Seminars in Ophthalmology, 2014; 29(1): 11–17 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2013.839813
Nihat Sayin1, Necip Kara2, Dilara Pirhan1 , Asli Vural1, Hatice Bilge Araz Ersan1, Ali Ismet Tekirdag3, Ibrahim Polat3, Bekir Gulac3, and Gokce Yilmaz3 1 2
Department of Ophthalmology, Kanuni Sultan Suleyman Education and Research Hospital, Istanbul, Turkey, Department of Ophthalmology, Sehitkamil State Hospital, Gaziantep, Turkey, and 3Department of Obstetrics & Gynecology, Kanuni Sultan Suleyman Education and Research Hospital, Istanbul, Turkey
ABSTRACT Purpose: To compare the subfoveal choroidal thickness (SFCT) in preeclampsia, normal pregnancy, and nonpregnant women using enhanced depth imaging optical coherence tomography (EDI-OCT). Methods: One hundred nineteen volunteers were enrolled in this prospective and comparative study. The participants were divided into three groups: group 1 (33 preeclamptic women), group 2 (46 normal pregnant), and group 3 (40 non-pregnant healthy women). The SFCT was measured by EDI-OCT. The refractive error, intraocular pressure (IOP), axial length (AL), central corneal thickness (CCT), systolic and diastolic blood pressure, and ocular perfusion pressure (OPP) were also measured. Medical records of pregnant women, including gestational age, maternal weight gain, weight, and proteinuria, were noted. Results: Mean SFCT of groups 1, 2, and 3 were 333.8 55.3 mm (range 235-440 mm), 368.6 67.6 mm (range 223-517 mm), and 334.8 59.9 mm (range 197-432 mm), respectively. The mean SFCT was thicker in group 2 than that in groups 1 and 3 (p = 0.045 and p = 0.038, respectively), whereas no significant difference was seen between groups 1 and 3 (p = 1.0). In group 1, SFCT showed a negative correlation with the CCT (p = 0.009, r = -0.493). In group 2, SFCT showed a positive correlation with OPP (p = 0.030, r = 0.321) and a negative correlation with gestational age and fetal weight (p = 0.008, r = -0.387 and p = 0.011, r = -0.373, respectively). Conclusion: Our results suggested that SFCT was significantly thicker in normal pregnant women than non-pregnant women. However, SFCT values of preeclamptic women were similar to those of non-pregnant women. Keywords: Preeclampsia, pregnancy, subfoveal choroidal thickness
INTRODUCTION
decrease in intraocular pressure (IOP), and changes in vision and ocular blood flow.10–14 Pregnancy complicated by preeclampsia may also lead to numerous ocular alterations, including visual symptoms (e.g., decreased vision, photopsia, and visual field defects) and abnormalities of the conjunctiva, retina and retinal vasculature, optic nerve, visual cortex, and choroid.15–17 The choroid is the most vascular structure within the eye, 18 and the fovea, situated at the center of the macula, has the highest photoreceptor density and metabolic activity. The choroid, being a vascular
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Subfoveal Choroidal Thickness in Preeclampsia: Comparison with Normal Pregnant and Nonpregnant Women
Preeclampsia is an obstetric disorder characterized by hypertension, peripheral edema, and proteinuria.1,2 It affects approximately 5% of pregnant women.3–7 Preeclampsia is a multisystem disorder that can cause cardiovascular changes, hematologic abnormalities, hepatic and renal impairment, and neurologic or cerebral manifestations.8,9 Pregnancy may induce several ocular changes, including a decrease in corneal sensitivity, an increase in central corneal thickness (CCT) and curvature, a
Received 26 May 2013; accepted 20 August 2013; published online 26 November 2013 Correspondence: Nihat Sayin, Atakent Mahallesi, 4, Cadde. C 2-7 Blok, Kat: 3 Daire: 13, Ku¨cu¨kcekmece, Istanbul, Turkey. E-mail: [email protected]
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12 N. Sayin et al. structure, is prone to being affected by systemic conditions such as hypertension. Chorioretinal findings in preeclampsia consist of acute changes, including serous retinal detachment and retinal pigment epithelial lesions secondary to choroidal ischemia, as well as occlusive retinal vascular disease. Late changes include retinal vascular narrowing, optic atrophy, atrophic pigmentary changes, and Elschnig spots.19–21 Traditional imaging modalities, such as indocyanine green angiography and B-scan ultrasonography, are limited in image resolution and measurement accuracy. Also, the invasive nature of angiography limits their potential diagnostic use in pregnant women because of the possible maternal and fetal complications.22 However, magnetic resonance imaging is non-invasive, yet differentiation between retina, choroid, and sclera is difficult.23 Until recently, choroidal thickness could not be accurately measured by any imaging modality A recent modification to the standard optical coherence tomography technique, called enhanced depth imaging optical coherence tomography (EDI-OCT), offers a non-invasive, rapid, objective, and reliable diagnostic modality for the imaging of choroidal alterations and allows in-vivo examination and quantification of the choroid. Many previous studies have focused on measuring subfoveal choroidal thickness (SFCT) in healthy participants as well as those with several pathologies.24–30 However, there has been no qualitative and quantitative study on choroidal morphology in preeclampsia. The purpose of the current study is to evaluate SFCT measured by EDI-OCT in preeclampsia.
