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Delayed macular development in preterm infants with spontaneously regressed retinopathy of prematurity

BMC Ophthalmology volume 25, Article number: 27 (2025) Cite this article

A Correction to this article was published on 28 April 2025

This article has been updated

Abstract

Purpose

To evaluate the macular development in preterm infants with spontaneously regressed retinopathy of prematurity (ROP) utilizing handheld spectral domain optical coherence tomography (SD-OCT) during the early postnatal period.

Design

A cross-sectional observational study.

Methods

Using handheld SD-OCT, OCT images were acquired in non-sedated infants ages about 37 weeks(w) post-menstrual-age (PMA = gestational age in weeks + chronological age). Central foveal thickness (CFT), mean parafoveal thickness (PT, mean of the temporal and nasal-lateral retinal thickness 1000 μm from the foveal center), the thickness of inner retina layers (IRL) and outer retina layers (ORL) of the foveal center and parafoveal, the depth of the macular fovea (FD), and the angle of the macular fovea (FA) were measured and analyzed.

Results

In contrast to the infants without ROP (group 1), OCT images of the infants with spontaneously regressed ROP (group 2) were more immature. The FD of Group 2 was shallower than Group 1 (P < 0.05); CFT and the foveal center IRL (FIRL) of Group 2 were thicker than Group 1 (P < 0.05); conversely, PT and the mean parafoveal IRL (PIRL) of Group 2 were thinner than Group 1 (P < 0.05); FA of Group 2 was bigger than Group 1 (P < 0.05); however, there was no significant difference in the foveal center ORL (FORL) and the mean parafoveal ORL (PORL) between Groups 1 and 2 (P > 0.05). Furthermore, in preterm infants, ROP was moderately correlated with FD, CFT, PT, FIRL, and PIRL (P < 0.05).

Conclusions

The spontaneously regressed ROP resulted in immature macular development in the early postnatal period. The inner retinal layers mainly contribute to this but not the outer retinal layers, indicating that the macular fovea’s inner and outer retina layers developed asynchronously. ROP is an influential factor in macular development and maturation. This may be associated with the higher probability of visual impairment in children with a history of spontaneous regression of ROP at a prior time.

Peer Review reports

Introduction

The human macula is responsible for high spatial resolution and central and color vision [1,2,3]. Abnormal development of the macula leads to visual impairment and may be related to occipital cortex paraphasia and disruptions in visual pathways at the level of the optic chiasm [4, 5]. The human macula forms in late gestation (between 25 and 27 weeks) and continues to develop in the first several years of life [6,7,8]. Unlike the in-utero environment, preterm infants’ macular maturation is easily affected by many factors in the ex-utero environment, such as premature birth, ROP, gestational ages (GA), birth weight (BW), sex, race, etc [9,10,11].

ROP is a vasoproliferative retinal disorder seen in infants who are premature and have low birth weight [12,13,14]. Long-term visual acuity may be highly variable in patients with a history of ROP, even in cases where macular anatomy appears ophthalmoscopically normal [15,16,17,18]. This may be related to the macular dysplasia [19, 20]. Studies have shown that patients with a history of ROP have many foveal anomalies, including abnormal foveal contour, preservation of multiple inner retinal layers within the fovea, and increased central retinal thickness [11, 21,22,23,24]. Bowl W et al. [25] demonstrated that macular developmental arrest had been reported in 44% of spontaneously regressed ROP and 27% of preterm infants without ROP. Jing Jin et al. [10] found that the macular fovea development of 4- to 18-year-old children with a history of mild ROP lagged behind those born at term. W. Ecsedy M [22] and Recchia FM [23] found that children with regressed ROP have greater total foveal thickness than full-term control children. Daniel X [24] considered that the fovea of subjects with a history of mild ROP had significant structural abnormalities that were probably a consequence of perturbations of neurovascular development. The foveal avascular zone (FAZ) and the tensile forces generated within the retinal layers are major factors in foveal development [26]. ROP may affect the development of FAZ, causing different types of blood vessels to branch in the fovea, which can lead to fovea dysplasia [27,28,29].

