Optic disc parameters and associations with early life exposures in over 3 000 12-year-old children: findings from the ALSPAC cohort

Optic disc parameters and associations with early life exposures in over 3 000 12-year-old children: findings from the ALSPAC cohort | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Optic disc parameters and associations with early life exposures in over 3 000 12-year-old children: findings from the ALSPAC cohort Alexandra Creavin, Kate Tilling, Nic Timpson, Cathy Williams This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4322862/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Feb, 2025 Read the published version in Eye → Version 1 posted 9 You are reading this latest preprint version Abstract Objectives We aimed to investigate the distribution of cupped and small optic discs in children and to examine associations with maternal and environmental factors. Methods Retinal photographs were graded from over 3000 12-year-olds in the Avon Longitudinal Study of Parents and Children. Regression models examined associations between disc parameters and maternal and early-life exposures. Results Mean cup-to-disc area ratio (CDAR) for 3288 children was 0.21 (95%CI 0.20,0.21). Cupped discs (CDAR >0.3) were present in 11%. The odds of disc cupping were increased nearly three-fold in underweight children (adjusted odds ratio (aOR) 2.9 (1.1, 7.3) p=0.03) and 28-fold in severely premature (<28 weeks) children (paOR 28 95%CI 4.6,172, p3) were present in 6% of which a third were bilateral. The odds of a small disc were increased in the offspring of mothers who smoked in pregnancy (aOR 1.7 (1.0,2.8) p=0.04) and more than doubled in children born with a small head circumference (aOR 2.5 (1.4,4.5) p<0.001). Conclusions Cupped and small optic discs are more frequent than usually supposed at age 12. The odds of disc cupping are increased by severe prematurity and pathologically low BMI. The odds of a small disc are increased by maternal smoking and small head circumference. Optimisation of risk factors in pregnancy and delivery and early childhood nutrition may play an important role in ophthalmic neurodevelopment and thus have a lifelong impact on ocular health. Health sciences/Risk factors Health sciences/Biomarkers/Predictive markers Figures Figure 1 Figure 2 Figure 3 Introduction In adults, an increasing cup size relative to the optic disc signifies nerve fibre loss, aiding disease diagnosis and monitoring, with a cup-to-disc ratio (CDR) > 0.3 indicating potential glaucoma. 1 However, defining normal versus abnormal thresholds in children, and interpreting asymmetry, remains uncertain. No evidence-based guidelines exist for managing children with cupping, often leading to referrals to hospital services following routine optometric examination. Optic nerve hypoplasia is a complex syndrome in which a small optic disc occurs in conjunction with non-ocular manifestations. The cup-to-fovea over disc diameter (CF/DD) is a dimensionless measure that can be used in identifying a small disc: suspected when CF/DD is greater than 3.0 and very likely if greater than 4.0. 2–4 Fig. 1 illustrates measurement of CF/DD. In cases of optic nerve hypoplasia visual acuity may range from no perception of light to normal. 5 Quantification of optic nerve head damage occurs in the context of many other clinical measures such as visual field tests and intraocular pressure. However, these can prove challenging in children, as measurement of visual fields shows poor reliability in those younger than eight, and nerve visualization and intra-ocular pressure measurement can be hampered by patient movement and lid squeezing, particularly when children are experiencing other neurodevelopmental problems. 6 While optical coherence tomography (OCT) aids diagnosis and monitoring, paediatric versions aren't universally accessible, sustaining the use of cup-to-disc ratio (CDR) and retinal photography globally. In practice, children with cupped or small optic discs often present a clinical dilemma. 7 Enhanced understanding of optic disc parameters in infants and children is crucial for diagnosing and monitoring ophthalmic and neurological diseases, minimizing unnecessary referrals and investigations, while emphasizing early detection to optimize visual, academic, and social outcomes. This study employs fundus photography-derived optic disc data from a substantial cohort to explore optic disc parameter distributions (CDAR and CF/DD) in children, gauging the prevalence of paediatric cupped or small discs and their associations with maternal and environmental factors. Subjects and methods We conducted an analysis of digital retinal photography data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based cohort study. 8,9 Pregnant women residing in Avon, UK, with expected delivery dates between April 1, 1991, and December 31, 1992, were invited to participate. Initially, 14,541 pregnancies were enrolled, resulting in 13,988 children alive at one year of age. For analyses after the age of seven, the total sample size was 15,447 pregnancies, with 14,901 children alive at one year of age. 8,9 Data on early-life and maternal exposures were collected through self-completion questionnaires, obstetric medical notes, observation, clinical examination, and biological samples. The study website contains details of the data through a searchable data dictionary and variable search tool. 10 Not all participants with retinal photographs completed all ALSPAC clinics and questionnaires and so varying numbers of participants had data for each exposure. Retinal photographs were taken at 12 years of age using a non-mydriatic Topcon camera. Attendees for retinal imaging were compared to non-attendees. Optic nerve images were graded monoscopically using semi-automated software by trained graders, who were blinded to clinical information. 11 The cup-to-disc area ratio (CDAR) and the cup-to-fovea over disc diameter (CF/DD) were automatically generated after manual placement of dots around the cup perimeter and on the fovea, respectively (see Figure 1). Seven technicians graded the images, requiring consideration of systematic differences in measurements due to grader identity. After training, an agreement exercise was performed on a subset of unique and repeat images representing a range of grading ease and disc parameters. Grader 3 did not complete the agreement exercise and so could not be included. The two-way random effects, absolute agreement, multiple intraclass correlation coefficient (ICC, (2, k )) with 95% confidence intervals was used to determine the variability between graders when grading the same image. Bland-Altman plots and analyses of variance (ANOVA) were used to compare graders to a reference standard (the lead optometrist for the glaucoma-shared care service). Tukey’s procedure was applied to pairwise comparisons. The label “Grader 8” was used where grader identify could not be ascertained (n=31). To mitigate confounding and reduce the standard error of estimates, covariates hypothesized to be associated with either CDAR and disc cupping or CF/DD and optic nerve hypoplasia were identified from literature and expert discussions. Table 1 gives details of the measurement of outcome, exposure, and confounder variables. Data cleaning and analyses were conducted using Stata version 13. The second delivered twin was excluded from analyses of multiple births. Outcome data were analysed as ratios based on unit differences. Left and right eyes were compared, and right eyes were used in subsequent analyses. The distribution of optic disc parameters was described using means, medians, and ranges. Maternal and child-related factors hypothesized to be associated with CDAR or with a small optic nerve head in the extreme phenotype of optic nerve hypoplasia were explored using stratification, chi-squared tests, and regression models incorporating inverse probability weighting to mitigate