Introduction

The necessity of eye disease screening for high-risk newborns has been widely recognized1,2,3,however, whether universal ocular screening should be implemented for full-term neonates remains controversial. Current studies4,5, have found that the most common abnormalities detected in eye disease screening of full-term neonatal include retinal hemorrhage, peripheral retinal exudation7 (or retinal white lesions), and familial exudative vitreoretinopathy (FEVR)-like9,10 fundus changes, among others. However, there have been no reports on the trends in the incidence of various retinal abnormalities. This study utilizes Chi-square tests and Joinpoint regression to analyze the results and incidence trends of eye disease screening abnormalities in full-term neonatal in Cixi City from 2016 to 2023, providing a scientific reference for the standardization of eye disease screening and follow-up for full-term neonatal.

Materials and methods

Screening subjects

A total of 17,378 full-term neonates born in our hospital from January 2016 to December 2023 were selected. The study was approved by the Clinical Research Ethics Committee of CiXi Maternity&Child Health Care Hospital (LCKY-L2024-64-02). All participants were screened in accordance with the ethical principles outlined in the Declaration of Helsinki for human research, and written informed consent was obtained from their guardians.

Screening methods

For full-term neonatal with a willingness for eye disease screening, the screening is conducted after their guardians sign an informed consent form. full-term neonatal undergo examination and image interpretation within one week after birth by two professional pediatric ophthalmologists trained in pediatric retinal examination. If there is a diagnostic discrepancy, a senior reviewer is consulted.

The examination consists of two parts: anterior segment examination and fundus examination. Feeding and drinking are prohibited for 60 min before the examination. Before the examination, 0.5% Tropicamide Phenylephrine Eye Drops (Santen Pharmaceutical Co., Ltd., Japan) are used to dilate the pupils (four drops per eye, one drop every 10 min). After dilation (pupil diameter reaching 6–8 mm), the neonate is brought by the guardian to the eye screening room for examination. Before the examination, the examiner administers 0.5% Proparacaine Hydrochloride Eye Drops (Alcaine Eye Drops, Alcon Laboratories Inc., Fort Worth, TX, USA) for conjunctival and corneal surface anesthesia in both eyes.

Anterior segment examination

The neonate is placed in a supine position. The examiner first observes the eyelids, then inserts an eyelid speculum. A handheld slit lamp and penlight are used to examine the conjunctiva, cornea, iris, pupil, lens, and red reflex.

Fundus examination

Ofloxacin Eye Ointment (Shenyang Xingqi Eye Drops Co., Ltd., China) or Gatifloxacin Eye Gel (Shenyang Xingqi Eye Drops Co., Ltd., China) is applied to the conjunctival sac. A wide-field imaging system (PanoCam from Suzhou Visunex Company, January 2016 - March 2018; Orthocone RS-B002 from Guangzhou Nuoxunde Medical Technology Co., Ltd., April 2018 - December 2023) with a 130-degree lens is used to capture retinal images of the posterior pole, macula, optic disc, temporal, nasal, superior, and inferior regions for fundus examination.

Findings in full-term neonatal fundus images include:

  • Retinal Hemorrhage6.

  • Retinal Exudates7(The peripheral retina of the fundus presents white lesions with clear or slightly blurred boundaries, distributed in patchy (isolated or continuous), striped, clustered (scattered and fused dot-like), or ring-shaped patterns (involving one or multiple quadrants, or even 360° around the retinal periphery.)

  • Retinal White spots7,8(Scattered throughout the fundus, with a size similar to the diameter of a retinal arteriole. The spots are beige or pure white in color, or white with a slight yellowish tint, and appear as single or multiple well-defined punctate lesions on the retina.)

  • Retinal Pigment abnormalities(This category included hypertrophy of retinal pigment, disordered retinal pigmentation, focal depigmentation, and retinal pigment nevi, all of which were collectively classified as retinal pigment abnormalities.)