OCT is widely used in adults to help diagnose and manage various retinal diseases. The use of OCT is limited in young children and infants due to issues with positioning and fixation. Handheld OCT has made it possible to image infants with and without sedation in a noninvasive and noncontact manner. The development of fovea can be followed noninvasively using handheld SD-OCT, and many of the key histologic features are captured with high fidelity. In a few studies in premature infants with ROP, subclinical macular findings have been demonstrated on SD-OCT [20, 30,31,32,33,34]. The persistence of inner retinal layers and the occurrence of cystoid macular edema (CME) were the findings described in these reports [30]. In Vinekar’s [31] reports, the CFT was increased in premature infants with ROP. Another research described that the fovea in eyes with a history of ROP is shallow and that persistent post-receptor cells and fine capillaries may be present where there is usually an avascular zone [34]. However, up to now, research on the relationship between ROP and macular development has focused on older children (4–26 years), but few studies on the early years after preterm birth. Herein, we use handheld SD-OCT to evaluate macular development in preterm infants with spontaneously resolved ROP during the early postnatal period.

Materials and methods

This study was approved by the Institutional Review Board of The Children’s Hospital of Fudan University and followed the tenets of the Declaration of Helsinki (approval number: Fudan No. 267 (2019)). Informed consent was obtained from the enrolled infants’ parents or legal guardians. This study was conducted on premature infants born earlier than 37 weeks of gestation between January 2022 and December 2023 in the Neonatal intensive care Unit (NICU) of our hospital. To compare mature macular structures, the same hand-held SD-OCT examination was performed in 5 healthy adults. One ophthalmologist examined all the infants and adults. Eyelid speculum and scleral indentation were used during examinations. All infants were placed in the supine position and given topical anesthesia during the examinations. To calm the infants, a pacifier dipped in 30% dextrose was used. A lubricant eye drop (Systane, Alcon Pharmaceuticals Ltd, Barcelona, Spain) was also used as necessary to hydrate the cornea.

Following the Chinese ROP screening guidelines, we examined all infants weighing less than 2000 g and/or 32 weeks of gestation, as well as infants deemed by the neonatologist to be at risk for ROP (over 2000 g or > 32 weeks) for ROP screening using a RetCam III digital camera (Clarity Medical Systems, USA). ROP was classified according to the International Classification of Retinopathy of Prematurity, Third Edition [13].

The inclusion criteria are as follows:

  1. 1.

    The guardian gives informed consent and signs the informed consent.

  2. 2.

    Must meet the fundus screening criteria and be able to obtain clear OCT images.

  3. 3.

    All enrolled infants must be systemically well and physiologically stable without requiring respiratory support.

  4. 4.

    Preterm infants with mild ROP (Zone II or III, stage 1 or 2, plus-) were enrolled only after ROP had completely regressed without any treatment, and when retinal blood vessels had developed normally at the follow-up time.

The exclusion criteria are as follows:

  1. 1.

    Patients with anterior segment anomalies such as congenital glaucoma or congenital cataract, as well as corneal edema, may also present with posterior segment anomalies including choroidal coloboma, familial exudative vitreoretinopathy (FEVR), persistent hyperplastic primary vitreous (PHPV), morning glory anomaly, and oculocutaneous albinism.

  2. 2.

    With severe ROP and requiring treatment.

  3. 3.

    Could not obtain clear OCT images.

  4. 4.

    The infants with CME had distorted retinal layers, which affected retinal thickness measurement and analysis.

Finally, sixty-five preterm infants were included in this study. The preterm infants were divided into two groups based on the presence of ROP: 33 infants without ROP were assigned to Group 1, and 32 infants with mild ROP (Zone II or III, stage 1 or 2, and plus -) were assigned to Group 2. Five healthy adults served as the control group.