bias from missing data. The weighting model used logistic regression to relate case completeness to baseline variables: maternal age, gestation, sex, maternal smoking, and parity and was used to estimate the probability of being a complete case for each person. Table 1: Variable categories and measurement TABLE 1 HERE Power calculation A subset of 1 250 ALSPAC photographs had previously been used to calculate a mean CDAR of 0.3 (SD 0.08). Analysis of approximately 3 300 images had 80% power with a significance of 0.05 to detect a minimum difference in means of 0.01 in CDAR for exposures affecting 15% of participants (e.g., maternal smoking) and a difference in means of 0.014 for exposures affecting 5% of ALSPAC participants (e.g., preterm birth). Results Attendees versus non-attendees Figure 2 is a flow diagram of participants. We compared individuals attending retinal photography and achieving gradable images with those who didn't. Children with photographs were more likely to be white, female, term-born, with normal birth weight, and have highly educated, non-smoking, older mothers (see supplementary Table 1: Socio-demographic characteristics, birth outcomes, and visual outcomes of participants attending and included in the analysis versus non-attending children). Both groups exhibited rare poor visual acuity and maternal heavy drinking. Figure 2: ALSPAC participants. FIGURE 2 HERE Sample description A gradable retinal image was obtained from 3 327 individuals, averaging 12.9 years old (SD 0.27, range 11 to 14 years). Females constituted just over half (50.7%), with 96.0% reporting white ethnicity, 95.5% born at term, and 95.8% with normal birth weight. Approximately 17.3% were born to mothers who smoked in the first trimester. Instances of heavy drinking during pregnancy (0.7%) and mothers over forty years old (1.5%) were rare. Rater agreement Inter-grader agreement was good for CDAR (ICC (95%CI) 0.74 (0.62, 0.84)) and moderate for CF/DD (ICC (95%CI) 0.57 (0.42, 0.72)). Repeatability was good for both CDAR (ICC (95%CI) 0.77 (0.59, 0.89)) and CF/DD (ICC (95% CI) 0.78 (0.61, 0.89)). Tukey post hoc test and ANOVA revealed slight underestimation of optic disc parameters by graders, particularly for larger measurements, compared to the reference standard. Distribution of optic disc parameters Cup-to-disc area ratio. CDAR measures were collected from 3 288 children. Among those with gradable images in both eyes (n=3,078) CDAR was similar in 99.5%: 92% showed ≤0.1 difference between eyes, 8% >0.1 but <0.2, and 0.5% ≥0.2. Mean (standard deviation (SD)) CDAR was 0.21 (0.09), median 0.20 and range 0.05 to 0.55. Mode CDAR was 0.15 (n=842). CDAR distribution was right skewed (see Figure 3). Male and female mean (sd) CDARs were comparable: 0.21 (0.1) and 0.20 (0.1) respectively. Large CDAR (> 0.3) prevalence was 11% (n=367). Cup-to-fovea over disc diameter. CF/DD measurements were obtained from 3 327 children. Mean (SD) CF/DD was 2.48 (0.36), median 2.45 and range 1.33 to 6.06. Mode CF/DD was 2.49 (n=65). CF/DD followed a normal distribution (see Figure 3). Male and female CF/DD were comparable: 2.48 (0.4) and 2.47 (0.4) respectively. Small optic disc (CF/DD >3) prevalence was 6% (n=212) with one third bilateral (n=75). Figure 3: Histogram of (a) CDAR and (b) CF/DD distribution in the ALSPAC. FIGURE 3 HERE Relationship with exposures Table 2 presents uni- and multi-variable logistic regression models for (a) CDAR >0.3 and (b) CF/DD >3 against each predetermined exposure. Table 2: Univariable and multivariable logistic regressions for (a) large CDAR and (b) large CF/DD (small OD) against predetermined exposures TABLE 2 HERE CDAR The odds of a cupped disc were comparable across groups for birth weight, maternal smoking, and head circumference at birth. Severely premature children born before 32 weeks’ gestation had 28 times higher odds of disc cupping at age twelve (partially adjusted odds ratio (paOR) (95% confidence interval (CI)) 28 (4.62, 172) p=<0.001). Numbers were insufficient to run the fully adjusted model. Children with a low BMI at age eleven had three times higher odds of disc cupping (adjusted odds ratio (aOR) 2.87 (1.13, 7.27) p=0.03). A cupped disc was identified in over a quarter (26%) of children born before 32 weeks (n=6) compared to just 8% of moderately preterm (n=9) and 11% of term children (n=339) with evidence of a difference between groups (, p=0.012). CF/DD The odds of a small disc were comparable across groups for birth weight, large head circumference, maternal alcohol, preterm birth, weight loss in trimester one, maternal age, and parity. Children with a small head circumference at birth had more than twice the odds of a small optic disc at age twelve (aOR 2.49 (1.37, 4.51) p=<0.001). A small optic disc was found in 7% (n=25) of those born with a small head circumference, 6% (n=52) with a large circumference and 4% (n=75) with a normal circumference (p=0.009). Children born to mothers who smoked in pregnancy also had increased odds of a small disc (aOR 1.69 (1.01, 2.84, p=0.04). There was a lack of association with some exposures hypothesized to cause the extreme phenotype of optic nerve hypoplasia: first trimester weight loss (aOR 0.66 (0.20,2.10)), maternal age (aOR 0.9 (0.19,4.29) p=0.89) and parity (aOR 1.12 (0.75,1.67) p=0.58). Discussion Strengths and limitations The ALSPAC study provides rich life course data for many participants across a geographic region, offering sufficient power to investigate rare exposures, though some adjusted analyses may have limited power. However, the lack of representation from ethnic minorities and less affluent families may restrict the generalisability of findings. 8 Self-reported data such as smoking or alcohol intake are susceptible to misreporting, potentially biasing associations towards null values. Observer variability and measurement errors may affect physical measures, despite training and protocols. Retinal photography, while widely used in clinical practice, faces challenges in optic disc measurement due to landmark identification and magnification error, mitigated by using dimensionless ratios like CDAR. Retinal photography and OCT have been demonstrated to yield comparable results with relative measures, though absolute measures may be around 10% smaller using photography. 12 Monoscopic software usage may underestimate CDAR compared to stereoscopic methods, reducing cupping prevalence estimations. 11 Although graders tended to underestimate parameters, their reasonable agreement questions the necessity of a reference standard with inherent errors. A priori analysis protocols aimed to minimize bias. Residual confounding from unmeasured exposures remains possible. Interpretation The average 12-year-old child typically exhibits a CDAR of around 0.2, regardless of gender, similar to findings in Australian six-year-olds. 13 While a cup-to-disc ratio > 0.2 has been reported to occur in fewer than 1% of children our study shows a prevalence of CDAR > 0.3 in 11% of participants, suggesting a potential need to reassess the clinical implications of CDAR thresholds. 14 Similarly, the mean cup-to-fovea over disc diameter (CF/DD) in our cohort was 2.48, with 6% of children exhibiting CF/DD > 3.0, questioning the appropriateness of this threshold for diagnosing optic nerve hypoplasia. 2,3 Regarding interocular differences, only 0.5% of children in our study showed asymmetry > 0.2, highlighting how rare pathological asymmetry is according to proposed thresholds of > 0.25. 15 Further exploration of asymmetry's clinical significance in childhood is warranted to establish appropriate abnormal interocular difference levels. A small head circumference below the 9th percentile was associated with a small optic disc. It is unlikely that this is a proportional phenomenon given that CF/DD is a ratio, and large optic discs were not seen in those with large head circumference. One study reported smaller disc diameter in Australian children with small head circumference, which was associated with larger cup-to-disc ratio. 