  • FEVR-like lesions9,10(Defined by avascular areas in the peripheral retina of one or both eyes in full-term neonates. These could be accompanied or not accompanied by peripheral blood vessel thinning and rigidity. Additional findings included peripheral retinal neovascularization or exudative changes, vitreoretinal adhesion and traction, or retinal detachment.This retinopathy was described as FEVR-like lesions due to the absence of genetic confirmation required for definitive FEVR diagnosis.)

Additionally, data on the neonate’s gender, gestational age, delivery method, and birth weight are collected. After the examination, Ofloxacin Eye Ointment or Gatifloxacin Eye Gel is applied to both eyes twice daily for three days to prevent infection.

Statistical analysis

An eye disease screening database was established using Excel 2019 to organize and extract all screening data for full-term neonates from 2016 to 2023. Statistical analysis was performed using SPSS 17.0. Categorical data were expressed as percentages (%), and group comparisons were conducted using the Chi-square (χ²) test. Joinpoint regression analysis was performed using the Joinpoint Regression Program (version 4.8.0.1) developed by the U.S. National Cancer Institute. A significance level of P < 0.05 was considered statistically significant.

Results

Screening results for full-term neonatal eye diseases from 2016 to 2023

A total of 17,378 full-term neonates participated in eye disease screening. Among them, 9,178 were male (52.81%), and 8,200 were female (47.19%) (Table 1). Vaginal deliveries accounted for 9,988 cases (57.47%), while cesarean sections accounted for 7,390 cases (42.53%). Initial screening identified 11,392 normal cases, with a pass rate of 65.55%, and 5,986 abnormal cases, resulting in an abnormality rate of 34.45%. Among the abnormalities, the five most common conditions were: Retinal hemorrhage, (Fig. 1a) (3,274 cases, 18.84%), Retinal white spots, (Fig. 1b) (1,440 cases, 8.29%), Retinal exudates, (Fig. 1c) (943 cases, 4.53%), Retinal pigment abnormalities, (Fig. 1d)(437 cases, 2.51%), FEVR-like lesions, (Fig. 1e) (228 cases, 1.31%). Among the 3,274 cases with retinal hemorrhages, 489 involved macular hemorrhages, including 287 unilateral cases and 202 bilateral cases.Foveal hemorrhage was identified in 45 of the 489 cases with macular hemorrhage.This study also identified 18 cases of congenital cataracts and 275 cases of other ocular abnormalities. Excluding subconjunctival hemorrhages, 141 cases of relatively rare retinal abnormalities were observed, including: choroidal coloboma, (Fig. 1f) (n = 45),vitreous opacity (n = 29),tortuous retinal arteries without other retinal changes (n = 19),peripheral retinal avascular zone (1–2 disc diameters) without other retinal changes (n = 18),corneal opacity (n = 5),abnormal cup-to-disc ratio (n = 5),persistent pupillary membrane (n = 3),eyelid hemangioma (n = 3),persistent hyaloid artery remnant, (Fig. 1g) (n = 2),abnormal retinal arteriovenous anastomosis (n = 2),microphthalmos with microcornea (n = 2),blepharophimosis (n = 2),retinoblastoma (RB), (Fig. 1h) (n = 1),persistent fetal vasculature (PFV), (Fig. 1i)(n = 1),lenticonus (n = 1),optic disc drusen (n = 1),conjunctival polyp (n = 1),and vitreous hemorrhage (n = 1).

Table 1 Summary of fundus screening for Full-Term neonates (2016–2023) (n).
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Fig. 1
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Abnormalities in Eye Disease Screening among full-term neonatal a:Retinal hemorrhage. b:Retinal white spots (several white spots in the superotemporal retina, as indicated by the arrows). c:Retinal Exudates, (Grayish-white exudative lesions in the temporal peripheral retina, as indicated by the arrows). d:Retinal pigment abnormalities,(Congenital Hypertrophy of the Retinal Pigment Epithelium, CHRPE). e:Familial exudative vitreoretinopathy (FEVR)-like fundus changes. f:Choroidal coloboma (a large coloboma inferior to the optic disc in the right eye, accompanied by minor retinal hemorrhage). g:Persistent Hyaloid Artery. h:retinoblastoma (RB). i:persistent fetal vasculature (PFV).