Handheld SD-OCT examination and image analysis

OCT images were obtained by handheld SD-OCT(Leica/Bioptigen Envisu C2300, RTP, NC)at the bedside while receiving ROP screening examinations. The lateral distance settings (defined for adults on the machine) were corrected to account for the smaller axial lengths in the infant population using a conversion table according to PMA and GA from the data presented by Maldonado et al. [35] One ophthalmologist examined all the infants. Two well-trained professionals, masked to all infants’ information at the time of imaging analyses, manually selected the clear images and the single B-scan that best captured the fovea. They marked the foveal center for each set of images based on the presence of an inner retinal divot or at the thinnest point of the retinal nerve fiber layer. The retinal thickness of all subjects was manually measured twice by the two well-trained professionals using the handhold SD-OCT software. Finally, the average of the two measurements was taken for analysis. FD, CFT, PT, FIRL, FORL, PIRL, PORL, and FA were measured and analyzed (Fig. 1). Additionally, ratios were calculated and analyzed, including the foveal to the mean parafoveal ratio (FPR, calculated as CFT divided by PT), the foveal IRL to the mean PIRL ratio (F/P IRL, calculated as FIRL divided by PIRL), and the foveal ORL to the mean PORL ratio (F/P ORL, calculated as FORL divided by PORL).

FD was defined as the distance from the lowest point of the fovea to the apex of the line between the highest points of the nasal and temporal fovea. CFT was defined as the thickness of the entire retina from the inner aspect of the inner limiting membrane (ILM) to the inner aspect of the retinal RPE at the foveal center. IRL included all retinal tissue from the inner aspect of the ILM to the outer border of the inner nuclear layer (INL). ORL was measured from the outer border of the INL to the inner border of the RPE.PT was defined as the mean of the temporal and nasal-lateral retinal thickness (the entire retina from the inner aspect of the ILM to the inner aspect of the RPE) at a distance of 1000 μm from the foveal center. FA was measured at the lowest point of the fovea, as well as at the parafoveal points on either side where the retinal contour began to flatten.

Statistical analyses

Only the left-eye images were used in this study for statistical analysis to avoid binocular repeatability errors. Mean values and standard deviations (SDs) were used for continuous variables. The correlation analysis of the SD-OCT measurements between the two trained professionals was completed using an interclass correlation coefficient (ICC). An independent sample t-test was used to compare the mean GA, BW, and PMA of the two groups. The Pearson chi-square test was used for the comparison of sex composition. All the SD-OCT measurements of the two groups were compared using the Mann-Whitney U test. The correlation analysis between ROP and OCT measurements was conducted using the correlation ratio (E2).

Statistical analyses were performed using IBM SPSS Statistics version 26.0. All data were approximately normally distributed, and the statistical significance was set at p < 0.05.

Results

In this study, 106 preterm infants and 5 healthy adults underwent SD-OCT examination. 12 infants who didn’t obtain clear images and 29 infants with CME (29 out of 94, 30.85%) were excluded. At last, 65 infants and 5 adults were enrolled.

The baseline of the two groups is presented in Table 1. The two groups’ mean GA, BW, and PMA were normally distributed according to the Shapiro–Wilk normality test, and variance homogeneity according to Levine’s variance homogeneity test. There were no differences in sex composition, mean GA, BW, and PMA between the two groups (P > 0.05).

Table 1 The baseline characteristics of the two groups
Full size table

High-quality OCT images were obtained from all enrolled infants’ eyes, and the foveal center was readily identified as the deepest central depression in the SD-OCT images. The structures of the macula fovea of the preterm infant and adult are shown in Fig. 1. The fovea of all preterm infants in both groups showed immature features compared to the adult fovea: a shallower foveal depression, the presence of IRL at the foveal center, thinner retinal layers overall, and attenuation of ORL with the absence of photoreceptor sub-layers.