16 Small head circumference has been reported to be associated with neurodevelopmental abnormalities such as attention deficit, which, in turn, has been associated with subtle morphological changes in the optic nerve. 17,18 Being underweight at age 11 was associated with disc cupping independent of maternal BMI, aligning with adult studies associating low BMI with smaller neuro-retinal rim area and larger vertical and area cup-to-disc ratios. 19,20 Nutritional deficiencies may mediate this association, given the optic nerve's vulnerability to deficiencies like B vitamins, folic acid, and proteins containing sulphur-containing amino acids. 21 In later life, glaucoma development has been linked with low vitamin A and vegetable fat intake. 22 Maternal smoking is a significant factor associated with small optic discs, likely due to its impact on foetal development and neuro-ophthalmic complications. Potential mechanisms include reduced placental blood flow through nicotine-induced vasoconstriction; foetal hypoxia from carbon monoxide binding to haemoglobin; vascular neogenesis; and endothelial function disturbance. 23 Additionally, direct toxic, ischaemic, or hypoxic effects on cell proliferation or migration during critical periods may contribute. 23 Studies of premature infants reported high mean CDAR and high prevalence of cupped discs, possibly influenced by factors precipitating preterm birth or immaturity-associated morbidity. 24 Immature apoptotic pruning of supernumerary fibres and extra-uterine environmental influences like oxygen delivery and carbon dioxide tension may cause excessive elimination of axons. 24 Persistence of cupping in older preterm children suggests limited catch up growth. Disentangling effects of gestational age from factors like low birth weight, ROP, cerebral injury, and early life events is challenging. Cupped appearance in white matter injury may stem from axonal interruption via retrograde trans-synaptic degeneration, akin to optic nerve hypoplasia, with the differing appearance due to the timing of the insult. 24,25 Some exposures hypothesized to cause the extreme phenotype of optic nerve hypoplasia, like maternal age and parity, showed a lack of evidence of association. Implications and future work This study contributes to a field primarily composed of small-scale investigations. We reveal that cupped and small optic discs may be more prevalent in children than previously believed. Therefore, it is crucial to scrutinize the clinical characteristics of children presenting with what is typically considered a cupped disc to ascertain whether these features are being overly referred, pathologized, or monitored. The long-term prognosis of preterm cupped discs remains uncertain. While a larger cup-to-disc ratio in adulthood is linked to a higher risk of glaucomatous optic neuropathy and associations have been reported between optic disc morphology and systemic neuro- and cardiovascular development in adults 26 , the significance of cupped discs in preterm children as a form of optic nerve hypoplasia remains unclear. Further research is needed to elucidate the relationship between visual acuity and disc size. Additionally, the association between small discs and head circumference raises questions about the need for further assessment in infants with smaller heads but not microcephaly. Work is needed to understand the relationship between timing and coordination of craniofacial growth and the morphology of optic fidelity. Finally, addressing maternal smoking, a preventable risk factor, is essential to combat health disparities among socioeconomic groups. Conclusion Retinal imaging of 3 000 12-year-olds revealed a mean cup-to-disc area ratio of 0.21 and mean CF/DD of 2.48, consistent across sexes. Cupping affected 11%, linked to preterm birth and low BMI. A small optic disc, found in 6% (one third bilateral), correlated with maternal smoking and small head circumference. These findings suggest the prevalence of cupped and small discs in children may be higher than previously thought. Optic nerve development may relate to extra-ocular growth and early-life factors, with distinct parameters in preterm children versus full-term counterparts. Declarations Acknowledgements We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. We extend particular thanks to Professor James Morgan who provided the original software for measurement of the optic nerve parameters on the photographs and to the Bristol Eye Hospital imaging team, in particular Abi Loos who organized the schedule for imagers to grade the ALPSAC photographs. Conflict of interest and ethical statement The authors do not have any competing financial interest in relation to the work described. Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees (see http://www.bristol.ac.uk/alspac/researchers/research-ethics/). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. Funding The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Dr Williams will serve as guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Dr Creavin completed this work as part of a National Institute for Health Research (NIHR) doctoral research fellowship (DRF-2015-08-018). Dr Williams was funded by an NIHR senior research fellowship (SRF_2015_08_005). Professor Tilling, Dr Timpson and Dr Creavin worked as part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is funded by the MRC grant code: MC_UU_12013/3. This article/paper/report presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. References Khalil HE-DM, Saif MYS, El-Khalek MOA, et al. Variations of Cup-to-Disc Ratio in Age Group (18–40) Years Old. Research in Ophthalmology 2013; 2: 4–9. Alvarez E, Wakakura M, Khan Z, et al. The disc-macula distance to disc diameter ratio: a new test for confirming optic nerve hypoplasia in young children. J Pediatr Ophthalmol Strabismus ; 25: 151–4. Zeki SM, Dudgeon J, Dutton GN. Reappraisal of the ratio of disc to macula/disc diameter in optic nerve hypoplasia. Br J Ophthalmol 1991; 75: 538–41. Dutton GN. Congenital disorders of the optic nerve: excavations and hypoplasia. Eye (Lond) 2004; 18: 1038–48. Garcia-Filion P, Borchert M. Prenatal determinants of optic nerve hypoplasia: review of suggested correlates and future focus. Surv Ophthalmol ; 58: 610–9. Akar Y, Yilmaz A, Yucel I. Assessment of an effective visual field testing strategy for a normal pediatric population. Ophthalmologica 2008; 222: 329–33. Park H-YL, Ha MJ, Shin SY. The effect of parental factors in children with large cup-to-disc ratios. PLoS One 2017; 12: e0175900. Boyd A, Golding J, Macleod J, et al. Cohort Profile: the ’children of the 90s’--the index offspring of the Avon Longitudinal Study of Parents and Children. Int J Epidemiol 2013; 42: 111–27. Fraser A, Macdonald-Wallis C, Tilling K, et al. Cohort Profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort. Int J Epidemiol 2013; 42: 97–110. Bristol University. ALSPAC Data Tool, http://www.bristol.ac.uk/alspac/researchers/our-data/ (accessed 29 September 2020). Morgan JE, Sheen NJL, North R V, et al. Digital imaging of the optic nerve head: monoscopic and stereoscopic analysis. Br J Ophthalmol 2005; 89: 879–84. Samarawickrama C, Hong T, Jonas JB, et al. Measurement of normal optic nerve head parameters. Surv Ophthalmol ; 57: 317–36. Samarawickrama C, Pai A, Tariq Y, et al. Characteristics and appearance of the normal optic nerve head in 6-year-old children. Br J Ophthalmol 2012; 96: 68–72. Liesegang TJ, Skuta GL, Cantour LB. Seciton 10 Glaucoma: Chap. 3 clinical evaluation. In: Basic and clinical science course . 