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Screening results for full-term neonates by gender and delivery method from 2016 to 2023

During the study, ocular screening was performed on 9,178 male and 8,200 female full-term neonates. The screening results were normal in 5,984 (65.20%) males and 5,409 (65.96%) females, and abnormal in 3,194 (34.80%) males and 2,791 (34.04%) females. No significant difference in the abnormality rate was observed between male and female neonates (χ² = 1.120, P = 0.290; Table 2). A total of 9,988 vaginally delivered full-term neonates were screened, with 5,581 normal (55.88%) and 4,407 abnormal (44.12%). For 7,390 neonates delivered via cesarean section, 5,812 were normal (78.65%) and 1,578 were abnormal (21.35%). The proportion of eye abnormalities was significantly higher in vaginal deliveries than in cesarean sections (X2 = 975.299, P = 0.000, Table 2).

Table 2 Comparison of screening results by gender and delivery method (n, %).
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Retinal abnormalities in full-term neonates by delivery method from 2016 to 2023

A comparison of retinal hemorrhage, retinal white spots, and retinal exudates by delivery method is shown in Table 3. Among the 9,988 neonates delivered vaginally, 7,013 (60.25%) had no retinal hemorrhage, while 2,975 (29.79%) had retinal hemorrhage. Among the 7,390 neonates delivered via cesarean section, 7,091 (95.95%) had no retinal hemorrhage, while 299 (4.05%) had retinal hemorrhage. Retinal hemorrhage was more common in neonates born vaginally (X2 = 1840.390, P = 0.000, Table 3).

Table 3 Comparison of retinal abnormalities by delivery method (n, %).
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Among the 9,988 neonates delivered vaginally, 9,171 (91.82%) had no retinal white spots, while 817 (8.18%) had retinal white spots. Among the 7,390 neonates delivered via cesarean section, 6,764 (91.53%) had no retinal white spots, while 626 (8.47%) had retinal white spots. There was no significant difference in the probability of retinal white spots between delivery methods (X2 = 0.473, P = 0.429, Table 3). Among the 9,988 neonates delivered vaginally, 9,397 (94.08%) had no retinal exudates, while 591 (5.92%) had retinal exudates. Among the 7,390 neonates delivered via cesarean section, 7,036 (95.21%) had no retinal exudates, while 354 (4.79%) had retinal exudates. Retinal exudates were more likely to occur in vaginal deliveries than in cesarean section (X2 = 10.488, P = 0.001, Table 3).

Referral cases from 2016 to 2023

This study recorded 8 cases of full-term neonates with significant ocular abnormalities identified during screening, which required referral to higher-level hospitals for further evaluation and treatment due to severe impact on visual development (Table 4). Among them:1 case of bilateral retinoblastoma (RB): Detected on the second day after birth; following active treatment, the child’s right eye had uncorrected visual acuity of 0.8, and the left eye retained light perception at the age of 5.1 case of familial exudative vitreoretinopathy (FEVR) like lesions: Classified as stage 3 A according to Laqua staging. 1 case of microcornea with lens opacity. Severe lens abnormalities:3 cases with bilateral total opacity of the posterior lens capsule, rendering the fundus unviewable. 1 case with unilateral cone-shaped lens and lens opacity.1 case of persistent fetal vasculature (PFV).

Table 4 Summary of referred cases of diseases affecting visual development (2016–2023).
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Cytomegalovirus testing results in children with peripheral retinal exudation

From 2016 to 2023, 943 cases of retinal exudation abnormalities were identified. Among them, 174 cases consented to CMV-IgG and CMV-IgM testing. The results showed:145 cases (83.33%) were CMV-IgG(+)/CMV-IgM(-),23 cases (13.22%) were CMV-IgG(+)/CMV-IgM(+),6 cases (3.45%) were CMV-IgG(-)/CMV-IgM(-).This suggests a strong association between cytomegalovirus infection and retinal exudation.

Trend analysis of eye diseases in full-term neonates

Joinpoint regression results from 2016 to 2023 showed the following: The overall abnormal rate in eye disease screenings exhibited a downward trend (AAPC = −6.9%, 95% CI: −12.1% to −1.5%, P = 0.0211, Table 5; Fig. 2). The incidence of retinal hemorrhage showed a significant downward trend (AAPC = −3.2%, 95% CI: −6.4% to 0.0%, P = 0.0499, Table 5; Fig. 3).