Fig. 1
figure 1

A shows the various layers of the macula in a preterm infant with ROP (zone II, stage 1, GA = 29.43w, BW = 1645 g, PMA = 36.43w), while B shows the layers of the macula in a healthy adult: Nerve Fiber, Ganglion Cell, Inner Plexiform, Inner Plexiform, Outer Plexiform, Outer Nuclear, external limiting membranes (ELM), Ellipsoid Zone (EZ), Interdigitation Zone (IZ), and RPE. FD is the distance from the lowest point of the fovea to the apex of the line between the highest points of the nasal and temporal fovea (white line). CFT was defined as the thickness of the entire retina from the inner aspect of the ILM to the inner aspect of the retinal RPE at the foveal center (Blue line plus red line). PT was the mean of the temporal and nasal-lateral retinal thickness 1000 μm from the foveal center (the mean of the two green lines plus the two yellow lines). FIRL included all retinal tissue from the inner aspect of the ILM to the outer border of the INL in the foveal center (blue line). FORL was measured from the outer border of the INL to the inner border of the RPE in the foveal center (red line). PIRL was the mean of the temporal and nasal-lateral inner retinal layer thickness at 1000 μm from the foveal center (the mean of the two green lines). PORL was the mean of the temporal and nasal-lateral outer retinal layer thickness at 1000 μm from the foveal center (the mean of the two yellow lines). FA was measured at the lowest point of the fovea and at the parafoveal points on either side where the retinal contour started to flatten, indicated by the angle between two slanted purple lines

Full size image

In addition, we found 29 cases of CME among 94 cases of premature infants (30.85%). The images of CME are shown in Fig. 2. CME was bilateral in all preterm infants. All cystoid spaces were found in the inner nuclear layer, and CME was categorized as mild edema (A), moderate edema (B), and severe edema (C). The CME distorted retinal layers and affected retinal thickness measurement and analysis, so we will not be analyzing them in this study.

Fig. 2
figure 2

shows the images of CME, with three levels of severity depicted. A: mild edema, defined as the presence of cystoid spaces that cause little to no deformation of the foveal contour; B: moderate edema, with the presence of cystoid spaces that cause either flattening or a slight upward bulging of the fovea and deformation of the foveal pit; C: severe edema, with the presence of cystoid spaces that cause severe upward bulging of the foveal contour

Full size image

Correlation analysis of the SD-OCT measurements between the two trained professionals was completed by ICC. The intraclass correlation coefficients for macula foveal measurements ranged from 0.780 to 0.932 (Table 2), indicating “good to excellent” agreement.

Table 2 Interclass correlation coefficients for macular foveal measurements
Full size table

The macula foveal measurements of the two groups are shown in Table 3. The FD of Group 2 was found to be shallower than that of Group 1 (P = 0.013). The CFT and FIRL measurements of Group 2 were significantly thicker than those of Group 1 (P = 0.024, 0.047), while the PT and PIRL measurements of Group 2 were significantly thinner than those of Group 1 (P = 0.038, 0.047). Additionally, the FA of Group 2 was significantly larger than that of Group 1 (P = 0.027). However, there was no significant difference in FORL and PORL between Groups 1 and 2 (P = 0.748, 0.806).

Table 3 The macula foveal measurements of the two groups
Full size table

Table 4 shows the FPR, F/P IRL, and F/P ORL of the two Groups. The FPR and F/P IRL of Group 2 were bigger than Group 1(P = 0.001, 0.000). However, there was no significant difference in F/P ORL between Group 1 and Group 2 (P = 0.885).

Table 4 The FPR, F/P IRL, and F/P ORL of the two groups
Full size table

Table 5 shows the correlation analysis between ROP and the measurements of the macula in the two groups. The results indicate that ROP was moderately correlated with FD, CFT, PT, FIRL, and PIRL in preterm infants (0.06 < E2 < 0.16, P < 0.05).