2008, pp. 51–52. Altemir I, Oros D, Elía N, et al. Retinal asymmetry in children measured with optical coherence tomography. Am J Ophthalmol 2013; 156: 1238–1243.e1. Samarawickrama C, Huynh SC, Liew G, et al. Birth weight and optic nerve head parameters. Ophthalmology 2009; 116: 1112–8. Murray E, Pearson R, Fernandes M, et al. Are fetal growth impairment and preterm birth causally related to child attention problems and ADHD? Evidence from a comparison between high-income and middle-income cohorts. J Epidemiol Community Health (1978) 2016; 70: 704–709. Grönlund MA, Aring E, Landgren M, et al. Visual function and ocular features in children and adolescents with attention deficit hyperactivity disorder, with and without treatment with stimulants. Eye 2007; 21: 494–502. Zheng Y, Cheung CYL, Wong TY, et al. Influence of height, weight, and body mass index on optic disc parameters. Invest Ophthalmol Vis Sci 2010; 51: 2998. Kim YJ, Kim JM, Shim SH, et al. Associations between Optic Cup-to-disc Ratio and Systemic Factors in the Healthy Korean Population. Korean Journal of Ophthalmology 2015; 29: 336. Grzybowski A, Zülsdorff M, Wilhelm H, et al. Toxic optic neuropathies: an updated review. Acta Ophthalmol 2015; 93: 402–410. Yoserizal M, Hirooka K, Yoneda M, et al. Associations of nutrient intakes with glaucoma among Japanese Americans. Medicine 2019; 98: e18314. Hackshaw A, Rodeck C, Boniface S. Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls. Hum Reprod Update 2011; 17: 589–604. Hellström A, Hård AL, Svensson E, et al. Ocular fundus abnormalities in children born before 29 weeks of gestation: a population-based study. Eye (Lond) 2000; 14 ( Pt 3A: 324–9. Jacobson L. Optic disc morphology may reveal timing of insult in children with periventricular leucomalacia and/or periventricular haemorrhage. British Journal of Ophthalmology 2003; 87: 1345–1349. Wagner SK, Bountziouka V, Hysi P, et al. Associations between unilateral amblyopia in childhood and cardiometabolic disorders in adult life: a cross-sectional and longitudinal analysis of the UK Biobank. EClinicalMedicine 2024; 70: 102493. Tables Tables 1-2 is available in the Supplementary Files section. Additional Declarations There is no conflict of interest Supplementary Files Table1.png Table 1 Table2copy.png Table 2 SupplementaryTable1.png Socio-demographic characteristics, birth outcomes, and visual outcomes of participants attending and included in the analysis versus non-attending children Cite Share Download PDF Status: Published Journal Publication published 22 Feb, 2025 Read the published version in Eye → Version 1 posted Editorial decision: revise 30 Sep, 2024 Review # 1 received at journal 27 Aug, 2024 Review # 2 received at journal 13 Aug, 2024 Reviewer # 2 agreed at journal 30 Jul, 2024 Reviewer # 1 agreed at journal 19 Jul, 2024 Reviewers invited by journal 13 May, 2024 Editor assigned by journal 09 May, 2024 Submission checks completed at journal 25 Apr, 2024 First submitted to journal 25 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4322862","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":301737809,"identity":"aa9c53a9-644f-47c4-8340-5a015d3c54a0","order_by":0,"name":"Alexandra Creavin","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-5076-862X","institution":"University of Bristol","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Alexandra","middleName":"","lastName":"Creavin","suffix":""},{"id":301737810,"identity":"c790da77-1a12-4744-8f85-c5aefa5adec2","order_by":1,"name":"Kate Tilling","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kate","middleName":"","lastName":"Tilling","suffix":""},{"id":301737811,"identity":"ef183c16-f45b-402c-9f63-e96b992900a5","order_by":2,"name":"Nic Timpson","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nic","middleName":"","lastName":"Timpson","suffix":""},{"id":301737812,"identity":"4239f559-5825-4cff-8c2e-2a1035a41c27","order_by":3,"name":"Cathy Williams","email":"","orcid":"","institution":"University of Bristol","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cathy","middleName":"","lastName":"Williams","suffix":""}],"badges":[],"createdAt":"2024-04-25 08:55:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4322862/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4322862/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41433-025-03716-2","type":"published","date":"2025-02-22T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57292015,"identity":"cc4ec832-16d7-42f1-91db-cff758944be5","added_by":"auto","created_at":"2024-05-28 18:01:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1146028,"visible":true,"origin":"","legend":"\u003cp\u003eRatio of the distance from the centre of the disc to the fovea, divided by disc diameter: CF/DD\u003c/p\u003e","description":"","filename":"Figure1copy.png","url":"https://assets-eu.researchsquare.com/files/rs-4322862/v1/a0d453664d024493fe4b9bc9.png"},{"id":57292900,"identity":"9e9332fc-34c7-48d3-8a55-f0094283359b","added_by":"auto","created_at":"2024-05-28 18:17:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":111745,"visible":true,"origin":"","legend":"\u003cp\u003eALSPAC participants.\u003c/p\u003e","description":"","filename":"Figure2copy.png","url":"https://assets-eu.researchsquare.com/files/rs-4322862/v1/a4e9d12d4ea0898a8a59a39a.png"},{"id":57292018,"identity":"d2c06377-fb37-49d8-a71f-b0fc477d6a9b","added_by":"auto","created_at":"2024-05-28 18:01:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":58528,"visible":true,"origin":"","legend":"\u003cp\u003eHistogram of (a) CDAR and (b) CF/DD distribution in the ALSPAC.\u003c/p\u003e","description":"","filename":"Figure3copy.png","url":"https://assets-eu.researchsquare.com/files/rs-4322862/v1/f3336c8d108a0b3a44672a8a.png"},{"id":76951722,"identity":"39efcba4-5805-4f2a-a38a-0c4b53069b39","added_by":"auto","created_at":"2025-02-23 08:07:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1809476,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4322862/v1/6b154709-a471-4302-b7a4-f50820c57c2c.pdf"},{"id":57292014,"identity":"dc580016-85d9-4b59-8467-c4e2283a3d32","added_by":"auto","created_at":"2024-05-28 18:01:29","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":222026,"visible":true,"origin":"","legend":"Table 1","description":"","filename":"Table1.png","url":"https://assets-eu.researchsquare.com/files/rs-4322862/v1/c10ce6775f738e6df5b0ff3e.png"},{"id":57292651,"identity":"eda7b08b-7f76-4511-acee-ff86bca83fa4","added_by":"auto","created_at":"2024-05-28 18:09:29","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":561516,"visible":true,"origin":"","legend":"Table 2","description":"","filename":"Table2copy.png","url":"https://assets-eu.researchsquare.com/files/rs-4322862/v1/78dcbb65eff19ae98c2bb95d.png"},{"id":57292019,"identity":"e3a72093-bac0-4304-94c2-a3a35b9a0b6a","added_by":"auto","created_at":"2024-05-28 18:01:29","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":178888,"visible":true,"origin":"","legend":"Socio-demographic characteristics, birth outcomes, and visual outcomes of participants attending and included in the analysis versus non-attending children","description":"","filename":"SupplementaryTable1.png","url":"https://assets-eu.researchsquare.com/files/rs-4322862/v1/452fc9323404ec50f536d1d5.png"}],"financialInterests":"There is no conflict of interest","formattedTitle":"Optic disc parameters and associations with early life exposures in over 3 000 12-year-old children: findings from the ALSPAC cohort","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn adults, an increasing cup size relative to the optic disc signifies nerve fibre loss, aiding disease diagnosis and monitoring, with a cup-to-disc ratio (CDR)\u0026thinsp;\u0026gt;\u0026thinsp;0.3 indicating potential glaucoma.\u003csup\u003e1\u003c/sup\u003e However, defining normal versus abnormal thresholds in children, and interpreting asymmetry, remains uncertain. No evidence-based guidelines exist for managing children with cupping, often leading to referrals to hospital services following routine optometric examination.