Table 5 Trend analysis of abnormality rates in eye disease screening of Full-Term neonates (2016–2023).
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Fig. 2
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Trend of Abnormal Findings in Eye Disease Screening of Full-Term Neonates from 2016 to 2023.

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Fig. 3
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Trend of Retinal Hemorrhage in Full-Term Neonates from 2016 to 2023.

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The incidence of retinal white spots showed a downward trend (AAPC = −15%, 95% CI: −29.0% to 1.6%, P = 0.0677, Table 5; Fig. 4), but the trend was not statistically significant. The incidence of retinal exudation showed a downward trend (AAPC = −14.3%, 95% CI: −33.3% to 10.0%, P = 0.2255, Table 5; Fig. 5), with an increasing trend from 2016 to 2020 (APC = 9.3%, 95% CI: −30.9% to 72.9%, P = 0.5818, Table 5; Fig. 5) and a decreasing trend from 2020 to 2023 (APC = −38.1%, 95% CI: −70.0% to 27.9%, P = 0.1260, Table 5; Fig. 5), neither of which was statistically significant. The incidence of retinal FEVR-like lesions showed a downward trend (AAPC = −2.5%, 95% CI: −12.6% to 8.6%, P = 0.5826, Table 5; Fig. 6), but the trend was not statistically significant. The incidence of retinal pigment abnormalities showed a significant downward trend (AAPC = −25.4%, 95% CI: −42.8% to −3.0%, P = 0.0342, Table 5; Fig. 7).

Fig. 4
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Trend of Retinal White Spots in Full-Term Neonates from 2016 to 2023.

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Fig. 5
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Trend of Retinal Exudates in Full-Term Neonates from 2016 to 2023.

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Fig. 6
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Trend of Retinal FEVR-like Lesions in Full-Term Neonates from 2016 to 2023.

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Fig. 7
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Trend of Retinal Pigment Abnormalities in Full-Term Neonates from 2016 to 2023.

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The incidence of other abnormalities showed an upward trend (AAPC = 0.8%, 95% CI: −7.3% to 9.6%, P = 0.8271, Table 5; Fig. 8), but the trend was not statistically significant.

Fig. 8
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Trend of Other Retinal Abnormalities in Full-Term Neonates from 2016 to 2023.

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Discussion

In recent years, an increasing number of countries and regions have adopted digital wide-field retinal imaging systems for neonatal eye disease screening, with retinal hemorrhage being the most prevalent ocular condition identified in neonates4,11,12.Early studies have identified vaginal delivery as a significant factor contributing to neonatal retinal hemorrhage, with neonates delivered vaginally being more prone to this condition compared to those delivered via cesarean section, consistent with the findings of this study. In addition to a history of vaginal delivery, other studies have identified low birth weight13,prolonged labor4,advanced maternal age, and maternal anemia14 as risk factors for neonatal retinal hemorrhage. Further research into retinal hemorrhage, such as that conducted by Coste et al.has revealed that underdeveloped retinal vascular walls in neonates provide the pathological basis for retinal hemorrhage15. During vaginal delivery, compression in the birth canal significantly increases neonatal intracranial pressure, impairs venous return, and causes rupture of the optic disc capillary network, leading to retinal hemorrhage. Most retinal hemorrhages resolve spontaneously16,typically within 4 weeks14. However, neonates with hemorrhage involving the foveal center may require long-term follow-up to monitor visual development and potential functional impairments17.

Currently, there is no specific research on the causes and pathogenesis of neonatal retinal white spots. In studies on the etiology of multiple evanescent white dot syndrome (MEWDS) in adults, Jampol et al.suggested that retinal white spots are an immune-related disease associated with genetic susceptibility and infection18. On the other hand, research by Gross NE et al.proposed that inflammation or circulatory disturbances in the choroidal capillaries could be a potential cause of retinal white spot lesions, which resolve spontaneously after inflammation subsides or perfusion improves19. In our study, a total of 1,440 cases of retinal white spots were identified, with an incidence rate of 8.29%. During follow-up, some of these lesions resolved spontaneously, while others showed no morphological changes even after 3 to 6 months of observation. Ma Yan et al.found that in most cases, retinal white spot-like, patch-like, or streak-like changes in infants and young children resolved spontaneously within 12 months, suggesting that such changes may be physiological in nature7.