METHODS Study Population and Design This prospective and comparative study was performed at the Obstetrics and Gynecology and Ophthalmology Departments of Istanbul Kanuni Sultan Suleyman Education and Research Hospital. The study followed the tenets of the Declaration of Helsinki and was approved by the local ethics committee. All participants received oral and written information about the study, and each participant provided written informed consent. The participants were divided into three groups. Group 1 consisted of pregnant women complicated by preeclampsia. Group 2 consisted of healthy pregnant women. Group 3 consisted of non-pregnant healthy women. Ocular exclusion criteria included the following: a best-corrected visual acuity worse than 20/ 20, glaucomatous optic disc changes such as excavation, notching, or focal thinning of the neuroretinal rim, peripapillary hemorrhage, glaucomatous visual
field defects, IOP readings greater than 22 mmHg, more than 2 diopters of cylindrical and/or 5 diopters of spherical refractive error, poor image quality, any history of ocular diseases, and history of previous intraocular surgery or laser therapy. Extraocular exclusion criteria included a history of systemic disease such as hypertension or diabetes mellitus, and the development of complications such as preeclampsia (except group 1).
Examination Protocol and Study Measurements All participants underwent a detailed ophthalmologic examination, including medical history, refractive error, best-corrected visual acuity, slit lamp microscopy, intraocular pressure, and funduscopic examination. A complete medical history including gestational age, fetal weight, and maternal weight gain was recorded. The quantification of 24-hour proteinuria and measured by dipstick values were also noted. Study participants underwent central corneal thickness (CCT) and axial length (AL) measurements using ultrasonic scans. Systolic blood pressure (sBP) and diastolic blood pressure (dBP) were measured before the choroidal thickness measurement. Mean blood pressure (mBP) was calculated as the dBP plus one-third of the difference between sBP and dBP. The ocular perfusion pressure (OPP) was calculated by measuring the difference between two out of three of the mBP and the IOP values.31,32 EDI-OCT Measurement: The SFCT was measured using spectral domain OCT (Cirrus-HD OCT, Carl Zeiss Meditec, Inc., Dublin, CA). The scan pattern used on Cirrus HD-OCT was HD 5 Line Raster spaced at 0.25 mm. It is a 6 mm line consisting of 1024 Ascan/B-scan and averaging 4 B-scans per image. To be included in this study, images had to be taken as close to the fovea as possible by choosing to image the thinnest point of the macula, with the understanding that slight differences in positioning could affect the measured thickness. Only high-quality images with signal-to-noise ratio 47 were selected for the study. SFCT was determined as the vertical distance from the hyperreflective line of the hyperreflective RPE to the line of the inner surface of the sclera centered on the fovea using a measuring tool with built-in linear measuring. The choroidal thickness measurements were performed by one ophthalmologist (NS) and assessed by one ophthalmologist (DP) who were masked in terms of groups (Figure 1).
Data Analyses One eye per patient was selected for the analyses. All statistical analyses were performed using Statistical Seminars in Ophthalmology
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Subfoveal Choroidal Thickness in Preeclampsia
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FIGURE 1. Cross-sectional imaging of the choroid using enhanced depth imaging optical coherence tomography (EDI-OCT). Subfoveal choroidal thickness (SFCT) was measured vertically from the outer border of the retinal pigment epithelium (RPE) to the inner border of the sclera. SFCT measured 326 um in a pregnant women complicated with preeclampsia (A), in 420 um in a normal pregnant women (B), and 304 um in a healthy non-pregnant women (C).
Package for the Social Sciences (SPSS) version 16. The normality of the data was confirmed using the Kolmogorov-Smirnov test (p40.05). The one-way ANOVA test was used to compare variables between groups. The Bonferroni method was used for adjustment for multiple comparisons. Pearson’s correlation was used to examine the relationships among the measured variables. A p value of less than 0.05 was considered signiEcant.
RESULTS Demographic and Clinical Characteristics The study included 119 eyes of 119 subjects: 33 subjects in group 1, 46 subjects in group 2, and 40 subjects in group 3. The clinical characteristics of all groups are given in Table 1. The mean age and mean spherical refraction of all groups did not differ significantly (p40.05). The mean gestational age, mean maternal weight gain, and mean fetal weight of groups 1 and 2 did not differ significantly (p40.05).
Choroidal Thickness and Other Ocular Measurements Table 2 shows the results of clinical measurements of the groups. Mean SFCT of groups 1, 2, and 3 were !