\u003c/p\u003e \u003cp\u003eOptic nerve hypoplasia is a complex syndrome in which a small optic disc occurs in conjunction with non-ocular manifestations. The cup-to-fovea over disc diameter (CF/DD) is a dimensionless measure that can be used in identifying a small disc: suspected when CF/DD is greater than 3.0 and very likely if greater than 4.0.\u003csup\u003e2\u0026ndash;4\u003c/sup\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates measurement of CF/DD. In cases of optic nerve hypoplasia visual acuity may range from no perception of light to normal.\u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eQuantification of optic nerve head damage occurs in the context of many other clinical measures such as visual field tests and intraocular pressure. However, these can prove challenging in children, as measurement of visual fields shows poor reliability in those younger than eight, and nerve visualization and intra-ocular pressure measurement can be hampered by patient movement and lid squeezing, particularly when children are experiencing other neurodevelopmental problems.\u003csup\u003e6\u003c/sup\u003e While optical coherence tomography (OCT) aids diagnosis and monitoring, paediatric versions aren't universally accessible, sustaining the use of cup-to-disc ratio (CDR) and retinal photography globally. In practice, children with cupped or small optic discs often present a clinical dilemma.\u003csup\u003e7\u003c/sup\u003e Enhanced understanding of optic disc parameters in infants and children is crucial for diagnosing and monitoring ophthalmic and neurological diseases, minimizing unnecessary referrals and investigations, while emphasizing early detection to optimize visual, academic, and social outcomes.\u003c/p\u003e \u003cp\u003eThis study employs fundus photography-derived optic disc data from a substantial cohort to explore optic disc parameter distributions (CDAR and CF/DD) in children, gauging the prevalence of paediatric cupped or small discs and their associations with maternal and environmental factors.\u003c/p\u003e"},{"header":"Subjects and methods","content":"\u003cp\u003eWe conducted an analysis of digital retinal photography data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based cohort study.\u003csup\u003e8,9\u003c/sup\u003e Pregnant women residing in Avon, UK, with expected delivery dates between April 1, 1991, and December 31, 1992, were invited to participate. Initially, 14,541 pregnancies were enrolled, resulting in 13,988 children alive at one year of age. For analyses after the age of seven, the total sample size was 15,447 pregnancies, with 14,901 children alive at one year of age.\u003csup\u003e8,9\u003c/sup\u003e Data on early-life and maternal exposures were collected through self-completion questionnaires, obstetric medical notes, observation, clinical examination, and biological samples. The study website contains details of the data through a searchable data dictionary and variable search tool.\u003csup\u003e10\u003c/sup\u003e Not all participants with retinal photographs completed all ALSPAC clinics and questionnaires and so varying numbers of participants had data for each exposure.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRetinal photographs were taken at 12 years of age using a non-mydriatic Topcon camera. Attendees for retinal imaging were compared to non-attendees. Optic nerve images were graded monoscopically using semi-automated software by trained graders, who were blinded to clinical information.\u003csup\u003e11\u003c/sup\u003e The cup-to-disc area ratio (CDAR) and the cup-to-fovea over disc diameter (CF/DD) were automatically generated after manual placement of dots around the cup perimeter and on the fovea, respectively (see Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeven technicians graded the images, requiring consideration of systematic differences in measurements due to grader identity.\u0026nbsp;After training, an agreement exercise was performed on a subset of unique and repeat images representing a range of grading ease and disc parameters. Grader 3 did not complete the agreement exercise and so could not be included. \u0026nbsp;The two-way random effects, absolute agreement, multiple intraclass correlation coefficient (ICC, (2,\u003cem\u003e\u0026nbsp;k\u003c/em\u003e)) with 95% confidence intervals was used to determine the variability between graders when grading the same image.\u003c/p\u003e\n\u003cp\u003eBland-Altman plots and analyses of variance (ANOVA) were used to compare graders to a reference standard (the lead optometrist for the glaucoma-shared care service). Tukey\u0026rsquo;s procedure was applied to pairwise comparisons. The label \u0026ldquo;Grader 8\u0026rdquo; was used where grader identify could not be ascertained (n=31).\u003c/p\u003e\n\u003cp\u003eTo mitigate confounding and reduce the standard error of estimates, covariates hypothesized to be associated with either CDAR and disc cupping or CF/DD and optic nerve hypoplasia were identified from literature and expert discussions. Table 1 gives details of the measurement of outcome, exposure, and confounder variables.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData cleaning and analyses were conducted using Stata version 13. The second delivered twin was excluded from analyses of multiple births. Outcome data were analysed as ratios based on unit differences. Left and right eyes were compared, and right eyes were used in subsequent analyses. The distribution of optic disc parameters was described using means, medians, and ranges. Maternal and child-related factors hypothesized to be associated with CDAR or with a small optic nerve head in the extreme phenotype of optic nerve hypoplasia were explored using stratification, chi-squared tests, and regression models incorporating inverse probability weighting to mitigate bias from missing data. The weighting model used logistic regression to relate case completeness to baseline variables: maternal age, gestation, sex, maternal smoking, and parity and was used to estimate the probability of being a complete case for each person.\u003c/p\u003e\n\u003cp\u003eTable 1: Variable categories and measurement\u003c/p\u003e\n\u003cp\u003eTABLE 1 HERE\u003c/p\u003e\n\u003ch2\u003ePower calculation\u003c/h2\u003e\n\u003cp\u003eA subset of 1 250 ALSPAC photographs had previously been used to calculate a mean CDAR of 0.3 (SD 0.08). Analysis of approximately 3 300 images had 80% power with a significance of 0.05 to detect a minimum difference in means of 0.01 in CDAR for exposures affecting 15% of participants (e.g., maternal smoking) and a difference in means of 0.014 for exposures affecting 5% of ALSPAC participants (e.g., preterm birth).\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003eAttendees versus non-attendees\u003c/h2\u003e\n\u003cp\u003eFigure 2\u0026nbsp;is a flow diagram of participants. We compared individuals attending retinal photography and achieving gradable images with those who didn\u0026apos;t. Children with photographs were more likely to be white, female, term-born, with normal birth weight, and have highly educated, non-smoking, older mothers (see supplementary Table 1: Socio-demographic characteristics, birth outcomes, and visual outcomes of participants attending and included in the analysis versus non-attending children). Both groups exhibited rare poor visual acuity and maternal heavy drinking.\u003c/p\u003e\n\u003cp\u003eFigure 2: ALSPAC participants.\u003c/p\u003e\n\u003cp\u003eFIGURE 2 HERE\u003c/p\u003e\n\u003ch2\u003eSample description\u003c/h2\u003e\n\u003cp\u003eA gradable retinal image was obtained from 3 327 individuals, averaging 12.9 years old (SD 0.27, range 11 to 14 years). Females constituted just over half (50.7%), with 96.0% reporting white ethnicity, 95.5% born at term, and 95.8% with normal birth weight. Approximately 17.3% were born to mothers who smoked in the first trimester. Instances of heavy drinking during pregnancy (0.7%) and mothers over forty years old (1.5%) were rare.