre-eclampsia when
comparing a model including clinical and uterine artery (UtA)
) (area under the curve (AUC), 0.82 (95%
Doppler variables (
CI, 0.770.86)) vs the final model including clinical, UtA and
) (AUC, 0.88 (95% CI,
ophthalmic artery Doppler variables (
0.830.91)).

the difference between areas being 0.06 (95% CI,

0.00040.12) (P = 0.03), indicating that this marker
significantly increased the discriminatory ability of clinical
prediction. The ROC-AUC of the model that included the
clinical and UtA Doppler variables was 0.82 (95% CI,
0.770.86) (P < 0.001), which increased to 0.88 (95% CI,

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Matias et al.

424
100

Sensitivity (%)

80

60

40

20

0
0

20

40
60
100 Specificity (%)

80

100

Figure 3 Receiveroperating characteristics curve (

) with
) for ophthalmic artery Doppler peak mesodiastolic
95% CI (
velocity (PMDV) in the prediction of pre-eclampsia, with area
under the curve of 0.73 (95% CI, 0.660.81). Arrow indicates
optimal cut-off point of PMDV > 22.11 cm/s.

0.830.91) (P < 0.001) when the ophthalmic artery

PMDV was included, to yield a difference between the
areas of 0.06 (95% CI, 0.060.10) (P = 0.007). In other
words, this marker increased the discriminatory capability
of prediction traditionally used in clinical practice,
which includes classical risk factors and UtA Doppler
(Figure 2).

Accuracy of ophthalmic artery PMDV in prediction

of PE
The ROC-AUC for PMDV was 0.73 (95% CI,
0.660.81), and the best cut-off for predicting PE was
a PMDV > 22.11 cm/s, with a corresponding sensitivity
of 70% (95% CI, 53.583.4%), specificity of 75% (95%
CI, 69.479.7%), positive likelihood ratio of 2.8 (95%
CI, 2.13.7) and negative likelihood ratio of 0.4 (95%
CI, 0.20.6). For this patient sample, which had a 12%
incidence of PE, the positive predictive value was 28%
(95% CI, 19.237.6%) and the negative predictive value
was 95% (95% CI, 91.097.3%) (Figure 3).

DISCUSSION
The results of this study indicate that an increase in the
ophthalmic artery PMDV during the second trimester of
pregnancy is an independent predictor of the subsequent
development of PE. Furthermore, when PMDV was added
to the clinical model in the multivariate analysis, there was
a significant increase in the models discriminatory ability
to predict PE.
Early identification of women at risk of development of
PE is critical to reducing maternal and perinatal morbidity

Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.

and mortality, as it allows for closer monitoring and

the adoption of prophylactic and therapeutic measures.
Traditionally, predictions regarding the development of
PE have been based on the detection of clinical risk
factors, and numerous studies in the literature have found
these markers to be associated with an increased risk
of PE7,23 28 . Because the prognostic accuracy of clinical
variables is moderate, many current studies focus on
identifying new risk predictors that can increase the ability
to predict PE either alone or in combination with other
biochemical or biophysical markers.
Several recent studies have suggested that as the
increased production of anti-angiogenic molecules such as
soluble fms-like tyrosine kinase-1 and soluble endoglin,
as well as the reduced production of angiogenic molecules
such as placental growth factor and vascular endothelial
growth factor, have been implicated in the pathogenesis
of PE8,29 , they therefore might be useful for diagnosis of
the disease and its related complications9,30 . However,
these tests are not accessible to the majority of pregnant
women.
Yu et al.31 reported that an increased risk of PE
occurrence was directly related to the number of risk
factors present in each pregnant woman. However,
the data from the current study show no statistically
significant difference in the number of risk factors between
patients who developed PE and those who did not. This
finding suggests that these predictive variables are not
independent of each other, thus weakening a prognostic
model comprising only clinical variables. Accordingly,
our logistic regression analysis showed that only one
clinical variable was an independent predictor, suggesting
that improvements to predictive models will depend on
the inclusion of new biomarkers such as physiological
variables from complementary examinations.
PE implies a hyperreactivity to vasoactive hormones
that is secondary to placental maladaptation, and this
change can be detected even before hypertension becomes
apparent4 . This normotensive state during pregnancy,
along with a high cardiac output and compensatory
vasodilatation, can be defined as latent or asymptomatic
PE32,33 . This pathophysiological process begins months
before the appearance of clinical disease and might
be present as early as the end of the first trimester32 .
Studies by Easterling and Benedetti34 and Bosio et al.35
have shown that there is a hyperdynamic circulatory
state during the latent phase of PE, characterized by
a significantly higher cardiac output prior to clinical
diagnosis but without a significant change in the total
peripheral resistance, consistent with the presence of
circulating vasodilators.
Among the ophthalmic artery Doppler parameters,
PMDV is the one that showed the greatest difference
in PE cases and is responsible for the observed rise in
PR values. This index is considered the most important
one for assessing the extent and severity of the disease
and represents signs of ocular hyperperfusion36,37 . The
mechanism that increases this ratio during PE remains