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333.8 55.3 mm (range 235-440 mm), 368.6 67.6 mm (range 223-517 mm), and 334.8 59.9 mm (range 197432 mm), respectively. The comparison involving all groups showed that the mean SFCT was thicker in group 2 than that in groups 1 and 3 (p = 0.015). The mean SFCT in group 1 was statistically significantly lower in comparison to that in group 2 (p = 0.045), but between groups 1 and 3 was not significantly different (p = 1.0). The mean AL among groups 1, 2, and 3 was not significantly different (p = 0.443). The mean CCT and IOP values in group 1 were not significantly different from groups 2 and 3 (for CCT: p = 1.0 and p = 0.243; for IOP: p = 1.0 and p = 0.153, respectively). The mean CCT values in group 2 were significantly thicker than group 3 (p = 0.015) and the mean IOP values in group 2 were significantly less than group 3 (p = 0.008). The mean OPP values in group 1 were significantly higher than the other groups (p50.001).
Correlation Analyses Table 3 shows the correlation analysis between SFCT and AL, CCT, IOP, OPP, age, spherical refraction, gestational age, maternal weight gain, fetal weight, and proteinuria in all groups. Except for the mean CCT, there was no significant correlation between the choroidal thickness and these measurements in group
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TABLE 1. Demographic and clinical characteristics of preeclamptic women, normal pregnant women, and non-pregnant controls.
Number of Eyes/Patients Age (Y) Mean SD Range Spherical refraction (D) Mean SD Range Gestational age (wk) Mean SD Range Maternal weight gain (kg) Mean SD Range Fetal weight (g) Mean SD Range Proteinuria (mg/24hr) Mean SD Range Proteinuria (dipstick) Mean SD Range
Group 1 Preeclampsia
Group 2 Normal-pregnant
Group 3 Non-pregnant control
33/33
46/46
40/40
30.5 7.6 19–46
28.1 6.2 20–41
30.2 6.2 18–42
0.30 0.7 2.75–1.25
0.15 0.8 4.75–1.00
0.18 0.5 1.00–1.25
p
0.197a 0.631a
29.7 5.5 16–36
28.0 5.8 17–37
na
0.203b
7.4 4.0 0–13
7.6 4.2 0–15
na
0.857b
1855 586 910–2700
1547 1213 185–5500
na
0.220b
2845 2403 256–8500
nd*
nd
2.6 0.7 1–3
nd*
nd
Y: year; SD: standard deviation; D: diopter; wk: week; kg: kilogram; g: gram; mg: milligram; nd: not determined; na: not applicable. *: Protein content of urine of healthy pregnant women was within normal ranges and not routinely recorded. a : One-way Anova-t test, b: Independent t test. TABLE 2. Subfoveal choroidal thickness and other clinical measurements of groups. Pairwise comparison (pb) Group 1
Group 2
Group 3
pa
Group 1– Group 2
Group 1– Group 3
Group 2– Group 3
SFCT, um Mean SD Range
333.8 55.3 235–440
368.6 67.6 223–517
334.8 59.9 197–432
0.015
0.045
1.0
0.038
AL, mm Mean SD Range
22.9 0.9 21.0–24.8
22.9 0.5 21.6–24.5
23.1 0.8 21.0–25.3
0.443
1.0
0.635
1.0
CCT, um Mean SD Range
575.6 33.4 512–646
583.5 42.7 503–724
556 49.5 473–655
0.017
1.0
0.243
0.015
IOP, mmHg Mean SD Range
14.5 2.2 10–19
14.1 2.2 11–20
15.6 2.2 10–21
0.009
1.0
0.153
0.008
OPP, mmHg Mean SD Range
50.2 9.7 37.1–69.0
39.0 4.7 28.6–48.0
37.9 6.3 25.6–49.6
50.001
50.001
50.001
1.0
SFCT: Subfoveal choroidal thickness; AL: Axial length; CCT: Central corneal thickness; IOP: Intraocular pressure; OPP: Ocular perfusion pressure; SD: Standard Deviation. a : One-way Anova-t test; b: Post-hoc test (Bonferroni).
1. The SFCT showed a negative correlation with the CCT in this group (p = 0.009, r = -0.493). In group 2, SFCT showed a positive correlation with OPP (p = 0.030, r = 0.321). Also, increased gestational age and fetal weight were demonstrated to be associated
with a significantly thinner choroid in group 2 (p = 0.008, r = -0.387 and p = 0.011, r = -0.373, respectively). In addition, in group 3, there was no significant correlation between the choroidal thickness and other parameters. Seminars in Ophthalmology
Subfoveal Choroidal Thickness in Preeclampsia
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TABLE 3. Correlation analyses between subfoveal choroidal thickness and other clinical and demographic factors in Group 1, Group 2, and Group 3. Group 1
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Pear Corr SFCT AL CCT IOP OPP Age Spherical refraction Gestational age Maternal weight gain Fetal weight Proteinuria Proteinuria grade
0.189 0.493 0.341 0.350 0.101 0.006 0.078 0.287 0.229 0.219 0.046
Group 2 p* 0.291 0.009 0.061 0.062 0.576 0.972 0.667 0.146 0.251 0.328 0.852
Pear Corr 0.144 0.079 0.054 0.321 0.263 0.147 0.387 0.190 0.373
Group 3 p* 0.341 0.603 0.719 0.030 0.077 0.328 0.008 0.215 0.011
Pear Corr 0.200 0.165 0.024 0.295 0.133 0.220
p* 0.216 0.308 0.882 0.065 0.412 0.190
SFCT: Subfoveal choroidal thickness; AL: Axial length; CCT: Central corneal thickness; IOP: Intraocular pressure; OPP: Ocular perfusion pressure. *: Pearson correlation test.
