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Journal ArticleDOI

Epidemiology of blindness in children.

01 Sep 2017-Archives of Disease in Childhood (BMJ)-Vol. 102, Iss: 9, pp 853-857
TL;DR: For children in higher income countries, cerebral visual impairment and optic nerve anomalies remain the most common causes of SVI/BL, while retinopathy of prematurity (ROP) and cataract are now the most avoidable causes.
Abstract: An estimated 1.4 million of the world's children are blind. A blind child is more likely to live in socioeconomic deprivation, to be more frequently hospitalised during childhood and to die in childhood than a child not living with blindness. This update of a previous review on childhood visual impairment focuses on emerging therapies for children with severe visual disability (severe visual impairment and blindness or SVI/BL).For children in higher income countries, cerebral visual impairment and optic nerve anomalies remain the most common causes of SVI/BL, while retinopathy of prematurity (ROP) and cataract are now the most common avoidable causes. The constellation of causes of childhood blindness in lower income settings is shifting from infective and nutritional corneal opacities and congenital anomalies to more resemble the patterns seen in higher income settings. Improvements in maternal and neonatal health and investment in and maintenance of national ophthalmic care infrastructure are the key to reducing the burden of avoidable blindness. New therapeutic targets are emerging for childhood visual disorders, although the safety and efficacy of novel therapies for diseases such as ROP or retinal dystrophies are not yet clear. Population-based epidemiological research, particularly on cerebral visual impairment and optic nerve hypoplasia, is needed in order to improve understanding of risk factors and to inform and support the development of novel therapies for disorders currently considered 'untreatable'.

Summary (3 min read)

Introduction

  • An estimated 1.4 million of the world’s children are blind.
  • 1 4 5 The differential between the blind and non-blind child is more pronounced in developing nations: whilst 10% of UK children die in the first year following the diagnosis of blindness, in lower income countries the equivalent mortality is 60%.
  • This article updates their previous review on childhood visual impairment,6 by summarising new evidence on the global epidemiology of, and the emerging therapies for, severe visual impairment and blindness (or SVI/BL, table 1.
  • The evidence base regarding children is inconclusive.
  • Moderate visual impairment (table 1) may impact on educational opportunities, with half of the UK’s moderately visually impaired children educated within specialised schools for children with physical or learning deficits.

Defining blindness

  • The 1972 WHO taxonomy still forms the basis of the International Classification for Disease (ICD) definition (table 1) of blindness.9.
  • As age and cognition may be obstacles to quantification of a child’s acuity level, childhood severe visual impairment (SVI) and blindness (BL) are often categorised together (SVI/BL).
  • 16 17 Children may also fail to present to health care services because families do not recognise that there is a problem,18 or because access to health care for children is limited by their carer’s own blindness.
  • KI methods enable researchers to capture a more representative study population, but are still likely to underestimate the true burden.
  • The review will now summarise key developments in the epidemiology and management of the most important causes of childhood severe visual impairment / blindness (table 2), i.e. those which are responsible for the highest proportion of affected children globally, and those which carry the highest burden of avoidable blindness.

Retinopathy of prematurity (ROP)

  • ROP develops when the vasoconstrictive response to hyperoxia, i.e. the immature retina of the eyes of premature children, is followed by a vasoproliferative phase which is driven by the surge in endothelial growth factors (EGFs) on the return to normal oxygenation.
  • Approximately 170,000 preterm babies worldwide developed some degree of ROP in 2010, and 54,000 required treatment for potentially blinding severe disease, but only an estimated 42% of these babies received this treatment.
  • This finding, consistent with others from low/middle-income countries demonstrates the power of epidemiology in determining setting-specific policy and practice.
  • The required infrastructure can be a challenge in higher income settings, where approximately 55 infants are examined for every infant treated.

Cataract

  • Cataract related to prenatal rubella infection is still an issue globally, for example accounting for 20% of childhood cataract in the Phillipines.45.
  • For the majority of affected children with bilateral cataract (and therefore at risk of blindness), aetiology is unknown, and prevention of blindness is focused on the prompt detection and treatment of visually significant lens opacity before deprivation amblyopia becomes intractable.
  • The Chinese Childhood Cataract Program , established with the support of the V2020 programme, resulted in earlier diagnosis of cases of congenital / infantile cataract, and an apparent increase in prevalence of childhood cataract, as a result of improved case detection in remote regions.
  • There are still many obstacles to prompt treatment for affected children.
  • In several countries patients need to supplement health costs, putting treatment beyond the means of many families.

