Eye (2007) 21, 1254–1260 & 2007 Nature Publishing Group All rights reserved 0950-222X/07 $30.00 www.nature.com/eye 1 2,3 2,3 CAMBRIDGE OPHTHALMOLOGY SYMPOSIUM Ophthalmological AR O’Connor , CM Wilson and AR Fielder problems associated with preterm birth Abstract learn that the incidence of cerebral palsy in infants of very low birth weight (less than 1500 g As survival of preterm infants improves, the and 32 weeks gestation) is falling in Europe3 long-term care of consequent ophthalmic although the actual number of children in the problems is an expanding field. Preterm birth population with cerebral palsy is increasing can inflict a host of challenges on the because of increased survival. Preterm infants developing ocular system, resulting in the are at increased risk of chronic illnesses such as visual manifestations of varied significance cerebral palsy and asthma, as well as having and pathological scope. The ophthalmic poor motor skills, poor adaptive functioning, condition most commonly associated with and low intelligence quotient.4–7 In addition, preterm birth is retinopathy of prematurity, cognitive deficits, behavioural, and emotional which has the potential to result in devastating problems are also more prevalent in this vision loss. However, the visual compromise population, which could cause or exacerbate the from increased incidence of refractive errors, academic deficiencies.8–10 strabismus, and cerebral vision impairment Ophthalmic challenges following preterm has significant impact on visual function, birth are numerous, and overall extremely low which also has influence on other birth weight ( 1000 g) infants are three times developmental aspects including o more likely to have a vision of less than psychological and educational. In this review, 6/60 than those born at term.11 However, the the normal ocular development is discussed, impact of prematurity on long-term ophthalmic aiming to exemplify the impact of early development is not confined to the smallest exteriorisation on one of the more naive organs infants.12 Effects of prematurity on ocular and of prematurity. This is then related to the 1 neurological development include retinopathy Division of Orthoptics, incidence and visual consequences of many University of Liverpool, of prematurity (ROP), refractive error, types of deficit, including refractive error, Liverpool, UK strabismus, cerebral visual impairment, colour strabismus, and loss of visual function in vision deficits, reduced contrast sensitivity (CS), 2St Mary’s Hospital NHS preterm populations, with comparisons to visual field defects, and decreased visual acuity Trust, London, UK term infant studies. Often these conditions are (VA). These factors will be discussed linked with causal and resultant factors being 3 individually, while recognising that many are Department of Optometry impossible to segregate, but the common not independent of each other. and Science Vision, factor of increased rates of all types of City University, London, ophthalmic deficits demonstrates that children UK born prematurely are indeed premature for life. Correspondence: Ocular development AR O’Connor, Eye (2007) 21, 1254–1260; doi:10.1038/sj.eye.6702838 Division of Orthoptics, The preterm infant has a shortened intrauterine University of Liverpool, Keywords: low birth weight; prematurity; period and is therefore removed from an Thompson Yates Building, Quadrangle, Brownlow Hill, strabismus; ROP environment uniquely designed for protection, Liverpool, L69 3GB, UK growth, and the appropriate stimulation of the Tel: þ 44 207 040 8339; fetus. In addition the exteriorised fetus, now the Fax: þ 44 207 040 8494. preterm neonate, is exposed to many abnormal Introduction E-mail: a.fielder@ environmental influences. While the light dose city.ac.uk Improved neonatal care has resulted in the experienced by the retina of the preterm infant 1,2 13 Received: 7 March 2007 increased survival of preterm infants, but this is related to postmenstrual age, this exposure Accepted in revised form: reduced mortality can be associated with to abnormal levels of light does not predispose 21 March 2007 long-term medical sequelae. It is encouraging to infants to ROP.14 Ophthalmological problems with preterm birth AR O’Connor et al 1255 The British Association of Perinatal Medicine Transverse ocular diameter measurements showed 6 mm introduced the concept of a ‘threshold of viability’ for of growth between 22 and 38 weeks from 9.57 to preterm births as being the period from 22 to 26 weeks 15.82 mm respectively.16 Ocular axial lengths increased gestational age (GA), which concurs with the survival 3.3 mm from 10.77 to 13.80 mm in the same time frame.17 rates in the EPICure study.15 Ocular development that The neural retina emerges around 26 days gestation, occurs during and after this period and