Table 5 Presents the correlation analysis of ROP and measurements of the macular fovea
Full size table

Discussion

This study evaluated the impact of spontaneously regressed ROP on foveal development in preterm infants around 37 weeks PMA. The findings demonstrate that the fovea was more immature in infants with ROP than those without ROP. Subclinical macular findings have been demonstrated on SD-OCT. These immaturities include a shallower macular fovea, thicker central retinal layers (specifically the inner retina), and thinner parafoveal inner retinal layers (Fig. 1).

Previous studies have extensively documented the long-term impact of ROP on macular development in older children and adolescents. However, these studies primarily focused on older age groups (4–26 years), making it challenging to discern the temporal onset of these abnormalities. Several studies have demonstrated that ROP can lead to lifelong functional and morphological ocular changes, which appear to have fetal origins for adult eye disease [15, 16, 36,37,38,39,40]. Wei-Chi Wu [16] found that patients(ages 6–14 years) with threshold ROP had significantly steeper corneal curvatures, shallower anterior chamber depths, thicker lenses, and retention of the layer of retinal ganglion cells, inner plexiform layer, and inner nuclear layer. Akula JD [36] considered the significantly larger parafovea and increased ONL thickness in 10–37 people with a history of ROP hint that some developmental process affecting the photoreceptors is not arrested in ROP but rather is supranormal.

The development of the macula is a complicated process that includes a centrifugal displacement of inner retinal cells and a centripetal displacement of photoreceptors at an early age. Macular foveal depression begins to emerge between 24 and 26 w, and the retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, INL, and outer plexiform layer are progressively extruded from the foveola until only the photoreceptor layers remain in the center of the foveal pit [6, 7, 41]. The foveal pit has been observed on SD-OCT from preterm infants as early as 32 weeks PMA. During human foveal maturing, it is possible to observe a deep foveal pit at 37–39 weeks PMA and continue to deepen until 43 weeks PMA [42]. The fovea does not reach histologic maturity until one to two years old. Ramiro S et al. [30] first illustrated in vivo human foveal development through handheld SD-OCT. They observed several signs of immaturity in preterm infants: a shallow foveal pit, persistence of IRL, and a thin PRL that was thinnest at the foveal center. This study evaluated macular development at a critical stage around 37 weeks PMA when the foveal pit begins to form. Consistent with Maldonado et al. [30] we observed that preterm infants exhibit shallow foveal depression, persistent inner retinal layers, and thin photoreceptor layers. Furthermore, we provide evidence that ROP exacerbates these features, particularly by inhibiting the centrifugal migration of the inner retinal layers. This finding supports the hypothesis that ROP disrupts the normal developmental trajectory of the inner retina during late gestation.

Our study highlights the asynchronous development of the inner and outer retinal layers in preterm infants with ROP. Although the inner retina in the foveal center remains thicker and less developed in ROP-affected infants, the outer retinal layers show no significant difference compared to non-ROP infants. Wu et al. [16] similarly noted that premature birth predominantly affects the maturation of the inner retina, while the outer retina remains relatively preserved. This asynchronous development pattern may reflect the distinct developmental timelines of the inner and outer retinal layers. As Hendrickson [7] and Yuodelis [41] described, the inner retinal layers undergo centrifugal migration during late gestation, whereas the outer retinal layers continue to mature postnatally, with cone packing and elongation extending into early childhood. In our study, we found that the photoreceptor layers of both groups had only one discontinuous thickened highly reflective band. This is consistent with previous research that a single hyper-reflective band, representing cone pedicles appears at the fovea in infants less than 42 weeks PMA, and the characteristic four hyper-reflective bands are evident across the fovea by 17–24 months postnatal age and mature into childhood until 13–16 years of age [43,44,45,46].

Notably, we found no significant differences in the outer retinal layers (FORL and PORL) between the two groups. This result is consistent with studies by Hammer [24], who observed similar photoreceptor thickness between ROP and control groups in adolescents. However, the implications of this finding remain uncertain, as photoreceptor development may continue to be influenced by ROP in later childhood, a subject warranting further longitudinal research.

