A structurally and functionally normal choroidal vasculature is essential for the function of the retina.25
Handheld SD-OCT imaging has allowed for noncontact in vivo high-resolution imaging of the retina without the use of anesthesia in term and preterm infants while still in infancy, but it has not previously been used to study the choroid in contrast to the adult. In this study, full subfoveal choroid was visible in 96% of preterm infants without the use of EDI techniques, but that visibility decreased with age, particularly in subjects of African American race and Hispanic ethnicity. We hypothesize that the ability to visualize the full depth of the choroid in preterm infants may be partially explained by the timing of development of pigmentation within RPE cells and choroidal melanocytes. Choroidal melanocytes derive from neural crest cell migration and RPE from optic cup, which is derived from the neuroectoderm, and they differ in developmental timing.26,27
RPE cell pigmentation occurs early in gestation, at approximately the second month. In contrast, choroidal pigmentation develops later, at approximately the eighth month.28
However, it is known that RPE cell density gradually increases in the macular area until up to 6 months of age.29
In this study, the preterm infants imaged before 37 weeks were imaged at a median age of 34 weeks PMA, near the proposed time of choroidal pigmentation development.28
Therefore, we propose that decreased choroidal melanin at this time after preterm birth (30–36 weeks PMA) is likely the reason for enhanced penetration of OCT signal through the choroid and subsequent reflectivity of outer choroidal structures and the CSJ. Unlike choroidal melanin, pigmentation of RPE cells does not vary by race, likely explaining the lack of variability in CSJ visibility by race in the young-preterm infants.30
In the term-aged preterm infants, CSJ visibility decreases as expected, coinciding with increased presence of choroidal melanin. However, the term-aged preterm infant subjects still had greater CSJ visibility than term infants of the same PMA, which suggests that prematurity may affect the timing of choroidal melanocyte development after birth.
The median SFCT measurements in young-preterm infants, term-aged preterm infants, and term infants increased from 176 ± 53 μm, 289 ± 92 μm, to 329 ± 66 μm, respectively, and these values were all statistically significantly different from one another. Although choroidal thicknesses increased with age in preterm infants, they remained significantly thinner than term infants, most likely representing delayed development. The median adult SFCT (258 ± 66 μm) was significantly less than that of term infants, which suggests a thinning of the choroid over time at some point after term age. On a previous study by Lin et al., the adult choroidal thickness was found to be comparable with choroidal thicknesses measured previously from the Cirrus (244 ± 56 μm) and Spectralis (223 ± 60 μm) systems.23
In addition, the adult choroid decreased in thickness with increasing age in our young adult population (aged 20–37 years), which agreed with the trend for data from other older adult studies—that choroidal thickness decreases with age.9,31
There was no significant difference in choroidal thickness in each group by sex or race and ethnicity, except for in term infants where there was a significant difference in choroidal thickness between Caucasian and Hispanic term infants.
This study demonstrates that choroidal development, both of pigmentation and thickness, continues after birth for preterm infants. Choroidal thickness in preterm infants increases with age; however, it lags behind that of term infants. The very few previous in vivo studies of the choroid in preterm infants in infancy have been either ultrasound based and focused on gross abnormalities such as choroidal hemorrhage, thickening, and calcification in eyes with retinal detachment from ROP,32–34
or based on fluorescein angiography with nonspecific choroidal filling abnormalities found in eyes with ROP.35
A recent OCT study of choroidal thickness in children aged between 4 and 10 years with a history of preterm or term birth showed that choroidal thickness at the fovea and seven of eight other locations in children born preterm was no different than that of children born full term at comparable ages,36
though this study was far after the period of early choroidal development.
It is known that the RPE is not fully developed at preterm birth, which may contribute to lack of completion of choroidal vascular development and thus a thinner choroid at term age.29
Although there have been limited studies of the molecular mechanism of choroidal vessel development, it is well accepted that a differentiated RPE plays a critical role.37–39
This has been demonstrated in animal models where an inactivation of VEGF expression in the RPE has led to the absence of choriocapillaris.40
For example, patients with colobomas have undeveloped choroidal vasculature.37
Furthermore, in vitro RPE cells are able to stimulate formation of choroidal cells.38,39
An alternative hypothesis for choroidal thickness in older preterm infants lagging below that of term infants could be the proposed mechanism of choroidal involution associated with ROP: that oxidative stress of the choroid causes damage to the vessels' endothelium and death as demonstrated in a rat model of ROP.41
However, the preterm infant lag in choroidal thickening could also be a manifestation of the known global developmental delay of preterm infants compared with normal term infants at the same age.42
These findings of thinner choroid in preterm infants and its delayed growth may play a role in future visual function in some infants. Photoreceptors are exclusively supplied with nutrients by the choroid and it is known that insufficient choroidal blood flow can result in photoreceptor death.25
Furthermore, during infancy, photoreceptors are still developing and have a high metabolic demand.43,44
In fact, Fulton et al. used multifocal electroretinography to show that infants with a history of mild ROP had a significantly decreased electroretinographic amplitude compared with normal controls.45
Park et al. found that children (aged 4–11 years) with a history of preterm birth had comparable choroidal thickness at the fovea and in most sites across the macula when compared with children with a history of term birth.36
The choroidal thickness at this later age did not correlate with visual acuity.36
Further studies are planned to evaluate the relationship between severity of ROP, systemic disease, birth age and weight, and choroidal thickness during infancy on visual acuity.
There are several limitations to this study. The ability to image the full thickness of the choroid at the fovea dropped off with age, particularly in African American and Hispanic subjects. Thus, although the CSJ was easily visible in most cases of preterm infants, without EDI, visualization of the choroid in the development analysis was limited in 16 of 51 (31%) term infants and 10/18 (56%) of adults. Although this demonstrates likely progressive onset of choroidal pigment with age, it also alerts one to potential imbalances in study populations when comparing choroidal thickness across racial and ethnic groups in the older subjects. For example, the subfoveal choroidal measurements in the term infants and adults in this pilot study are not fully representative of the population. We understand this potential limitation and are currently developing a method to incorporate EDI with handheld SD-OCT in a future study. This study is also limited by a relatively small sample size and by design as a cross-sectional study, with minimal longitudinal follow-up in few preterm infants. Finally, the preterm infants imaged at term age may represent a sicker population since they were still in the neonatal intensive care unit during this time, introducing potential bias to the analysis.
To our knowledge, this is the first in vivo description of human choroidal thickness and development in infancy (31–41 weeks PMA) of preterm and term infants using SD-OCT. It highlights the utility of handheld SD-OCT imaging in this population, the increase in thickness of the choroid, and decrease in choroidal signal likely due to increased pigmentation with age. Most importantly, this study demonstrates persisting thin choroid in preterm infants, which is likely to represent a delay in choroidal development. These findings highlight the importance of both choroidal and retinal vasculature in the developing infant eye and the potential to better understand the role of the choroid in retinopathy of prematurity through future clinical studies.