Corneal opacity

  • Corneal opacity secondary to vitamin A deficiency (VAD), infection or toxicity from traditional remedies, remains the most common cause of childhood severe visual impairment / blindness in Sub-Saharan Africa and areas of extreme deprivation,1 despite recent V2020 programmes on nutritional supplementation, measles and rubella vaccination and health education.
  • Childhood corneal transplants have a high failure rate, due to rejection, new scar formation, or infection.
  • The advent of hypothermia (head cooling or whole body cooling) as a therapy for HIE within the ‘golden window’ has resulted in modest improvements in neurodevelopmental outcomes.

Optic nerve anomalies

  • Anterior visual pathway disorders are responsible for almost a quarter of childhood SVI/BL in some higher income settings, and optic nerve hypoplasia (ONH), is the commonest single cause of severe visual impairment / blindness in industrialised nations.
  • In most cases the cause is unknown, but ONH is independently associated with younger maternal age and nulliparity.
  • 56-58 59 ONH is a clinical diagnosis based on the appearance of the optic nerve, and the absence of a standardised clinical phenotype for the classification of hypoplasia limits epidemiological research.
  • There is evidence of the relatively frequent co-existence of ONH and CVI, but the aetiological or clinical significance of this is unclear.
  • Hand-held optical coherence tomography devices, which are non-contact diagnostic tools able to produce biomicroscopical images of the paediatric eye, are an emerging technology which may be able to aid the classification of paediatric optic nerve disease.

Inherited retinal disorders

  • Photoreceptor dystrophies are the most common inherited retinal disorders amongst children with SVI/BL.5 61 These constitute the global photoreceptor dystrophy of Leber’s amarosis (LCA), dystrophies affecting rod photoreceptors more than cones (the retinitis pigmentosas), and the cone dystrophies.
  • The RPE65 gene, mutations of which cause LCA type 2 and retinitis pigmentosa, has been a target for gene therapies.
  • Following intraretinal injection of adenoviral delivered copies of functioning RPE65, children with LCA2 initially had improved visual function.
  • This improvement was not maintained in follow up studies, due to degeneration of treated retina.
  • 62 Further human trials of genetic therapeutics are underway.

Summary

  • Childhood visual impairment and blindness remains an important public health issue, and alongside local or disease specific successes, there has been an emergence, or re-emergence, of other causes of early onset visual impairment, particularly retinopathy of prematurity (in middle income settings) and cerebral visual impairment (within higher income settings).
  • Solebo AL, Rahi J. Epidemiology, aetiology and management of visual impairment in children.

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ADC review Epi Blindness
Title page:
Epidemiology of childhood blindness
Authors: Ameenat Lola Solebo
1,2,3,4
, Lucinda Teoh
1
,Jugnoo S Rahi
1,2,3,4
1. Lifecourse Epidemiology and Biostatistics Section, Population, Policy and
Practice Programme, Institute of Child Health University College London, 30 Guilford
Street, London, WC1N 1EH, UK
2. Great Ormond Street Hospital / Institute of Child Heath NIHR Biomedical
Research Centre, London, UK
3. Moorfields Eye Hospital and Institute of Ophthalmology NIHR Biomedical
Research Centre, London, UK
4. Ulverscroft Vision Research Group, London, UK
Corresponding Author (and address for reprints)
Professor J S Rahi
Lifecourse Epidemiology and Biostatistics Section, Population, Policy and Practice
Programme
University College London Institute of Child Health, 30 Guilford Street, London,
WC1N 1EH, UK
Email: j.rahi@ucl.ac.uk
Phone: +44 (0)20 7905 2250
Fax: +44 (0) 20 7905 3258
Financial Support:
This work was undertaken at UCL Institute of Child Health / Great Ormond Street
Hospital for children which received a proportion of funding from the Department of
Health’s NIHR Biomedical Research Centres funding scheme. Lola Solebo is
funded, and Jugnoo Rahi is supported in part by the National Institute for Health
Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital
NHS Foundation Trust and UCL Institute of Ophthalmology. Lucinda Teoh is
supported by a Fight for Sight grant. The views expressed are those of the author(s)
and not necessarily those of the funders, the NHS, the NIHR or the Department of
Health.
The funding organizations had no role in the design or conduct of this research.
No conflicting relationship exists for any author.
Key terms: Blindness; Vision disorders; Epidemiology
Word count: 3256

