Viewpoint

Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2024-327003 on 11 April 2024. Downloaded from http://fn.bmj.com/ on April 17, 2024 at Serials Unit Hlth Sciences
Retinopathy of prematurity comes necrotising enterocolitis, but a lower risk
of sight-­threatening ROP.9 Thus, it is not
a question of simply reducing exposure to
full circle supplemental oxygen, but rather one of
fine tuning its administration to optimise
1 2 3 quality survival while decreasing the risk
Alistair R Fielder ‍ ‍, Graham E Quinn, Parag K Shah,
4 5 of sight-­threatening ROP—in essence the
Brian A Darlow, Neil Marlow ‍ ‍ dilemma posed by Cross in 1973.10 Given
this, services need to monitor the occur-
In the 70 years since the first description, together with indications for treatment. rence of ROP closely and provide timely
retinopathy of prematurity (ROP) has Treatment options have evolved from therapeutic intervention; the disease
been the focus of intensive basic and clin- peripheral retinal ablation using cryo- might not be preventable but vision loss is
ical research. Over time, worldwide, there therapy to laser therapy, and since the largely avoidable through timely screening
have been several phenotypes of ROP early 2010s, injection of antivascular and treatment.
described. Here, we explore whether these endothelial factor (VEGF) agents. In regions where resources for medical
are part of a single spectrum or are sepa- The fundamental prerequisite for care are more limited, survival at low
rate and distinct entities. the development of ROP is incomplete gestations is less common, and sight-­
First described in 1942 by Terry, clin- peripheral retinal vascularisation, for threatening disease frequently affects more
ical1 and experimental studies2 3 provided which gestational age is the major deter- mature infants (33–35 weeks of gestation,
compelling evidence that ‘retrolental minant. Elevated blood oxygen concentra- around 2000 g birth weight) who have
fibroplasia’—as ROP was then known— tions (compared with normal intrauterine received unblended/unregulated supple-
11
was related to uncontrolled oxygen expo- levels) lead to interruption of retinal mental oxygen. Recently, a particularly
sure, although some acknowledged that vascular growth and retinal ischaemia, aggressive phenotype has been described,

Library Univ of Wisconsin. Protected by copyright.