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Ophthalmic artery Doppler and PE

unclear, but the ratio appears to be the most sensitive
indicator of orbital vascular changes related to the disease.
This study identified a statistically significant increase
in the ophthalmic artery PMDV during the second
trimester of pregnancy in women who later developed
PE. This phenomenon could be interpreted as an initial
compensatory and autoregulatory phase of latent PE,
with macrocirculatory vasodilatation (in the ophthalmic
artery) in response to microcirculatory vasoconstriction
(in the retinal arterioles) before the onset of clinically
identifiable signs and symptoms. Orbital vessels and
cerebral arterioles have anatomical, embryological and
functional similarities, and hence study of the orbital
vessels allows us to make inferences about cerebral
hemodynamics. Our findings are consistent with those
of Riskin-Mashiah et al.38 and Belfort et al.39 , who used
transcranial Doppler to study the middle cerebral artery
and reported low resistance in this artery during the
second trimester of pregnancy in women who later
developed PE. These findings were attributed to the action
of circulating vasodilators produced by the placenta.
The multivariate analysis in the present study showed
a significant increase in the ROC-AUC when the PMDV
was incorporated into the clinical model; in other words,
there was an increase in the discriminatory capability
of the model to predict PE. These findings highlight the
originality of this study because, as far as we are aware,
it is the first to test the predictive value of ophthalmic
artery Doppler indices with respect to the development of
PE in a prospective study with an adequate sample size.
All the published studies to date were limited to studying
characteristics of the cerebral and orbital vessels during
the clinical disease phase in cross-sectional protocols.
Additionally, this study demonstrates that the performance of ophthalmic artery Doppler is at least equal to
that of UtA Doppler for predicting PE during the second trimester of pregnancy and that ophthalmic artery
Doppler increases the discriminatory capability of disease prediction when combined with classical clinical risk
factors and UtA Doppler.
The main limitation of this study is that it studied a
sample of pregnant women with risk factors for PE, and
therefore the results cannot be extrapolated to the general
screening of pregnant women. Further studies should
be performed to confirm our findings and to verify the
discriminatory capability of ophthalmic artery Doppler
relative to the occurrence of PE in the general population.
Accordingly, another cohort would be needed to validate
the new model. An understanding of the mechanism
behind the increase in PMDV might be the key to using
this parameter as a prognostic marker for pregnancy and
postpartum recovery or as a screening test for the early
detection of PE.
In conclusion, the increase in the ophthalmic artery
PMDV during the second trimester of pregnancy is
an independent predictor of PE that increases the
discriminatory capability for predicting this condition
when combined with clinical markers and UtA Doppler
velocimetry.

Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.

425

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SUPPORTING INFORMATION ON THE INTERNET

The following supporting information may be found in the online version of this article:
Table S1 Summary of logistic regression model including clinical variables for prediction of pre-eclampsia
Table S2 Summary of logistic regression model including ophthalmic artery Doppler variables for prediction
of pre-eclampsia
Table S3 Summary of logistic regression model including uterine artery Doppler variables for prediction of
pre-eclampsia
Table S4 Summary of logistic regression model including clinical and uterine (UtA) artery Doppler variables
for prediction of pre-eclampsia
Table S5 Summary of final logistic regression model including clinical and uterine and ophthalmic artery
Doppler variables for prediction of pre-eclampsia

Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.

Ultrasound Obstet Gynecol 2014; 44: 419426.