ADC review Epi Blindness
Abstract
An estimated 1.4 million of the world’s children are blind. A blind child is more likely
to live in socioeconomic deprivation, to be more frequently hospitalized during
childhood, and to die in childhood than a child not living with blindness. This update
of a previous review on childhood visual impairment focuses on emerging therapies
for children with severe visual disability (severe visual impairment and blindness or
SVI/BL).
For children in higher income countries, cerebral visual impairment and optic nerve
anomalies remain the most common causes of SVI/BL, whilst ROP and cataract are
now the most common avoidable causes. The constellation of causes of childhood
blindness in lower income settings is shifting from infective and nutritional corneal
opacities, and congenital anomalies, to more resemble the patterns seen in higher
income settings. Improvements in maternal and neonatal health, and investment in
and maintenance of national ophthalmic care infrastructure is key to reducing the
burden of avoidable blindness. New therapeutic targets are emerging for childhood
visual disorders, although the safety and efficacy of novel therapies for diseases
such as retinopathy of prematurity or retinal dystrophies are not yet clear. Population
based epidemiological research, particularly on cerebral visual impairment and optic
nerve hypoplasia, is needed in order to improve understanding of risk factors, and to
inform and support the development of novel therapies for disorders currently
considered ‘untreatable’.

ADC review Epi Blindness
Introduction
An estimated 1.4 million of the world’s children are blind.
1
A blind child is more likely
to live in socioeconomic deprivation,
1-3
to have delayed or disordered development,
to be more frequently hospitalized during childhood and to die in childhood than a
child not living with blindness.
1 4 5
The differential between the blind and non-blind
child is more pronounced in developing nations: whilst 10% of UK children die in the
first year following the diagnosis of blindness, in lower income countries the
equivalent mortality is 60%.
2
This article updates our previous review on childhood visual impairment,
6
by
summarising new evidence on the global epidemiology of, and the emerging
therapies for, severe visual impairment and blindness (or SVI/BL, table 1. It is now
recognised that in adults even mild visual impairment is associated with lower
socioeconomic status and poorer general and mental health status.
7
The evidence
base regarding children is inconclusive. Moderate visual impairment (table 1) may
impact on educational opportunities, with half of the UK’s moderately visually
impaired children educated within specialised schools for children with physical or
learning deficits.
8
However, there is still a paucity of research on the epidemiology
and impact of childhood moderate visual impairment. For example, it is well
recognised that the majority of blind children will have other non-ophthalmic
disorders or impairments,
5
but it is unknown whether the same is true of those with
moderate VI.
Defining blindness
The 1972 WHO taxonomy still forms the basis of the International Classification for
Disease (ICD) definition (table 1) of blindness.
9
The recent creation of an additional
diagnosis of ‘monocular blindness’ is important as these individuals have a lifelong
increased risk of binocular blindness due to visual loss in the seeing eye,
10
but the
impact on global development for children with monocular blindness is unclear.

ADC review Epi Blindness
Table 1. World Health Organisation ICD Classification of visual impairment (VI),
severe visual impairment (SVI) and blindness (BL)
11
Category of impairment
Mild or no visual impairment
Vision better than or equal to 0.48 logMAR (6/18
Snellen)
Moderate visual impairment
(VI)
Vision worse than 0.48, but equal to or better than
1.0 (6/60 Snellen)
Severe sight impairment
(SVI)
Vision worse than 1.0, but equal to or better than
1.3 (3/60 Snellen)
Blindness
(BL)
Vision worse than 1.3
All humans are born with vision below adult acuity norms, as the average neonate
having acuity worse than 1.0 logMAR. This improves rapidly in the first year of life
(figure 1).
12 13
There is no child specific taxonomy for visual disability. As age and
cognition may be obstacles to quantification of a child’s acuity level, childhood
severe visual impairment (SVI) and blindness (BL) are often categorised together
(SVI/BL).
2 5
Children diagnosed in the first year of life, who constitute the majority of
blind children in many populations, invariably have clinical signs consistent with very
poor vision, such as absence of preferential looking behaviour when presented with
high contrast visual stimuli, or obvious severe ocular anomalies.
5
Although SVI/BL
children often have similar causative disease profiles and similar ocular phenotypes,
by definition this grouping includes both children with vision sufficient to navigate
around the world independently (eg 1.1 logMAR) and those with absolutely no
perception of light (‘NPL’). The life experiences, cognitive, developmental and
educational outcomes for children at the two ends of this spectrum may differ, and
until very recently there was a paucity of child-centric measures of experiences and
outcomes.
14 15
Global burden of childhood blindness
The major challenge to quantifying burden is the rarity of the disability and the
individual causative conditions. Population based approaches are required to
capture a representative picture. Additionally, there are varying definitions of both
childhood (<14, WHO), <16, UNICEF and <18, UN Convention of the Child) and
blindness.

