Low birth weight is often associated with prenatal malnutrition and preterm birth. In former preterm infants an increased risk for the development of myopia in childhood was observed independently of postnatal occurrence of retinopathy of prematurity (ROP).1–7 Authors have described myopia that develops in people with a history of prematurity as having different ocular features like a steeper corneal curvature, smaller anterior chamber depth and thicker lens accompanied by a smaller axial length in relation to the dioptric value8 with an earlier onset of myopia compared to those born full term.9

As origin for these morphological changes an arrested anterior eye segment development is assumed and probably caused by the differences between the higher intrauterine and the lower extrauterine temperature after preterm birth.10 These authors measured that preterm newborns suffer a thermal deficit of around 1–2 degree of the corneal surface which is never caught up in postnatal development leading to a less flattening of corneal geometry resulting in a steeper corneal shape contributing to myopia. This hypothesis was supported by animal studies where thermal gradients of the eye surface were a factor contributing to myopia.11

Retinopathy of prematurity as complication of preterm birth and its treatment were detected to be other important factors for myopia development. Various reports could demonstrate that particularly advanced stages and treatment with laser or cryotherapy of ROP are important factors contributing to myopia in these children.3,4,12,13 Furthermore, ROP is accompanied by characteristic biometric alterations contributing to an altered ocular and refractive error development which has also to be considered as origin for myopic refractive changes in former preterm individuals. Anatomic sequelae for ROP are particularly a steeper cornea, a shorter axial length and a thicker and more power full lens.14–16

Several studies describe the association of low birth weight and preterm birth with myopic refractive error in childhood.1–6 However, no population-based data exist investigating the long-term effects in middle and late adulthood on the association of ocular biometry and refractive error. As preterm infants have usually a low birth weight, this parameter may be used as a surrogate to analyze this association. We recently described that low birth weight is associated with increased myopic refractive error17 and altered ocular biometry such as a steeper corneal geometry and a smaller axial length in adults aged 40–80 years.18

However, it is unclear which ocular geometric alterations lead to an increase in myopic refractive error in these adults. Therefore, we now move one step further and analyze whether refractive error in low birth weight subjects is due to changes of axial length or of biometric alterations like steeper anterior segment. We will explore via linear regression analyses associations between spherical equivalent with corneal power, anterior chamber depth, lens thickness and axial length and its interaction with BW. Our hypothesis is that myopic refractive error in low birth weight adults is linked to alterations of the steeper cornea rather than to axial length.

This study presents new results on the relation of refractive error and corneal power, anterior chamber depth, lens thickness and axial length considering effect modification by birth weight. Our results show that axial length variation explains the majority of variance in refractive error. Low birth weight is not linked to larger effects of steeper corneal shape on myopic refractive error, while the effect of axial length on myopia is enlarged in those subjects compared to newborns with normal birth weight.

Low birth weight is regarded as proxy for intrauterine malnutrition and/or preterm birth. These parameters are strong related with each other because the more premature the infants are born the lower is the birth weight.24 Furthermore, adverse intrauterine nutrition is also associated with low birth weight. All these parameters have frequently common origins in maternal nutritional and health status24 and several studies showed a relationship of these parameters on both, myopia1–5 and ocular shape25 development in childhood. The mechanism of developing myopia in this population is not well understood and there has been conflicting evidence in the literature.26 Only few population-based studies exist assessing the association of low birth weight with altered ocular geometry in childhood. They found in low birth weight children a steeper corneal curvature27,28 and smaller axial length.27 In congruence, in our recent report18 and data of Sun and colleagues of the Australian Twin Study29 it was demonstrated that steeper corneal shape and smaller axial length in former low birth weight individuals seem to persist until adulthood. In contrast to our results, no association between low birth weight and refraction was reported in a twin study in participants aged from 18 to 86 years30 and in another study in participants aged 5–80 years.29 The authors hypothesized that compensatory emmetropization processes are leading to a normal refraction in later life in former low birth weight newborns despite the alterations of ocular geometry like a steeper cornea and a smaller axial length. In our recent report of the GHS, we could show that former low birth weight individuals have a slightly higher myopic refractive error in middle and late adulthood.17 We could previously demonstrate that low birth weight adults wear more frequently glasses for distance vision and had more frequently a myopic refractive error above 3 and 6 diopter17; these results may underline the clinical importance of our findings. However, with this analysis we want to close the gap of missing data about the correlation of ocular geometry and refractive error.