DISCUSSION This cross-sectional study compared the choroid thickness between the pregnant women with and without preeclampsia and non-pregnant healthy controls. We found some new results that contribute to the literature. The subfoveal choroidal thickness in healthy pregnant women was significantly higher than non-pregnant healthy controls. Also, no significant difference was found between the preeclamptic women and non-pregnant healthy controls and between the preeclamptic women and healthy pregnant women. Pregnancy without any complications leads to an increase in cardiac output resulting from increases in heart rate, cardiac contractility, and circulating volume, combined with decreased peripheral vascular resistance.33 Therefore, blood flow has been increased in many organs.34–36 Previous studies have also reported that ocular blood flow increases throughout gestation.11,37,38 Based on these changes, we suggest that choroidal thickness increases during normal pregnancy and may be associated with increased ocular blood flow. In preeclampsia, blood pressure is elevated, systemic vascular resistance is increased, and the response to vasoconstrictors is maintained and not attenuated, as otherwise seen in normal pregnancy.39 Rath et al. reported that in patients with preeclampsia, as a result of endotelyal dysfunction, activation of intravascular coagulation occurs with fibrin deposition in the capillaries and consecutive microcirculation disorders.40 Previous studies have reported that preeclampsia may affect both retinal and choroidal circulation.15,41 The most common ocular finding is constriction of retinal arterioles,15–17 occurring in approximately 60% of patients with preeclampsia in one study.16 Also, in the preeclamptic women, !
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vasoconstriction and hematological changes may decrease blood flow, leading to choroidal thrombosis or infarction.19 The constriction may be generalized or localized.16,17 If the constriction is severe, other changes associated with hypertensive retinopathy may occur, including retinal edema, hemorrhages, exudates, and cotton wool spots.17 On indocyanine green angiography, patients with preeclampsia demonstrate early choroidal nonperfusion and late staining of choroidal vessel walls.6 Although many angiographic studies have been conducted on retinal and choroidal circulation in preeclamptic women, no quantitative studies have been conducted on choroidal morphology in these patients. The study showed that the preeclamptic pregnant women had comparable choroidal thickness when compared with healthy non-pregnant women, unlike the normal pregnant women. These results showed that the effect of normal pregnancy on choroidal thickness is limited when pregnancy is complicated by preeclampsia. Many physiological factors may influence choroidal thickness. It has been reported that thinner choroidal thickness was associated with older age, longer AL, higher IOP, and thicker CCT.25–30,42–45 In this study, no significant correlation was found between the SFCT and age, refractive error, and AL, except for the mean CCT in the preeclamptic women. The SFCT showed a negative correlation with the CCT in this group, similar to the literature. We also found that SFCT value was not associated with gestational age, maternal weight gain, fetal weight, and proteinuria in the preeclamptic group. A recent study investigated the association between choroidal thickness and OPP values, and no significant correlation was found in healthy subjects.46 Similarly, in nonpregnant healthy women, there was no significant correlation between the choroidal thickness and these
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16 N. Sayin et al. measurements. However, SFCT showed a positive correlation with OPP and negative correlation with gestational age and fetal weight in pregnant women without preeclampsia. To the best of our knowledge, our study is the first work that has assessed choroidal thickness in preeclamptic women and its association with ocular parameters and pregnancy-related factors. On the other hand, the present study had several limitations. Repeatability is critical when an imaging technique is to be implemented in practice. For EDI-OCT, there is no automated software to measure choroidal thickness. All measurements must be done manually. This raises concern regarding inter-observer and intersession repeatability. Although good inter-observer repeatability was produced with manual measurements, there are still some difficulties. The main problems are the relatively lower resolution in choroidal images than in conventional retinal scans and the lack of eye-tracking in some models of OCT (only the Heidelberg Spectralis is currently able to perform eye-tracking for EDI-OCT). To enhance repeatability, automated measurement software should be developed for choroidal measurements and eye-tracking function should be ideally incorporated into every OCT machine. In summary, SFCT in normal pregnant women was significantly thicker than in non-pregnant healthy women, whereas SFCT values of preeclamptic pregnant were similar to non-pregnant women. However, SFCT values showed a significant correlation with only central corneal thickness in the preeclamptic women. This result should be taken into consideration when choroidal thickness is evaluated for pregnancy-related disease or clinical research. Improved in-vivo visualization of the choroid and measurement of choroidal thickness using EDI-OCT could improve our understanding of a variety of pregnancy-related disorders such as preeclampsia in the future.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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Nihat Sayin1, Necip Kara2, Dilara Pirhan1 , Asli Vural1, Hatice Bilge Araz Ersan1, Ali Ismet Tekirdag3, Ibrahim Polat3, Bekir Gulac3, and Gokce Yilmaz3 1 2