ADC review Epi Blindness
Much of the literature on the epidemiology of childhood blindness is based on study
populations drawn from schools for children with disabilities or children seen within
heath care centres.
6
These methodologies are often at risk of under-ascertainment
and bias particularly in lower income settings,
16
where there are significant obstacles
to accessing education or health care.
17
There is evidence that research has failed to
capture girls, rural communities, or children with multi-system impairments.
16 17
Children may also fail to present to health care services because families do not
recognise that there is a problem,
18
or because access to health care for children is
limited by their carer’s own blindness.
18
There can also be a lack of awareness
amongst health care givers, with half of a group of primary care workers in Tanzania
unaware of the urgent nature of referrals for congenital cataract, or that children with
albinism may have visual impairment.
19
Key informant (KI) studies, in which trained volunteers with a pre-existing ‘key’ role
identify children with disorders in their community, enabling referral to health care
professionals, have been validated as a low-cost alternative to other population
based approaches. KI methods enable researchers to capture a more representative
study population, but are still likely to underestimate the true burden.
20
Using the available estimates of childhood blindness, derived through robust
population based approaches, the prevalence of blindness in individuals aged under
16 years (the definition used most consistently within the research) has been
estimated at 12-15 per 10,000 children in very poor regions, and 3-4/10,000 in
affluent areas (figure 2).
1
As the birth rate remains higher within lower income
countries, these countries have a disproportionately higher absolute number of blind
children.
1
Trends in the global causes of childhood blindness
For children in higher income countries, cerebral visual impairment and optic nerve
anomalies remain the most common causes of SVI/BL, whilst ROP, cataract,
glaucoma and non-accidental injury are now the most common avoidable causes.
3 21
Recent work from the UK has suggested an increasing certification of children with

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Cites background from "Epidemiology of blindness in childr..."

  • ...Inherited retinal diseases are a frequent cause of blindness in paediatric and working age populations in many countries (Liew et al., 2014; Rahman et al., 2020; Solebo and Rahi, 2014; Solebo et al., 2017)....

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References
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TL;DR: It is indicated that visual impairment in 2010 is a major health issue that is unequally distributed among the WHO regions; the preventable causes are as high as 80% of the total global burden.
Abstract: Aim From the most recent data the magnitude of visual impairment and its causes in 2010 have been estimated, globally and by WHO region. The definitions of visual impairment are the current definitions of presenting vision in the International Classification of Diseases version 10. Methods A systematic review was conducted of published and unpublished surveys from 2000 to the present. For countries without data on visual impairment, estimates were based on newly developed imputation methods that took into account country economic status as proxy. Results Surveys from 39 countries satisfied the inclusion criteria for this study. Globally, the number of people of all ages visually impaired is estimated to be 285 million, of whom 39 million are blind, with uncertainties of 10–20%. People 50 years and older represent 65% and 82% of visually impaired and blind, respectively. The major causes of visual impairment are uncorrected refractive errors (43%) followed by cataract (33%); the first cause of blindness is cataract (51%). Conclusion This study indicates that visual impairment in 2010 is a major health issue that is unequally distributed among the WHO regions; the preventable causes are as high as 80% of the total global burden.