Fielder et al.26 categorized three different types of myopia in former preterm infants: 1) physiological and temporary myopia, 2) myopia of prematurity, and 3) myopia induced by severe ROP. As anatomic characteristics for this type of myopia, a flatter anterior chamber, more spherical lens, and a shorter axial length9 were described. In contrast to theses alterations, myopia of prematurity describes an earlier development of myopia as an abnormal refractive condition compared to full-term myopes with different anatomic features, like a steeper corneal curvature, smaller anterior chamber depth, and thicker lens accompanied by a smaller axial length in relation to the dioptric value.8 Various theories have been postulated to explain myopia development in former preterm infants. One theory discussed that lower ambient temperature after preterm birth (in comparison to intrauterine temperature) contributes to a less flattening of the cornea.10 Other theories were alterations of bone deficiency, light perception, visual deprivation and abnormal retinal function, or the occurrence and treatment of postnatal ROP.26 Particularly low birth weight newborns are at increased risk for ROP. In several studies strong associations between retinopathy of prematurity and its treatment with the development of significant refractive error could be observed explaining these by an anterior segment arrest.25,31–33 Unfortunately, no data was available about postnatal occurrence of ROP which is a major flaw in our study and has to be considered at data interpretation.

Our data extends these previous reports17,18 indicating that axial length variation explains the majority of variance in refractive error, while steeper corneal shape has no effects on refractive error. Low birth weight is not linked to slightly larger effects of steeper corneal shape on myopic refractive error, while the effect of axial length on myopia is fractionally enlarged in those subjects. Additional factors such as crystalline lens position and sphericity were not measured and could have played a role in the development of myopic refractive error in our subjects. In a previous report Barker et al. described that prenatal adverse growth during important organ developmental periods affects various organs morphology and functioning life-long.34,35 Supporting this hypothesis, we could show in a recent report that there are fetal origins for adult eye disease because we found an increased risk for age related macular degeneration in low birth weight individuals.20 Consequently, one may speculate that our results of a more myopic refractive error and different ocular biometry compared to normal birth weight individuals are in line with these previous results. Refractive development is a visually guided process, and its components grow in relationship to each other at least until early adulthood. Our data could be potentially a hint that low birth weight affects the emmetropization process.

One major strength of the presented study is the population-based study design with a large sample size. As study staff were masked to birth weight data, an investigator-dependent bias could be excluded.

There are several limitations. First, about 44% of the GHS study participants did not report their birth weight.17 Another limitation is that birth weight was self-reported and not obtained from birth records. We reported earlier, that the birth weight distribution of our cohort was comparable to governmental reports of the early 1970s.17,23 In a previous report of a population-based study, a high reliability of self-reported birth weight was observed comparing self-reported birth weight to medical record data (intra-class correlation coefficient of 0.98; 95% CI 0.97– 0.98),29 which underlines the validity of birth weight self-reports. However, we cannot fully rule out that misclassification might have impacted our results. Another limitation is that there may be other factors probably influencing our analysis on myopia for which we could not adjust (e.g. leisure time activities in early childhood and adolescence including daily time of outdoor activities and nearwork). In addition, one major restriction is the lack of data for gestational age at birth and postnatal occurrence of ROP. Therefore, we cannot separate the effects of low birth weight, preterm birth, and ROP and its impacts on the relationship between myopia and ocular geometric factors. For all three parameters, it is well known that they may affect refractive error and morphologic eye development.25 Because low birth weight infants are more likely to be born with low gestational age and have postnatal ROP occurrence, we assume that low birth weight may also reflect the influence of preterm birth to some extent. A further restriction is that we cannot provide any information about the strength of correlation between birth weight and gestational age in our population-based study design. Refractive error was not measured in cycloplegic state. This could be a further limitation of the study, especially in younger subjects. In addition, we do neither have the shape and position of the human lens nor the refractive power and, thus, cannot state on any differences across birth weight groups. In previous reports, more extreme low birth weight subjects were investigated, which may lead to a larger impact of extreme low birth weight subjects on the results. This is in contrast to our study, which represents a more general and population-based approach. Furthermore, there is the possibility that our study is over-powered.