Department of Ophthalmology, Kanuni Sultan Suleyman Education and Research Hospital, Istanbul, Turkey, Department of Ophthalmology, Sehitkamil State Hospital, Gaziantep, Turkey, and 3Department of Obstetrics & Gynecology, Kanuni Sultan Suleyman Education and Research Hospital, Istanbul, Turkey
ABSTRACT Purpose: To compare the subfoveal choroidal thickness (SFCT) in preeclampsia, normal pregnancy, and nonpregnant women using enhanced depth imaging optical coherence tomography (EDI-OCT). Methods: One hundred nineteen volunteers were enrolled in this prospective and comparative study. The participants were divided into three groups: group 1 (33 preeclamptic women), group 2 (46 normal pregnant), and group 3 (40 non-pregnant healthy women). The SFCT was measured by EDI-OCT. The refractive error, intraocular pressure (IOP), axial length (AL), central corneal thickness (CCT), systolic and diastolic blood pressure, and ocular perfusion pressure (OPP) were also measured. Medical records of pregnant women, including gestational age, maternal weight gain, weight, and proteinuria, were noted. Results: Mean SFCT of groups 1, 2, and 3 were 333.8 55.3 mm (range 235-440 mm), 368.6 67.6 mm (range 223-517 mm), and 334.8 59.9 mm (range 197-432 mm), respectively. The mean SFCT was thicker in group 2 than that in groups 1 and 3 (p = 0.045 and p = 0.038, respectively), whereas no significant difference was seen between groups 1 and 3 (p = 1.0). In group 1, SFCT showed a negative correlation with the CCT (p = 0.009, r = -0.493). In group 2, SFCT showed a positive correlation with OPP (p = 0.030, r = 0.321) and a negative correlation with gestational age and fetal weight (p = 0.008, r = -0.387 and p = 0.011, r = -0.373, respectively). Conclusion: Our results suggested that SFCT was significantly thicker in normal pregnant women than non-pregnant women. However, SFCT values of preeclamptic women were similar to those of non-pregnant women. Keywords: Preeclampsia, pregnancy, subfoveal choroidal thickness
INTRODUCTION
decrease in intraocular pressure (IOP), and changes in vision and ocular blood flow.10–14 Pregnancy complicated by preeclampsia may also lead to numerous ocular alterations, including visual symptoms (e.g., decreased vision, photopsia, and visual field defects) and abnormalities of the conjunctiva, retina and retinal vasculature, optic nerve, visual cortex, and choroid.15–17 The choroid is the most vascular structure within the eye, 18 and the fovea, situated at the center of the macula, has the highest photoreceptor density and metabolic activity. The choroid, being a vascular
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Subfoveal Choroidal Thickness in Preeclampsia: Comparison with Normal Pregnant and Nonpregnant Women
Preeclampsia is an obstetric disorder characterized by hypertension, peripheral edema, and proteinuria.1,2 It affects approximately 5% of pregnant women.3–7 Preeclampsia is a multisystem disorder that can cause cardiovascular changes, hematologic abnormalities, hepatic and renal impairment, and neurologic or cerebral manifestations.8,9 Pregnancy may induce several ocular changes, including a decrease in corneal sensitivity, an increase in central corneal thickness (CCT) and curvature, a
Received 26 May 2013; accepted 20 August 2013; published online 26 November 2013 Correspondence: Nihat Sayin, Atakent Mahallesi, 4, Cadde. C 2-7 Blok, Kat: 3 Daire: 13, Ku¨cu¨kcekmece, Istanbul, Turkey. E-mail: [email protected]
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12 N. Sayin et al. structure, is prone to being affected by systemic conditions such as hypertension. Chorioretinal findings in preeclampsia consist of acute changes, including serous retinal detachment and retinal pigment epithelial lesions secondary to choroidal ischemia, as well as occlusive retinal vascular disease. Late changes include retinal vascular narrowing, optic atrophy, atrophic pigmentary changes, and Elschnig spots.19–21 Traditional imaging modalities, such as indocyanine green angiography and B-scan ultrasonography, are limited in image resolution and measurement accuracy. Also, the invasive nature of angiography limits their potential diagnostic use in pregnant women because of the possible maternal and fetal complications.22 However, magnetic resonance imaging is non-invasive, yet differentiation between retina, choroid, and sclera is difficult.23 Until recently, choroidal thickness could not be accurately measured by any imaging modality A recent modification to the standard optical coherence tomography technique, called enhanced depth imaging optical coherence tomography (EDI-OCT), offers a non-invasive, rapid, objective, and reliable diagnostic modality for the imaging of choroidal alterations and allows in-vivo examination and quantification of the choroid. Many previous studies have focused on measuring subfoveal choroidal thickness (SFCT) in healthy participants as well as those with several pathologies.24–30 However, there has been no qualitative and quantitative study on choroidal morphology in preeclampsia. The purpose of the current study is to evaluate SFCT measured by EDI-OCT in preeclampsia.