\u003c/p\u003e\n\u003ch2\u003eRater agreement\u003c/h2\u003e\n\u003cp\u003eInter-grader agreement was good for CDAR (ICC (95%CI) 0.74 (0.62, 0.84)) and moderate for CF/DD (ICC (95%CI) 0.57 (0.42, 0.72)). Repeatability was good for both CDAR (ICC (95%CI) 0.77 (0.59, 0.89)) and CF/DD (ICC (95% CI) 0.78 (0.61, 0.89)). Tukey post hoc test and ANOVA revealed slight underestimation of optic disc parameters by graders, particularly for larger measurements, compared to the reference standard.\u003c/p\u003e\n\u003ch2\u003eDistribution of optic disc parameters\u003c/h2\u003e\n\u003ch3\u003eCup-to-disc area ratio.\u003c/h3\u003e\n\u003cp\u003eCDAR measures were collected from 3 288 children. Among those with gradable images in both eyes (n=3,078) CDAR was similar in 99.5%: 92% showed \u0026le;0.1 difference between eyes, 8% \u0026gt;0.1 but \u0026lt;0.2, and 0.5% \u0026ge;0.2.\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMean (standard deviation (SD)) CDAR was 0.21 (0.09), median 0.20 and range 0.05 to 0.55. Mode CDAR was 0.15 (n=842). CDAR distribution was right skewed (see Figure 3). Male and female mean (sd) CDARs were comparable: 0.21 (0.1) and 0.20 (0.1) respectively. Large CDAR (\u0026gt; 0.3) prevalence was 11% (n=367).\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eCup-to-fovea over disc diameter.\u003c/h3\u003e\n\u003cp\u003eCF/DD measurements were obtained from 3 327 children. Mean (SD) CF/DD was 2.48 (0.36), median 2.45 and range 1.33 to 6.06. Mode CF/DD was 2.49 (n=65). CF/DD followed a normal distribution (see Figure 3). Male and female CF/DD were comparable: 2.48 (0.4) and 2.47 (0.4) respectively. Small optic disc (CF/DD \u0026gt;3) prevalence was 6% (n=212) with one third bilateral (n=75).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFigure 3: Histogram of (a) CDAR and (b) CF/DD distribution in the ALSPAC.\u003c/p\u003e\n\u003cp\u003eFIGURE 3 HERE\u003c/p\u003e\n\u003ch2\u003eRelationship with exposures\u003c/h2\u003e\n\u003cp\u003eTable 2 presents uni- and multi-variable logistic regression models for (a) CDAR \u0026gt;0.3 and (b) CF/DD \u0026gt;3 against each predetermined exposure.\u003c/p\u003e\n\u003cp\u003eTable 2: Univariable and multivariable logistic regressions for (a) large CDAR and (b) large CF/DD (small OD) against predetermined exposures\u003c/p\u003e\n\u003cp\u003eTABLE 2 HERE\u003c/p\u003e\n\u003ch3\u003eCDAR\u003c/h3\u003e\n\u003cp\u003eThe odds of a cupped disc were comparable across groups for birth weight, maternal smoking, and head circumference at birth. Severely premature children born before 32 weeks\u0026rsquo; gestation had 28 times higher odds of disc cupping at age twelve (partially adjusted odds ratio (paOR) (95% confidence interval (CI)) 28 (4.62, 172) p=\u0026lt;0.001). Numbers were insufficient to run the fully adjusted model. Children with a low BMI at age eleven had three times higher odds of disc cupping (adjusted odds ratio (aOR) 2.87 (1.13, 7.27) p=0.03).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA cupped disc was identified in over a quarter (26%) of children born before 32 weeks (n=6) compared to just 8% of moderately preterm (n=9) and 11% of term children (n=339) with evidence of a difference between groups (, p=0.012).\u003c/p\u003e\n\u003ch3\u003eCF/DD\u003c/h3\u003e\n\u003cp\u003eThe odds of a small disc were comparable across groups for birth weight, large head circumference, maternal alcohol, preterm birth, weight loss in trimester one, maternal age, and parity. Children with a small head circumference at birth had more than twice the odds of a small optic disc at age twelve (aOR 2.49 (1.37, 4.51) p=\u0026lt;0.001). A small optic disc was found in 7% (n=25) of those born with a small head circumference, 6% (n=52) with a large circumference and 4% (n=75) with a normal circumference (p=0.009).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChildren born to mothers who smoked in pregnancy also had increased odds of a small disc (aOR 1.69 (1.01, 2.84, p=0.04). There was a lack of association with some exposures hypothesized to cause the extreme phenotype of optic nerve hypoplasia: first trimester weight loss (aOR 0.66 (0.20,2.10)), maternal age (aOR 0.9 (0.19,4.29) p=0.89) and parity (aOR 1.12 (0.75,1.67) p=0.58).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eStrengths and limitations\u003c/p\u003e \u003cp\u003eThe ALSPAC study provides rich life course data for many participants across a geographic region, offering sufficient power to investigate rare exposures, though some adjusted analyses may have limited power. However, the lack of representation from ethnic minorities and less affluent families may restrict the generalisability of findings.\u003csup\u003e8\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSelf-reported data such as smoking or alcohol intake are susceptible to misreporting, potentially biasing associations towards null values. Observer variability and measurement errors may affect physical measures, despite training and protocols.\u003c/p\u003e \u003cp\u003eRetinal photography, while widely used in clinical practice, faces challenges in optic disc measurement due to landmark identification and magnification error, mitigated by using dimensionless ratios like CDAR. Retinal photography and OCT have been demonstrated to yield comparable results with relative measures, though absolute measures may be around 10% smaller using photography.\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMonoscopic software usage may underestimate CDAR compared to stereoscopic methods, reducing cupping prevalence estimations.\u003csup\u003e11\u003c/sup\u003e Although graders tended to underestimate parameters, their reasonable agreement questions the necessity of a reference standard with inherent errors. A priori analysis protocols aimed to minimize bias. Residual confounding from unmeasured exposures remains possible.\u003c/p\u003e \u003cp\u003eInterpretation\u003c/p\u003e \u003cp\u003eThe average 12-year-old child typically exhibits a CDAR of around 0.2, regardless of gender, similar to findings in Australian six-year-olds.\u003csup\u003e13\u003c/sup\u003e While a cup-to-disc ratio\u0026thinsp;\u0026gt;\u0026thinsp;0.2 has been reported to occur in fewer than 1% of children our study shows a prevalence of CDAR\u0026thinsp;\u0026gt;\u0026thinsp;0.3 in 11% of participants, suggesting a potential need to reassess the clinical implications of CDAR thresholds.\u003csup\u003e14\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSimilarly, the mean cup-to-fovea over disc diameter (CF/DD) in our cohort was 2.48, with 6% of children exhibiting CF/DD\u0026thinsp;\u0026gt;\u0026thinsp;3.0, questioning the appropriateness of this threshold for diagnosing optic nerve hypoplasia.\u003csup\u003e2,3\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRegarding interocular differences, only 0.5% of children in our study showed asymmetry\u0026thinsp;\u0026gt;\u0026thinsp;0.2, highlighting how rare pathological asymmetry is according to proposed thresholds of \u0026gt;\u0026thinsp;0.25.\u003csup\u003e15\u003c/sup\u003e Further exploration of asymmetry's clinical significance in childhood is warranted to establish appropriate abnormal interocular difference levels.\u003c/p\u003e \u003cp\u003eA small head circumference below the 9th percentile was associated with a small optic disc. It is unlikely that this is a proportional phenomenon given that CF/DD is a ratio, and large optic discs were not seen in those with large head circumference. One study reported smaller disc diameter in Australian children with small head circumference, which was associated with larger cup-to-disc ratio.\u003csup\u003e16\u003c/sup\u003e Small head circumference has been reported to be associated with neurodevelopmental abnormalities such as attention deficit, which, in turn, has been associated with subtle morphological changes in the optic nerve.