2,935 citations

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TL;DR: Strategies need to be region specific, based on activities to prevent blindness in the community--through measles immunization, health education, and control of vitamin A deficiency--and the provision of tertiary-level eye care facilities for conditions that require specialist management.
Abstract: The major causes of blindness in children vary widely from region to region, being largely determined by socioeconomic development, and the availability of primary health care and eye care services. In high-income countries, lesions of the optic nerve and higher visual pathways predominate as the cause of blindness, while corneal scarring from measles, vitamin A deficiency, the use of harmful traditional eye remedies, and ophthalmia neonatorum are the major causes in low-income countries. Retinopathy of prematurity is an important cause in middle-income countries. Other significant causes in all countries are cataract, congenital abnormalities, and hereditary retinal dystrophies. It is estimated that, in almost half of the children who are blind today, the underlying cause could have been prevented, or the eye condition treated to preserve vision or restore sight. The control of blindness in children is a priority within the World Health Organization's VISION 2020 programme. Strategies need to be region specific, based on activities to prevent blindness in the community--through measles immunization, health education, and control of vitamin A deficiency--and the provision of tertiary-level eye care facilities for conditions that require specialist management.

1,021 citations

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TL;DR: Extended HDTBR has a different impact on CCA and CFA structure and flow, probably depending on the characteristics of the vascular bed perfused.
Abstract: The effects of simulated microgravity on the static and dynamic properties of large arteries are still mostly unknown. The present study evaluated, using an integrated vascular approach, changes in structure and function of the common carotid and femoral arteries (CCA and CFA) after prolonged head-down tilt bed rest (HDTBR). Ten healthy men were enrolled in a 5-week HDTBR study endorsed by the Italian Space Agency (ASI). Arterial geometry, flow, stiffness, and shear rate were evaluated by ultrasound. Local carotid pulse pressure and wave reflection were studied by applanation tonometry. After five weeks of HDTBR, CFA showed a decrease in lumen diameter without significant changes in wall thickness (IMT), resulting in an inward remodeling. Local carotid pulse pressure decreased and carotid-to-brachial pressure amplification increased. The ratio of systolic-to-diastolic volumetric flow in CFA decreased, whereas in CCA it tended to increase. Indices of arterial stiffness and shear rate did not change during HDTBR, either in CCA or CFA. In summary, prolonged HDTBR has a different impact on CCA and CFA structure and flow, probably depending on the characteristics of the vascular bed perfused.

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TL;DR: These findings suggest that larger, more mature infants are developing severe ROP in countries with low/moderate levels of development compared with highly developed countries.
Abstract: OBJECTIVE: Retinopathy of prematurity (ROP) is a potentially avoidable cause of blindness in children. The proportion of blindness as a result of ROP varies greatly among countries depending on their level of development, being influenced by the availability of neonatal care, neonatal outcomes, and whether effective screening and treatment programs are in place. The objective of this study was to compare characteristics of premature infants who developed severe ROP between 1996 and 2002 in highly developed countries with less developed countries. METHODS: This was an observational study. A questionnaire was completed by ophthalmologists in countries with low, moderate, and high development rankings (3 highly developed countries and from 10 less well-developed countries) who screen for ROP in which they supplied birth weights and gestational ages (GAs) of infants who were treated for threshold ROP or identified with more advanced stages of the disease. Birth weights and GAs of infants with severe ROP were measured. RESULTS: The mean birth weights of infants from highly developed countries ranged from 737 to 763 g compared with values ranging from 903 to 1527 g in less developed countries. Mean GAs of infants from highly developed countries ranged from 25.3 to 25.6 weeks compared with 26.3 to 33.5 weeks in less developed countries. A total of 13.0% of 1091 infants from poorly developed countries exceeded United Kingdom screening criteria; 3.6% exceeded a criteria of <34 weeks' GA and/or <1750 g birth weight. CONCLUSIONS: These findings suggest that larger, more mature infants are developing severe ROP in countries with low/moderate levels of development compared with highly developed countries. ROP screening programs need to use criteria that are appropriate for their local population.