METHODS Study Population and Design This prospective and comparative study was performed at the Obstetrics and Gynecology and Ophthalmology Departments of Istanbul Kanuni Sultan Suleyman Education and Research Hospital. The study followed the tenets of the Declaration of Helsinki and was approved by the local ethics committee. All participants received oral and written information about the study, and each participant provided written informed consent. The participants were divided into three groups. Group 1 consisted of pregnant women complicated by preeclampsia. Group 2 consisted of healthy pregnant women. Group 3 consisted of non-pregnant healthy women. Ocular exclusion criteria included the following: a best-corrected visual acuity worse than 20/ 20, glaucomatous optic disc changes such as excavation, notching, or focal thinning of the neuroretinal rim, peripapillary hemorrhage, glaucomatous visual
field defects, IOP readings greater than 22 mmHg, more than 2 diopters of cylindrical and/or 5 diopters of spherical refractive error, poor image quality, any history of ocular diseases, and history of previous intraocular surgery or laser therapy. Extraocular exclusion criteria included a history of systemic disease such as hypertension or diabetes mellitus, and the development of complications such as preeclampsia (except group 1).
Examination Protocol and Study Measurements All participants underwent a detailed ophthalmologic examination, including medical history, refractive error, best-corrected visual acuity, slit lamp microscopy, intraocular pressure, and funduscopic examination. A complete medical history including gestational age, fetal weight, and maternal weight gain was recorded. The quantification of 24-hour proteinuria and measured by dipstick values were also noted. Study participants underwent central corneal thickness (CCT) and axial length (AL) measurements using ultrasonic scans. Systolic blood pressure (sBP) and diastolic blood pressure (dBP) were measured before the choroidal thickness measurement. Mean blood pressure (mBP) was calculated as the dBP plus one-third of the difference between sBP and dBP. The ocular perfusion pressure (OPP) was calculated by measuring the difference between two out of three of the mBP and the IOP values.31,32 EDI-OCT Measurement: The SFCT was measured using spectral domain OCT (Cirrus-HD OCT, Carl Zeiss Meditec, Inc., Dublin, CA). The scan pattern used on Cirrus HD-OCT was HD 5 Line Raster spaced at 0.25 mm. It is a 6 mm line consisting of 1024 Ascan/B-scan and averaging 4 B-scans per image. To be included in this study, images had to be taken as close to the fovea as possible by choosing to image the thinnest point of the macula, with the understanding that slight differences in positioning could affect the measured thickness. Only high-quality images with signal-to-noise ratio 47 were selected for the study. SFCT was determined as the vertical distance from the hyperreflective line of the hyperreflective RPE to the line of the inner surface of the sclera centered on the fovea using a measuring tool with built-in linear measuring. The choroidal thickness measurements were performed by one ophthalmologist (NS) and assessed by one ophthalmologist (DP) who were masked in terms of groups (Figure 1).
Data Analyses One eye per patient was selected for the analyses. All statistical analyses were performed using Statistical Seminars in Ophthalmology
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Subfoveal Choroidal Thickness in Preeclampsia
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FIGURE 1. Cross-sectional imaging of the choroid using enhanced depth imaging optical coherence tomography (EDI-OCT). Subfoveal choroidal thickness (SFCT) was measured vertically from the outer border of the retinal pigment epithelium (RPE) to the inner border of the sclera. SFCT measured 326 um in a pregnant women complicated with preeclampsia (A), in 420 um in a normal pregnant women (B), and 304 um in a healthy non-pregnant women (C).
Package for the Social Sciences (SPSS) version 16. The normality of the data was confirmed using the Kolmogorov-Smirnov test (p40.05). The one-way ANOVA test was used to compare variables between groups. The Bonferroni method was used for adjustment for multiple comparisons. Pearson’s correlation was used to examine the relationships among the measured variables. A p value of less than 0.05 was considered signiEcant.
RESULTS Demographic and Clinical Characteristics The study included 119 eyes of 119 subjects: 33 subjects in group 1, 46 subjects in group 2, and 40 subjects in group 3. The clinical characteristics of all groups are given in Table 1. The mean age and mean spherical refraction of all groups did not differ significantly (p40.05). The mean gestational age, mean maternal weight gain, and mean fetal weight of groups 1 and 2 did not differ significantly (p40.05).
Choroidal Thickness and Other Ocular Measurements Table 2 shows the results of clinical measurements of the groups. Mean SFCT of groups 1, 2, and 3 were !