\u003csup\u003e17,18\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBeing underweight at age 11 was associated with disc cupping independent of maternal BMI, aligning with adult studies associating low BMI with smaller neuro-retinal rim area and larger vertical and area cup-to-disc ratios.\u003csup\u003e19,20\u003c/sup\u003e Nutritional deficiencies may mediate this association, given the optic nerve's vulnerability to deficiencies like B vitamins, folic acid, and proteins containing sulphur-containing amino acids.\u003csup\u003e21\u003c/sup\u003e In later life, glaucoma development has been linked with low vitamin A and vegetable fat intake.\u003csup\u003e22\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMaternal smoking is a significant factor associated with small optic discs, likely due to its impact on foetal development and neuro-ophthalmic complications. Potential mechanisms include reduced placental blood flow through nicotine-induced vasoconstriction; foetal hypoxia from carbon monoxide binding to haemoglobin; vascular neogenesis; and endothelial function disturbance.\u003csup\u003e23\u003c/sup\u003e Additionally, direct toxic, ischaemic, or hypoxic effects on cell proliferation or migration during critical periods may contribute.\u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eStudies of premature infants reported high mean CDAR and high prevalence of cupped discs, possibly influenced by factors precipitating preterm birth or immaturity-associated morbidity.\u003csup\u003e24\u003c/sup\u003e Immature apoptotic pruning of supernumerary fibres and extra-uterine environmental influences like oxygen delivery and carbon dioxide tension may cause excessive elimination of axons.\u003csup\u003e24\u003c/sup\u003e Persistence of cupping in older preterm children suggests limited catch up growth. Disentangling effects of gestational age from factors like low birth weight, ROP, cerebral injury, and early life events is challenging. Cupped appearance in white matter injury may stem from axonal interruption via retrograde trans-synaptic degeneration, akin to optic nerve hypoplasia, with the differing appearance due to the timing of the insult.\u003csup\u003e24,25\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSome exposures hypothesized to cause the extreme phenotype of optic nerve hypoplasia, like maternal age and parity, showed a lack of evidence of association.\u003c/p\u003e \u003cp\u003eImplications and future work\u003c/p\u003e \u003cp\u003eThis study contributes to a field primarily composed of small-scale investigations. We reveal that cupped and small optic discs may be more prevalent in children than previously believed. Therefore, it is crucial to scrutinize the clinical characteristics of children presenting with what is typically considered a cupped disc to ascertain whether these features are being overly referred, pathologized, or monitored.\u003c/p\u003e \u003cp\u003eThe long-term prognosis of preterm cupped discs remains uncertain. While a larger cup-to-disc ratio in adulthood is linked to a higher risk of glaucomatous optic neuropathy and associations have been reported between optic disc morphology and systemic neuro- and cardiovascular development in adults\u003csup\u003e26\u003c/sup\u003e, the significance of cupped discs in preterm children as a form of optic nerve hypoplasia remains unclear. Further research is needed to elucidate the relationship between visual acuity and disc size.\u003c/p\u003e \u003cp\u003eAdditionally, the association between small discs and head circumference raises questions about the need for further assessment in infants with smaller heads but not microcephaly. Work is needed to understand the relationship between timing and coordination of craniofacial growth and the morphology of optic fidelity.\u003c/p\u003e \u003cp\u003eFinally, addressing maternal smoking, a preventable risk factor, is essential to combat health disparities among socioeconomic groups.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eRetinal imaging of 3 000 12-year-olds revealed a mean cup-to-disc area ratio of 0.21 and mean CF/DD of 2.48, consistent across sexes. Cupping affected 11%, linked to preterm birth and low BMI. A small optic disc, found in 6% (one third bilateral), correlated with maternal smoking and small head circumference. These findings suggest the prevalence of cupped and small discs in children may be higher than previously thought. Optic nerve development may relate to extra-ocular growth and early-life factors, with distinct parameters in preterm children versus full-term counterparts.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eWe are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe extend particular thanks to Professor James Morgan who provided the original software for measurement of the optic nerve parameters on the photographs and to the Bristol Eye Hospital imaging team, in particular Abi Loos who organized the schedule for imagers to grade the ALPSAC photographs.\u003c/p\u003e\n\u003ch2\u003eConflict of interest and ethical statement\u003c/h2\u003e\n\u003cp\u003eThe authors do not have any competing financial interest in relation to the work described.\u003c/p\u003e\n\u003cp\u003eEthical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLocal Research Ethics Committees (see http://www.bristol.ac.uk/alspac/researchers/research-ethics/). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eFunding\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Dr Williams will serve as guarantor for the contents of this paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDr Creavin completed this work as part of a National Institute for Health Research (NIHR) doctoral research fellowship (DRF-2015-08-018). Dr Williams was funded by an NIHR senior research fellowship (SRF_2015_08_005). Professor Tilling, Dr Timpson and Dr Creavin worked as part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is funded by the MRC grant code: MC_UU_12013/3. This article/paper/report presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKhalil HE-DM, Saif MYS, El-Khalek MOA, et al. Variations of Cup-to-Disc Ratio in Age Group (18\u0026ndash;40) Years Old. \u003cem\u003eResearch in Ophthalmology\u003c/em\u003e 2013; 2: 4\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eAlvarez E, Wakakura M, Khan Z, et al. The disc-macula distance to disc diameter ratio: a new test for confirming optic nerve hypoplasia in young children. \u003cem\u003eJ Pediatr Ophthalmol Strabismus\u003c/em\u003e; 25: 151\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eZeki SM, Dudgeon J, Dutton GN. Reappraisal of the ratio of disc to macula/disc diameter in optic nerve hypoplasia. \u003cem\u003eBr J Ophthalmol\u003c/em\u003e 1991; 75: 538\u0026ndash;41.\u003c/li\u003e\n\u003cli\u003eDutton GN. Congenital disorders of the optic nerve: excavations and hypoplasia. \u003cem\u003eEye (Lond)\u003c/em\u003e 2004; 18: 1038\u0026ndash;48.\u003c/li\u003e\n\u003cli\u003eGarcia-Filion P, Borchert M. Prenatal determinants of optic nerve hypoplasia: review of suggested correlates and future focus. \u003cem\u003eSurv Ophthalmol\u003c/em\u003e; 58: 610\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eAkar Y, Yilmaz A, Yucel I. Assessment of an effective visual field testing strategy for a normal pediatric population. \u003cem\u003eOphthalmologica\u003c/em\u003e 2008; 222: 329\u0026ndash;33.\u003c/li\u003e\n\u003cli\u003ePark H-YL, Ha MJ, Shin SY. The effect of parental factors in children with large cup-to-disc ratios. \u003cem\u003ePLoS One\u003c/em\u003e 2017; 12: e0175900.\u003c/li\u003e\n\u003cli\u003eBoyd A, Golding J, Macleod J, et al. Cohort Profile: the \u0026rsquo;children of the 90s\u0026rsquo;--the index offspring of the Avon Longitudinal Study of Parents and Children. \u003cem\u003eInt J Epidemiol\u003c/em\u003e 2013; 42: 111\u0026ndash;27.\u003c/li\u003e\n\u003cli\u003eFraser A, Macdonald-Wallis C, Tilling K, et al. Cohort Profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort. \u003cem\u003eInt J Epidemiol\u003c/em\u003e 2013; 42: 97\u0026ndash;110.