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TL;DR: Improved care, including oxygen delivery and monitoring, for preterm babies in all facility settings would reduce the number of babies affected with ROP and improve data tracking and coverage of locally adapted screening/treatment programs.
Abstract: Retinopathy of prematurity (ROP) is a leading cause of potentially avoidable childhood blindness worldwide. We estimated ROP burden at the global and regional levels to inform screening and treatment programs, research, and data priorities. Systematic reviews and meta-analyses were undertaken to estimate the risk of ROP and subsequent visual impairment for surviving preterm babies by level of neonatal care, access to ROP screening, and treatment. A compartmental model was used to estimate ROP cases and numbers of visually impaired survivors. In 2010, an estimated 184,700 (uncertainty range: 169,600–214,500) preterm babies developed any stage of ROP, 20,000 (15,500–27,200) of whom became blind or severely visually impaired from ROP, and a further 12,300 (8,300–18,400) developed mild/moderate visual impairment. Sixty-five percent of those visually impaired from ROP were born in middle-income regions; 6.2% (4.3–8.9%) of all ROP visually impaired infants were born at >32-wk gestation. Visual impairment from other conditions associated with preterm birth will affect larger numbers of survivors. Improved care, including oxygen delivery and monitoring, for preterm babies in all facility settings would reduce the number of babies affected with ROP. Improved data tracking and coverage of locally adapted screening/treatment programs are urgently required.

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Frequently Asked Questions (16)
Q1. What contributions have the authors mentioned in the paper "An estimated 1.4 million of the world’s children are blind. a blind child is more likely to live in socioeconomic deprivation, to be more frequently hospitalized during childhood, and to die in childhood than a child not living with blindness. this update of a previous review on childhood visual impairment focuses on emerging therapies for children with severe visual disability (severe visual impairment and blindness or svi/bl). for children in higher income countries, cerebral visual impairment and optic nerve" ?

This update of a previous review on childhood visual impairment focuses on emerging therapies for children with severe visual disability ( severe visual impairment and blindness or SVI/BL ). 

Population based epidemiological research, particularly on cerebral visual impairment and optic nerve hypoplasia, is needed in order to improve understanding of risk factors, and to inform and support the development of novel therapies for disorders currently considered ‘untreatable’. 

Improvements in maternal and neonatal health, and investment in and maintenance of national ophthalmic care infrastructure is key to reducing the burden of avoidable blindness. 

In order to reduce the burden of childhood blindness attributable to diseases previously considered ‘untreatable’,particularly cerebral visual impairment and optic nerve hypoplasia, population based epidemiological studies are needed. 

Genetic and environmental factors are likely to play a role in the degree and duration of hyperoxia necessary to trigger the process, the resultant surge in vascular growth factors, and the severity of disease which develops. 

Anterior visual pathway disorders are responsible for almost a quarter of childhood SVI/BL in some higher income settings, and optic nerve hypoplasia (ONH), is the commonest single cause of severe visual impairment / blindness in industrialised nations. 

There are several currently underway trials of adjuvant therapies hoped to further improve outcome, including noble gases (NCT 00934700, NCT 01545271), melatonin (NCT01862250) and erythropoietin derivatives (NCT 01913340). 

The advent of hypothermia (head cooling or whole body cooling) as a therapy for HIE within the ‘golden window’ has resulted in modest improvements in neurodevelopmental outcomes. 

The Chinese Childhood Cataract Program (CCPMOH), established with the support of the V2020 programme, resulted in earlier diagnosis of cases of congenital / infantile cataract, and an apparent increase in prevalence of childhood cataract, as a result of improved case detection in remote regions. 

For two thirds of children who have vision worse than 1.0 logMAR due to CVI, visual impairment is part of a global developmental sequelae to hypoxic ischaemic encephalopathy (HIE). 

In industrialised settings CVI is a more important cause of visual impairment for a preterm child, but globally, ROP remains the major threat to vision for preterm infants. 

The constellation of causes of childhood blindness in lower income settings is shifting from infective and nutritional corneal opacities, and congenital anomalies, to more resemble the patterns seen in higher income settings. 

26 27 Of 231,000 children (aged under 16 years) examined as part of a major recent Indian rural population based, 8 per 10,000 had vision worse than 3/60 (95% CI 40-110/10,000).28 

Retinal laser ablation therapy is challenging, time consuming and implicitly destructive, but remains the gold standard intervention to prevent central sight loss in children with severe RO. 

The recent creation of an additional diagnosis of ‘monocular blindness’ is important as these individuals have a lifelong increased risk of binocular blindness due to visual loss in the seeing eye,10 but the impact on global development for children with monocular blindness is unclear. 

20Using the available estimates of childhood blindness, derived through robust population based approaches, the prevalence of blindness in individuals aged under 16 years (the definition used most consistently within the research) has been estimated at 12-15 per 10,000 children in very poor regions, and 3-4/10,000 in affluent areas (figure 2).1 

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