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333.8 55.3 mm (range 235-440 mm), 368.6 67.6 mm (range 223-517 mm), and 334.8 59.9 mm (range 197432 mm), respectively. The comparison involving all groups showed that the mean SFCT was thicker in group 2 than that in groups 1 and 3 (p = 0.015). The mean SFCT in group 1 was statistically significantly lower in comparison to that in group 2 (p = 0.045), but between groups 1 and 3 was not significantly different (p = 1.0). The mean AL among groups 1, 2, and 3 was not significantly different (p = 0.443). The mean CCT and IOP values in group 1 were not significantly different from groups 2 and 3 (for CCT: p = 1.0 and p = 0.243; for IOP: p = 1.0 and p = 0.153, respectively). The mean CCT values in group 2 were significantly thicker than group 3 (p = 0.015) and the mean IOP values in group 2 were significantly less than group 3 (p = 0.008). The mean OPP values in group 1 were significantly higher than the other groups (p50.001).
Correlation Analyses Table 3 shows the correlation analysis between SFCT and AL, CCT, IOP, OPP, age, spherical refraction, gestational age, maternal weight gain, fetal weight, and proteinuria in all groups. Except for the mean CCT, there was no significant correlation between the choroidal thickness and these measurements in group
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TABLE 1. Demographic and clinical characteristics of preeclamptic women, normal pregnant women, and non-pregnant controls.
Number of Eyes/Patients Age (Y) Mean SD Range Spherical refraction (D) Mean SD Range Gestational age (wk) Mean SD Range Maternal weight gain (kg) Mean SD Range Fetal weight (g) Mean SD Range Proteinuria (mg/24hr) Mean SD Range Proteinuria (dipstick) Mean SD Range
Group 1 Preeclampsia
Group 2 Normal-pregnant
Group 3 Non-pregnant control
33/33
46/46
40/40
30.5 7.6 19–46
28.1 6.2 20–41
30.2 6.2 18–42
0.30 0.7 2.75–1.25
0.15 0.8 4.75–1.00
0.18 0.5 1.00–1.25
p
0.197a 0.631a
29.7 5.5 16–36
28.0 5.8 17–37
na
0.203b
7.4 4.0 0–13
7.6 4.2 0–15
na
0.857b
1855 586 910–2700
1547 1213 185–5500
na
0.220b
2845 2403 256–8500
nd*
nd
2.6 0.7 1–3
nd*
nd
Y: year; SD: standard deviation; D: diopter; wk: week; kg: kilogram; g: gram; mg: milligram; nd: not determined; na: not applicable. *: Protein content of urine of healthy pregnant women was within normal ranges and not routinely recorded. a : One-way Anova-t test, b: Independent t test. TABLE 2. Subfoveal choroidal thickness and other clinical measurements of groups. Pairwise comparison (pb) Group 1
Group 2
Group 3
pa
Group 1– Group 2
Group 1– Group 3
Group 2– Group 3
SFCT, um Mean SD Range
333.8 55.3 235–440
368.6 67.6 223–517
334.8 59.9 197–432
0.015
0.045
1.0
0.038
AL, mm Mean SD Range
22.9 0.9 21.0–24.8
22.9 0.5 21.6–24.5
23.1 0.8 21.0–25.3
0.443
1.0
0.635
1.0
CCT, um Mean SD Range
575.6 33.4 512–646
583.5 42.7 503–724
556 49.5 473–655
0.017
1.0
0.243
0.015
IOP, mmHg Mean SD Range
14.5 2.2 10–19
14.1 2.2 11–20
15.6 2.2 10–21
0.009
1.0
0.153
0.008
OPP, mmHg Mean SD Range
50.2 9.7 37.1–69.0
39.0 4.7 28.6–48.0
37.9 6.3 25.6–49.6
50.001
50.001
50.001
1.0
SFCT: Subfoveal choroidal thickness; AL: Axial length; CCT: Central corneal thickness; IOP: Intraocular pressure; OPP: Ocular perfusion pressure; SD: Standard Deviation. a : One-way Anova-t test; b: Post-hoc test (Bonferroni).
1. The SFCT showed a negative correlation with the CCT in this group (p = 0.009, r = -0.493). In group 2, SFCT showed a positive correlation with OPP (p = 0.030, r = 0.321). Also, increased gestational age and fetal weight were demonstrated to be associated
with a significantly thinner choroid in group 2 (p = 0.008, r = -0.387 and p = 0.011, r = -0.373, respectively). In addition, in group 3, there was no significant correlation between the choroidal thickness and other parameters. Seminars in Ophthalmology
Subfoveal Choroidal Thickness in Preeclampsia
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TABLE 3. Correlation analyses between subfoveal choroidal thickness and other clinical and demographic factors in Group 1, Group 2, and Group 3. Group 1
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Pear Corr SFCT AL CCT IOP OPP Age Spherical refraction Gestational age Maternal weight gain Fetal weight Proteinuria Proteinuria grade
0.189 0.493 0.341 0.350 0.101 0.006 0.078 0.287 0.229 0.219 0.046
Group 2 p* 0.291 0.009 0.061 0.062 0.576 0.972 0.667 0.146 0.251 0.328 0.852
Pear Corr 0.144 0.079 0.054 0.321 0.263 0.147 0.387 0.190 0.373
Group 3 p* 0.341 0.603 0.719 0.030 0.077 0.328 0.008 0.215 0.011
Pear Corr 0.200 0.165 0.024 0.295 0.133 0.220
p* 0.216 0.308 0.882 0.065 0.412 0.190
SFCT: Subfoveal choroidal thickness; AL: Axial length; CCT: Central corneal thickness; IOP: Intraocular pressure; OPP: Ocular perfusion pressure. *: Pearson correlation test.