\u003c/li\u003e\n\u003cli\u003eBristol University. ALSPAC Data Tool, http://www.bristol.ac.uk/alspac/researchers/our-data/ (accessed 29 September 2020).\u003c/li\u003e\n\u003cli\u003eMorgan JE, Sheen NJL, North R V, et al. Digital imaging of the optic nerve head: monoscopic and stereoscopic analysis. \u003cem\u003eBr J Ophthalmol\u003c/em\u003e 2005; 89: 879\u0026ndash;84.\u003c/li\u003e\n\u003cli\u003eSamarawickrama C, Hong T, Jonas JB, et al. Measurement of normal optic nerve head parameters. \u003cem\u003eSurv Ophthalmol\u003c/em\u003e; 57: 317\u0026ndash;36.\u003c/li\u003e\n\u003cli\u003eSamarawickrama C, Pai A, Tariq Y, et al. Characteristics and appearance of the normal optic nerve head in 6-year-old children. \u003cem\u003eBr J Ophthalmol\u003c/em\u003e 2012; 96: 68\u0026ndash;72.\u003c/li\u003e\n\u003cli\u003eLiesegang TJ, Skuta GL, Cantour LB. Seciton 10 Glaucoma: Chap. 3 clinical evaluation. In: \u003cem\u003eBasic and clinical science course\u003c/em\u003e. 2008, pp. 51\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003eAltemir I, Oros D, El\u0026iacute;a N, et al. Retinal asymmetry in children measured with optical coherence tomography. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e 2013; 156: 1238\u0026ndash;1243.e1.\u003c/li\u003e\n\u003cli\u003eSamarawickrama C, Huynh SC, Liew G, et al. Birth weight and optic nerve head parameters. \u003cem\u003eOphthalmology\u003c/em\u003e 2009; 116: 1112\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eMurray E, Pearson R, Fernandes M, et al. Are fetal growth impairment and preterm birth causally related to child attention problems and ADHD? Evidence from a comparison between high-income and middle-income cohorts. \u003cem\u003eJ Epidemiol Community Health (1978)\u003c/em\u003e 2016; 70: 704\u0026ndash;709.\u003c/li\u003e\n\u003cli\u003eGr\u0026ouml;nlund MA, Aring E, Landgren M, et al. Visual function and ocular features in children and adolescents with attention deficit hyperactivity disorder, with and without treatment with stimulants. \u003cem\u003eEye\u003c/em\u003e 2007; 21: 494\u0026ndash;502.\u003c/li\u003e\n\u003cli\u003eZheng Y, Cheung CYL, Wong TY, et al. Influence of height, weight, and body mass index on optic disc parameters. \u003cem\u003eInvest Ophthalmol Vis Sci\u003c/em\u003e 2010; 51: 2998.\u003c/li\u003e\n\u003cli\u003eKim YJ, Kim JM, Shim SH, et al. Associations between Optic Cup-to-disc Ratio and Systemic Factors in the Healthy Korean Population. \u003cem\u003eKorean Journal of Ophthalmology\u003c/em\u003e 2015; 29: 336.\u003c/li\u003e\n\u003cli\u003eGrzybowski A, Z\u0026uuml;lsdorff M, Wilhelm H, et al. Toxic optic neuropathies: an updated review. \u003cem\u003eActa Ophthalmol\u003c/em\u003e 2015; 93: 402\u0026ndash;410.\u003c/li\u003e\n\u003cli\u003eYoserizal M, Hirooka K, Yoneda M, et al. Associations of nutrient intakes with glaucoma among Japanese Americans. \u003cem\u003eMedicine\u003c/em\u003e 2019; 98: e18314.\u003c/li\u003e\n\u003cli\u003eHackshaw A, Rodeck C, Boniface S. Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls. \u003cem\u003eHum Reprod Update\u003c/em\u003e 2011; 17: 589\u0026ndash;604.\u003c/li\u003e\n\u003cli\u003eHellstr\u0026ouml;m A, H\u0026aring;rd AL, Svensson E, et al. Ocular fundus abnormalities in children born before 29 weeks of gestation: a population-based study. \u003cem\u003eEye (Lond)\u003c/em\u003e 2000; 14 ( Pt 3A: 324\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eJacobson L. Optic disc morphology may reveal timing of insult in children with periventricular leucomalacia and/or periventricular haemorrhage. \u003cem\u003eBritish Journal of Ophthalmology\u003c/em\u003e 2003; 87: 1345\u0026ndash;1349.\u003c/li\u003e\n\u003cli\u003eWagner SK, Bountziouka V, Hysi P, et al. Associations between unilateral amblyopia in childhood and cardiometabolic disorders in adult life: a cross-sectional and longitudinal analysis of the UK Biobank. \u003cem\u003eEClinicalMedicine\u003c/em\u003e 2024; 70: 102493.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1-2 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4322862/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4322862/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe aimed to investigate the distribution of cupped and small optic discs in children and to examine associations with maternal and environmental factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRetinal photographs were graded from over 3000 12-year-olds in the Avon Longitudinal Study of Parents and Children. \u0026nbsp;Regression models examined associations between disc parameters and maternal and early-life exposures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMean cup-to-disc area ratio (CDAR) for 3288 children was 0.21 (95%CI 0.20,0.21). \u0026nbsp;Cupped discs (CDAR \u0026gt;0.3) were present in 11%. \u0026nbsp;The odds of disc cupping were increased nearly three-fold in underweight children (adjusted odds ratio (aOR) 2.9 (1.1, 7.3) p=0.03) and 28-fold in severely premature (\u0026lt;28 weeks) children (paOR 28 95%CI 4.6,172, p\u0026lt;0.001) with nearly one in four children affected.\u003c/p\u003e\n\u003cp\u003eMean cup-to-fovea/disc diameter (CF/DD) for\u003cstrong\u003e \u003c/strong\u003e3327 children was 2.48 (95%CI 2.47,2.50). Small discs (CF/DD \u0026gt;3) were present in 6% of which a third were bilateral. \u0026nbsp;The odds of a small disc were increased in the offspring of mothers who smoked in pregnancy (aOR 1.7 (1.0,2.8) p=0.04) and more than doubled in children born with a small head circumference (aOR 2.5 (1.4,4.5) p\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCupped and small optic discs are more frequent than usually supposed at age 12. \u0026nbsp;The odds of disc cupping are increased by severe prematurity and pathologically low BMI. The odds of a small disc are increased by maternal smoking and small head circumference. Optimisation of risk factors in pregnancy and delivery and early childhood nutrition may play an important role in ophthalmic neurodevelopment and thus have a lifelong impact on ocular health.\u003c/p\u003e","manuscriptTitle":"Optic disc parameters and associations with early life exposures in over 3 000 12-year-old children: findings from the ALSPAC cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-28 18:01:25","doi":"10.21203/rs.3.rs-4322862/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-09-30T08:00:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-08-27T04:03:47+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-08-13T09:09:00+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-07-30T10:06:48+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-07-19T13:52:05+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-05-13T06:52:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-09T14:49:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-25T09:18:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Eye","date":"2024-04-25T08:53:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c216c419-bb0c-4121-ae02-7c32d5582816","owner":[],"postedDate":"May 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":31833003,"name":"Health sciences/Risk factors"},{"id":31833004,"name":"Health sciences/Biomarkers/Predictive markers"}],"tags":[],"updatedAt":"2025-02-23T08:06:56+00:00","versionOfRecord":{"articleIdentity":"rs-4322862","link":"https://doi.org/10.1038/s41433-025-03716-2","journal":{"identity":"eye","isVorOnly":false,"title":"Eye"},"publishedOn":"2025-02-22 05:00:00","publishedOnDateReadable":"February 22nd, 2025"},"versionCreatedAt":"2024-05-28 18:01:25","video":"","vorDoi":"10.1038/s41433-025-03716-2","vorDoiUrl":"https://doi.org/10.1038/s41433-025-03716-2","workflowStages":[]},"version":"v1","identity":"rs-4322862","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4322862","identity":"rs-4322862","version":["v1"]},"buildId":"cTy_lsJlmDsVRNrSptgXS","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}