In addition, we observed that the mean GA and BW of preterm infants with ROP were smaller compared to those without ROP. However, there was no statistically significant difference between the two groups (Table 1). This could be attributed to the fact that the infants with ROP had mild cases (Zone II or III, stage 1 or 2, plus -) that resolved spontaneously without treatment, and the preterm infants were in good general condition and did not need respiratory support. Furthermore, as in previous studies [47, 48], we also found CME in both two groups (30.85%). The cause of the occurrence of CME is unknown, and the current results show that the occurrence of CME does not seem to be related to the severity of ROP [20]. The analysis of the characteristics and related factors of CME has not been carried out in this study, which will be a focus of our future research.

Our findings have significant clinical relevance. While spontaneously regressed ROP is often considered benign, our study shows that it can still lead to measurable immaturity in macular development. These structural abnormalities may contribute to visual impairment later in life, even in cases without severe ROP requiring treatment. The higher central retinal thickness and shallower foveal depression observed in the ROP group suggest an incomplete redistribution of inner retinal neurons, which may impact foveal function. These insights emphasize the need for long-term ophthalmologic follow-up in children with a history of ROP, regardless of the severity.

However, our study has some limitations. The sample size was relatively small, and we only made cross-sectional observations without conducting continuous research on different PMA times. Future studies should incorporate larger cohorts and longitudinal designs to track macular changes across different postnatal stages. Second, although adults were included as a reference group to illustrate mature macular features, a more appropriate comparison would involve term-born infants without ROP. These infants would provide a closer developmental baseline for evaluating preterm macular immaturity. Lastly, we did not investigate the relationship between macular abnormalities and long-term visual outcomes, an area requiring further exploration.

In summary, this study reveals that spontaneously regressed ROP results in immature macular development during the early postnatal period. The primary contribution to these immaturities arises from delayed inner retinal layer development, while the outer retina remains relatively unaffected. These findings provide new insights into the mechanisms of macular development and emphasize the importance of monitoring preterm infants with a history of ROP for potential visual impairments.

Data availability

The data used to support the findings of this study are available from the corresponding authors upon request.

Change history

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Acknowledgements

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Funding

This research was supported by the Shenkang Multi-Center Clinical Research Project for Major Diseases (Project number SHD2020CR1009A).

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Authors and Affiliations

  1. Department of Ophthalmology, Children’s Hospital of Fudan University, National Children’s Medical Center, Wanyuan Road No.399, Shanghai, 201102, China

    Xiaojing Cai, Xiaohong Zhou, Tiancheng Wu, Yian Li, Weiming Yang & Chenhao Yang

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  1. Xiaojing Cai
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  2. Xiaohong Zhou
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  3. Tiancheng Wu
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  4. Yian Li
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Contributions

XJC and TCW collected information and drafted the initial manuscript. XJC performed fundus screening and SD-OCT examination. XJC and WMY carried out the image measurement and analysis. XJC and YAL conducted statistical analysis. CHY and XHZ conceptualized the study and critically reviewed the manuscript. All authors reviewed, revised the manuscript, and approved the final manuscript as submitted.

Corresponding authors

Correspondence to Weiming Yang or Chenhao Yang.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of both Children’s Hospital of Fudan University in Shanghai (approval number: Fudan No. 267 (2019)). This study conformed to the guidelines proposed in the Helsinki Convention. Written informed consent was obtained from the parents of each participant in the study.

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Not Applicable.

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The authors declare no competing interests.

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Cai, X., Zhou, X., Wu, T. et al. Delayed macular development in preterm infants with spontaneously regressed retinopathy of prematurity. BMC Ophthalmol 25, 27 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12886-025-03867-6

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Keywords

BMC Ophthalmology

ISSN: 1471-2415

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