DISCUSSION This cross-sectional study compared the choroid thickness between the pregnant women with and without preeclampsia and non-pregnant healthy controls. We found some new results that contribute to the literature. The subfoveal choroidal thickness in healthy pregnant women was significantly higher than non-pregnant healthy controls. Also, no significant difference was found between the preeclamptic women and non-pregnant healthy controls and between the preeclamptic women and healthy pregnant women. Pregnancy without any complications leads to an increase in cardiac output resulting from increases in heart rate, cardiac contractility, and circulating volume, combined with decreased peripheral vascular resistance.33 Therefore, blood flow has been increased in many organs.34–36 Previous studies have also reported that ocular blood flow increases throughout gestation.11,37,38 Based on these changes, we suggest that choroidal thickness increases during normal pregnancy and may be associated with increased ocular blood flow. In preeclampsia, blood pressure is elevated, systemic vascular resistance is increased, and the response to vasoconstrictors is maintained and not attenuated, as otherwise seen in normal pregnancy.39 Rath et al. reported that in patients with preeclampsia, as a result of endotelyal dysfunction, activation of intravascular coagulation occurs with fibrin deposition in the capillaries and consecutive microcirculation disorders.40 Previous studies have reported that preeclampsia may affect both retinal and choroidal circulation.15,41 The most common ocular finding is constriction of retinal arterioles,15–17 occurring in approximately 60% of patients with preeclampsia in one study.16 Also, in the preeclamptic women, !
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vasoconstriction and hematological changes may decrease blood flow, leading to choroidal thrombosis or infarction.19 The constriction may be generalized or localized.16,17 If the constriction is severe, other changes associated with hypertensive retinopathy may occur, including retinal edema, hemorrhages, exudates, and cotton wool spots.17 On indocyanine green angiography, patients with preeclampsia demonstrate early choroidal nonperfusion and late staining of choroidal vessel walls.6 Although many angiographic studies have been conducted on retinal and choroidal circulation in preeclamptic women, no quantitative studies have been conducted on choroidal morphology in these patients. The study showed that the preeclamptic pregnant women had comparable choroidal thickness when compared with healthy non-pregnant women, unlike the normal pregnant women. These results showed that the effect of normal pregnancy on choroidal thickness is limited when pregnancy is complicated by preeclampsia. Many physiological factors may influence choroidal thickness. It has been reported that thinner choroidal thickness was associated with older age, longer AL, higher IOP, and thicker CCT.25–30,42–45 In this study, no significant correlation was found between the SFCT and age, refractive error, and AL, except for the mean CCT in the preeclamptic women. The SFCT showed a negative correlation with the CCT in this group, similar to the literature. We also found that SFCT value was not associated with gestational age, maternal weight gain, fetal weight, and proteinuria in the preeclamptic group. A recent study investigated the association between choroidal thickness and OPP values, and no significant correlation was found in healthy subjects.46 Similarly, in nonpregnant healthy women, there was no significant correlation between the choroidal thickness and these
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16 N. Sayin et al. measurements. However, SFCT showed a positive correlation with OPP and negative correlation with gestational age and fetal weight in pregnant women without preeclampsia. To the best of our knowledge, our study is the first work that has assessed choroidal thickness in preeclamptic women and its association with ocular parameters and pregnancy-related factors. On the other hand, the present study had several limitations. Repeatability is critical when an imaging technique is to be implemented in practice. For EDI-OCT, there is no automated software to measure choroidal thickness. All measurements must be done manually. This raises concern regarding inter-observer and intersession repeatability. Although good inter-observer repeatability was produced with manual measurements, there are still some difficulties. The main problems are the relatively lower resolution in choroidal images than in conventional retinal scans and the lack of eye-tracking in some models of OCT (only the Heidelberg Spectralis is currently able to perform eye-tracking for EDI-OCT). To enhance repeatability, automated measurement software should be developed for choroidal measurements and eye-tracking function should be ideally incorporated into every OCT machine. In summary, SFCT in normal pregnant women was significantly thicker than in non-pregnant healthy women, whereas SFCT values of preeclamptic pregnant were similar to non-pregnant women. However, SFCT values showed a significant correlation with only central corneal thickness in the preeclamptic women. This result should be taken into consideration when choroidal thickness is evaluated for pregnancy-related disease or clinical research. Improved in-vivo visualization of the choroid and measurement of choroidal thickness using EDI-OCT could improve our understanding of a variety of pregnancy-related disorders such as preeclampsia in the future.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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