Predictive Value of Ophthalmic Artery Doppler Velocimetry in Relation To Development of Pre-Eclampsia
Predictive Value of Ophthalmic Artery Doppler Velocimetry in Relation To Development of Pre-Eclampsia
Predictive Value of Ophthalmic Artery Doppler Velocimetry in Relation To Development of Pre-Eclampsia
Published online 2 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.13313
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
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
ORIGINAL PAPER
Matias et al.
420
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
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
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).
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).
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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).
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422
P < 0.001
Value
Doppler parameter
50.0
40.0
30.0
20.0
10.0
0.0
No
Yes
Multivariate analysis
Pre-elcampsia
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.
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.
100
80
Sensitivity (%)
60
40
20
0
0
20
40
60
100 Specificity (%)
80
100
Matias et al.
424
100
Sensitivity (%)
80
60
40
20
0
0
20
40
60
100 Specificity (%)
80
100
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
425
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