This study reports new results on the relation between refractive error and ocular geometry considering effect modification by birth weight. Our results indicate that axial length variation explains the majority of variance in refractive error, while steeper corneal shape has no effects on refractive error. Low birth weight is not linked to slightly larger effects of steeper corneal shape on myopic refractive error, while the effect of axial length on myopia is fractionally enlarged in those subjects.

The study protocol and study documents were approved by the local ethics committee of the Medical Chamber of Rhineland-Palatinate, Germany (reference no. 837.020.07; original vote: 22.3.2007, latest update: 20.10.2015). According to the tenets of the Declaration of Helsinki, written informed consent was obtained from all participants prior to entering the study.

Not applicable

The authors declare that they have no competing interests.

All authors: The Gutenberg Health Study is funded through the government of Rhineland-Palatinate (“Stiftung Rheinland-Pfalz für Innovation“, contract AZ 961-386261/733), the research programs “Wissen schafft Zukunft” and “Center for Translational Vascular Biology (CTVB)” of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and PHILIPS Medical Systems, including an unrestricted grant for the Gutenberg Health Study. Wild PS is funded by the Federal Ministry of Education and Research (BMBF 01EO1503) and he is PI of the German Center for Cardiovascular Research (DZHK).

Schuster AK holds the professorship for ophthalmic healthcare research donated by „Stiftung Auge “and financed by „Deutsche Ophthalmologische Gesellschaft “and „Berufsverband der Augenärzte Deutschland e.V.“ He received research funding from Bayer Vital, Novartis, Heidelberg Engineering, Allergan and Plusoptix.

Pfeiffer N: receives financial support and grants by Novartis, Ivantis, Santen, Thea, Boehringer Ingelheim Deutschland GmbH & Co. KG, Alcon, Sanoculis; Nickels S: received reimbursement of travel expenses from Heidelberg Engineering GmbH; Beutel ME received speakers honorary from Pfizer Deutschland GmbH, Shire Deutschland GmbH and currently research grants from the governments of Rhineland-Palatinate and Nordrhein-Westfalen, the German Association of Psychoanalysis and Psychotherapy (DGPT), the German Research Foundation, the German Ministry of Research, the German Cancer Aid and the European Union; Fieß A, Schulz A, Münzel T, Urschitz M, Lackner KJ: none

Conceived and designed the study: MEB, NP, AF, AKS, SN; analyzed the data: AF, AKS, AS, SN; wrote the paper: AF, revised it critically: SN, AS, TM, PSW, MEB, MU, KJL, NP, AKS; all authors read and approved the final manuscript.

AS and PSW had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Statistical analyses were performed by AS.

The analysis presents clinical data of a large-scale population-based cohort with ongoing follow-up examinations. This project constitutes a major scientific effort with high methodological standards and detailed guidelines for analysis and publication to ensure scientific analyses on highest level. Therefore, data are not made available for the scientific community outside the established and controlled workflows and algorithms. To meet the general idea of verification and reproducibility of scientific findings, we offer access to data at the local database in accordance with the ethics vote upon request at any time. The GHS steering committee, which comprises a member of each involved department and the coordinating PI of the Gutenberg Health Study (PSW), convenes once a month. The steering committee decides on internal and external access of researchers and use of the data and biomaterials based on a research proposal to be supplied by the researcher. Interested researchers make their requests to the coordinating PI of the Gutenberg Health Study (Philipp S. Wild; philipp.wild@unimedizin-mainz.de. More detailed contact information is available at the homepages of the GHS (www.gutenberghealthstudy.org).