the mechanism was likely complex. This with neovascularisation at the advancing mainly from India, which occurs in more
12
led clinicians to the restriction of supple- margin of vascular growth during the mature infants given unblended oxygen.
mental oxygen concentrations to less than recovery phase. Thus, among the most This novel type and APROP have been
40%, with predictions that this would immature infants in whom vascularisation categorised as ‘aggressive retinopathy of
6
eliminate an important cause of infant has yet to advance into the periphery the prematurity’ (AROP). It is instructive to
5
blindness. Sadly, such forecasts were not disease is located posteriorly—closer to reflect that the RLF of 1953 strikingly
fulfilled, and ROP-­induced blindness still the optic disc. This contrasts with more resembles this novel phenotype.
occurred. Subsequently with increasing mature infants for whom vascularisation Retinal vascular development
preterm survival, the population devel- has already progressed more peripherally. commences in utero but can be
oping ROP had ever decreasing gesta- In addition to gestational age and oxygen perturbed ex utero when the baby is
tional age. Other risk factors for ROP exposure, several factors increase the risk exposed to higher oxygen levels than
were recognised, leading to the notion of ROP, including fetal growth restric- those experienced during fetal life.
that ROP ‘cannot always be prevent- tion, poor postnatal growth and causes of Experimentally this induces cessation of
ed’4—a view which prevailed for several oxidative stress including neonatal sepsis retinovascular growth with some loss/
decades. regression of pre-­e xisting vessels 2 3; the
and systemic inflammation.7 8 vascular changes being related both to
The classification of retrolental fibro-
ROP affects different populations the absolute level and wide fluctuations
plasia published in 19535 did not describe
across the world. In high-­ income coun- in oxygen tension. As the eye develops,
features of early acute ROP, likely due
tries, the risk of sight-­ threatening ROP the mismatch between vascular supply
to limitations from the use of the direct
is mostly confined to posterior disease and the increasing oxygen require-
ophthalmoscope. The three iterations of
among extremely preterm (<28 weeks of ments of the developing retina, renders
the International Classification of Reti-
gestation) or extremely low birth weight the retina relatively hypoxic, triggering
nopathy of Prematurity (ICROP) of 1984,
(<1000 g birth weight) infants, who rarely vascular endothelial growth factor-­
2005 and 2021 (for all, see Chiang et
6 survived in the 1950s. In 2005, aggressive-­ induced neovascularisation, which
al) describe ROP in far more detail and
posterior ROP (APROP) was incorporated is the first visually detected sign of
have changed clinical practice worldwide.
into ICROP as an acute severe phenotype. ROP. Importantly, in animal models of
ICROP facilitated a number of clinical
This primarily affects extremely premature oxygen-­ i nduced retinopathy, all other
studies and trials documenting which
infants and is a consequence of research-­ conditions are kept constant and only
forms of ROP will regress spontaneously
and which will likely require intervention, driven advances in neonatal care, leading the oxygen exposure varied, a situa-
to increasing survival. It remains difficult tion challenging to replicate in clin-
to control blood oxygen concentrations ical studies. Vessel die-­ b ack to more
1 with absolute precision, meaning that posterior retinal zones, ‘reversing’ the
City, University of London, London, UK
2
University of Pennsylvania, Philadelphia, Pennsylvania, primary prevention is not always possible. direction of vascular development, is a
USA The Neonatal Oxygen Prospective Meta-­ feature of these studies.
3
Department of Pediatric Retina, Ocular Oncology analysis collaboration of five international The reports of Shah et al, 12 Padhi et
Aravind Eye Hospital, Coimbatore, Tamilnadu, India trials of two different oxygen saturation 13
al and others have provided the first
4
Paediatrics, University of Otago Christchurch,
Christchurch, New Zealand (SpO2) targets enrolled 4695 infants of objective evidence of vessel die- back
5
Institute for Womens Health, University College <28 weeks of gestation. Compared with in the human infant (figure 1), which
London, London, UK an SpO2 target of 91%–95%, aiming had not previously been observed in
Correspondence to Professor Alistair R Fielder, City, for 85%–89% was associated with the human infant, both because of late
University of London, London, UK; a​ .​fielder@c​ ity.​ac.​uk increased mortality and prevalence of referral and the challenge of repeatedly
Arch Dis Child Fetal Neonatal Ed Month 2024 Vol 0 No 0    F1
 Viewpoint
Figure 1 ROP development. Male infant born at 30 weeks gestation and 1,380 g birthweight.A shows a featureless peripheral retina at 31 weeks 3
days postmenstrual age with early retinopathy and vessels visible in anterior Zone II. B at 33 weeks and 3 days) the vessels had regressed to posterior
Zone II. C at 34 weeks PMA regression with vessel die back to Zones I and II. This infant received oxygen at 100% for around 7 days. NICU has no
oxygen blenders. Clinical sepsis was diagnosed and treated with antibiotics.
and objectively measuring the periph-
eral extent of retinal vascularisation
during the neonatal period. Thus, the
retinal lesion appears to commence
peripherally, but progressively retreats
to posterior retinal regions which
are more likely to threaten sight. We
contend that these different manifes-
tations of ROP are expressions of a
similar aetiopathogenesis differing only
in the oxygen management.
Where the management of supple-
mental oxygen is not optimal, sight-­
threatening ROP currently occurring
in larger preterm infants should be
preventable. Avoidance of unblended
100% oxygen during postdelivery
stabilisation and neonatal care, with
careful titration when supplemental
oxygen is required, demands careful
education and investment in air/oxygen
blenders and monitoring equipment.
There is an urgent need to educate
and train all who care for the newborn
in the use of supplemental oxygen,
as well as other key elements of care
such as the prevention of sepsis, 14 and
to increase awareness of this disease
in the ophthalmologic community in
developing economies. 15 To fail in
this effort increases the likelihood of
blindness from a largely preventable
condition and increases the burden of
ROP screening in these settings where
fewer resources are directed to the care
F2
of preterm infants and ROP detection
and treatment. To fail sends us back
to the 1950s, to before we understood
the condition and its aetiology. The
circle is very nearly complete with one
important difference—we now have
better understanding what we need to
do!
Funding The authors have not declared a specific
grant for this research from any funding agency in the
public, commercial or not-­for-­profit sectors.
Competing interests None declared.
Patient consent for publication Consent obtained
from parent(s)/guardian(s)
Ethics approval Not applicable.
Provenance and peer review Not commissioned;
externally peer-­reviewed.
© Author(s) (or their employer(s)) 2024. No commercial
re-­use. See rights and permissions. Published by BMJ.
To cite Fielder AR, Quinn GE, Shah PK, et al. Arch Dis
Child Fetal Neonatal Ed Epub ahead of print: [please
include Day Month Year]. doi:10.1136/archdischild-­
2024-­327003
Received 14 February 2024
Accepted 2 April 2024
Arch Dis Child Fetal Neonatal Ed 2024;0:F1–F2.
doi:10.1136/fetalneonatal-2024-327003
ORCID iDs
Alistair R Fielder http://orcid.org/0000-0003-0756-​
8929
Neil Marlow http://orcid.org/0000-0001-5890-2953
Arch Dis Child Fetal Neonatal Ed Month 2024 Vol 0 No 0
Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2024-327003 on 11 April 2024. Downloaded from http://fn.bmj.com/ on April 17, 2024 at Serials Unit Hlth Sciences
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