In the study of the causes of neonatal retinal exudates, Ma Yan et al.conducted an eye disease screening of 481 full-term newborns and found that factors such as the neonate gender, family history of high myopia, preterm birth, low birth weight, macrosomia, intrauterine fetal distress, umbilical abnormalities, neonatal asphyxia, meconium aspiration syndrome, neonatal anemia, maternal delivery method, abnormal labor process, amniotic fluid contamination, thyroid disease, preeclampsia, and gestational diabetes were not risk factors for retinal white lesions7. Ying Xiafen et al.studied 2,612 full-term neonates and found that retinal exudative-like changes in full-term neonates were associated with factors such as gestational diabetes, umbilical cord twisting, and nuchal cord abnormalities20.

Additionally, early research discovered that cytomegalovirus (CMV) could migrate to the retina via leukocytes in peripheral blood21. CMV crosses the retinal vascular endothelium through endocytosis, replicates within cells, disrupts the integrity of the blood-retinal barrier, and ultimately involves retinal pigment epithelial cells, forming retinal white or yellow-white lesions. It was observed in our study that vaginal delivery was associated with an increased incidence of retinal exudate-like lesions in full-term newborns. Among 174 cases of retinal exudates from 943 identified cases, 168 (96.55%) had evidence of cytomegalovirus infection, with CMV-IgG(+). This study identified vaginal delivery as a risk factor for retinal exudates, differing from previous research. This discrepancy may be due to the larger sample size in this study, which exposed this factor. The extremely high prevalence of CMV-IgG(+) in cases of retinal exudates further supports a significant association between retinal exudates and cytomegalovirus infection. Previous studies have demonstrated that neonates with immature vascular wall development are susceptible to retinal capillary rupture during vaginal delivery, which compromises the integrity of the blood-retinal barrier (BRB)15. BRB impairment may further facilitate CMV penetration through the vasculature, enabling viral invasion of retinal pigment epithelial (RPE) cells. This study observed that retinal exudation in full-term neonates delivered vaginally is associated with CMV infection, suggesting that a compromised ocular barrier enhances viral tropism for RPE cells. Neonates with vascular immaturity may thus represent a high-risk population, making CMV screening potentially necessary.

When analyzing the incidence trends of eye diseases in full-term neonates from 2016 to 2023, we found a significant downward trend in both the overall abnormality rate and specifically in retinal pigment abnormalities. This overall improvement may be attributed to advancements in the diagnosis and treatment of obstetric, gynecologic, and pediatric disorders, which have contributed to a reduction in perinatal complications among newborns22.Similarly, the incidence of retinal hemorrhage also showed a notable decline. We speculate that this reduction may be related to our hospital’s adoption of the moderate perineal protection method during delivery in recent years, which alleviates compression of the fetal head in the birth canal.

Although the incidence rates of retinal white spots, retinal exudates, and FEVR-like lesions also exhibited a downward trend, and other abnormalities showed a slight upward trend, none of these changes were statistically significant. This indicates that retinal white spots, retinal exudates, and FEVR-like lesions may have stable incidence rates in full-term neonates.

In summary, retinal hemorrhage remains the most common eye disease in full-term neonates, and we must pay attention to the impact of foveal hemorrhage on visual development. Vaginal delivery is significantly associated with retinal hemorrhage and exudation in full-term neonates, and cytomegalovirus infection may be an important cause of retinal exudation. Fortunately, thanks to advancements in modern medical technology and early neonatal screening, the overall incidence of neonatal eye diseases is declining. This progress encourages further research into quantifying specific interventions, such as early pregnancy screening for ocular malformations or remote monitoring of retinopathy, to improve visual outcomes in neonates.