the subsequent with the inner layer of the optic vesicle undergoing damage caused by premature exteriorisation will be mitosis producing three or four compact layers of cells.18 reviewed. Retinal development is centred around the putative At term, the eyeball is relatively well developed macula and proceeds centroperipherally,19 with mitotic compared to the rest of the body, and the most active activity being gradually confined to the periphery until stage of its development is between 6 months and term, 24 weeks of gestation when all mitosis ceases. The retinal time normally spent in utero. The gross structure of the surface area is still expanding, but does so by growth and globe becomes recognisable at approximately 7 weeks maturation of individual cells until 3 weeks after birth.19 GA, and by threshold viability at 22 weeks GA many of Later, retinal growth is mainly in the periphery, the disc the structures of the globe, such as the uveal tract and to macular distance remaining almost constant.20 Retinal sclera, are near to full development. For example, the vasculogenesis commences from the optic nerve head sclera is formed of 50 cell layers by 6 months GA, and no circumperipherally before 14 weeks GA, and is replaced further mitoses are seen following this. However, the at 21 weeks GA by angiogenesis, which is complete by cornea, lens, retina, and macula have to develop further term. There is a trend for an increase in the total vessel before term. The basic structure of the cornea is formed angle as the arcades develop through GAs.21 by 4 months GA: however, it undergoes structural change of flattening and increasing diameter just before term. The proportion of gamma crystalline in the lens Retinopathy of prematurity increases throughout gestation, and the lens alters in Population studies in England,22 Sweden,23 and New shape from elongated to become spheroidal at term. Cell Zealand24 show that ROP incidence, either mild or division ceases by 24 weeks GA yet retinal surface area severe, for infants born at less than 1500–1700 g lies doubles in size from 24 weeks GA until term. In addition between 22 and 49%. Although these epidemiological to the development of individual structures, the overall studies were undertaken about two decades ago, they eye size, as shown by in utero ultrasound investigations, provided the basis for subsequent detailed long-term increases significantly with growth spurts occurring at outcome studies, which have attempted to differentiate 16–20 weeks, 28–32 weeks, and finally after 37 weeks GA. the effects of preterm birth per se from both ROP and neurological insults. The sequelae of severe ROP have been well documented by the CRYO-ROP Study and Table 1 Ocular dimensions in preterm population measured at more recently the ETROP Study; however, the purpose of 26 10–12 years of age compared to ocular dimensions in term this article is to consider the more subtle effects of population measured at 10 years of age27 prematurity, which include mild ROP. O’Connor et al26 Zadnik et al27 Corneal power (D) 44.59 (1.71) 43.66 (1.73) Refractive state Axial length (mm) 22.47 (0.99) 23.31 (0.83) AC depth (mm) 3.56 (0.31) 3.78 (0.23) It is well known that term infants are most commonly Lens thickness (mm) 3.50 (0.18) 3.42 (0.15) slightly hypermetropic.25 This type of hypermetropia is Vitreous depth (mm) 15.41 (0.92) 16.11 (0.83) primarily axial with the reduction in hypermetropia Table 2 Refractive outcomes in preterm population compared to term population Larsson term Larsson O’Connor26 Holmstrom69 Fledelius70 Darlow48 controls37 preterms37 Age of study population (years) 10 10 10–12 2.5 7–10 7–8 Myopia % (dioptres included) 11.1 (o0) 15.2 (o0) 18.9 (o0) 10 (o0) 10.7 (o-0.25) N/R (o0) Hypermetropia % (dioptres included) 0.9 (43) 4.2 (43) 6.6 (X3) 4 (43) N/R 18 (40) Astigmatism % (dioptre cylinder) 4.1 (X1) 44 (X1) 13.7 (X1) 26 (X1) 16 (40) 11 (40) Anisometropia % (dioptre difference in MSE R&L) 0.9 (X1) 8.9 (X1) 9 (X1) 8.4 (X1) 6 (X2) N/R Abbreviations: N/R, not recorded; MSE, mean spherical equivalent. Eye Ophthalmological problems with preterm birth AR O’Connor et al 1256 occurring over time through the process of other refractive errors is also high, as shown in Table 2. In emmetropisation. This results in the minimisation of a population-based study of 293 low birth weight ametropia in the presence of increasing axial length, children who were assessed at 10–12 years of age, there flattening of the lens, and changes in other refractive was an increased incidence of myopia (mean spherical components of the eye. Paradoxically, despite the shorter equivalent of o0.0, 9%) and high hypermetropia (mean axial lengths, myopia is recognised to be associated with spherical equivalent of X þ 3.0, 6.6%).26 In contrast, the preterm birth, as illustrated in Tables 1 and 2.