The Gutenberg Prematurity Eye Study (GPES) is a single-center, retrospective cohort study conducted at the University Medical Center of the Johannes Gutenberg-University Mainz in Germany (UMCM) with prospective data acquisition including an ophthalmic examination in adulthood. The GPES recruited individuals born preterm or at term in the UMCM between 1969 and 2002 aged 18 to 52 years at study examination. Following an invitation algorithm, every former preterm newborn with a gestational age at birth (GA) ≤32 weeks and every second randomly selected preterm newborn with GA 33–36 weeks were approached. For each calendar month (from 1969 to 2002), 6 randomly selected full-term subjects (3 males and 3 females) with a BW between the 10th and 90th percentile were invited to serve as controls as reported earlier.23-29 The flowchart for eligibility and the effective recruitment efficacy proportion is displayed in Supplementary Figure 1.

Participants were grouped into full-term participants with a GA ≥37 weeks (group 1); preterm participants with a GA between 33 and 36 weeks without ROP (group 2); preterm participants with GA between 29 and 32 weeks without ROP (group 3); preterm participants with GA ≤28 weeks without ROP (group 4); and preterm participants with untreated ROP (group 5) or treated ROP (group 6). In the case of only one eye previously having ROP, the other non-ROP eye was excluded from the analysis. Moreover, participants with a history of corneal surgery and corneal trauma were excluded.

Written informed consent was obtained from all participants before they entered the study. The GPES complies with Good Clinical Practice (GCP), Good Epidemiological Practice (GEP), and the ethical principles of the Declaration of Helsinki. The study protocol and documents were approved by the local ethics committee of the Medical Chamber of Rhineland-Palatinate, Germany (reference no. 2019-14161; original vote: 29.05.2019, latest update: 02.04.2020).

A detailed ophthalmologic examination including ocular biomicroscopy, Scheimpflug imaging, and a personal interview was conducted between 2019 and 2021. In addition, the perinatal and maternal medical records of each participant were reviewed. Objective refraction and distant-corrected visual acuity (ARK-1s, NIDEK, Oculus, Wetzlar, Germany), and ocular biomicroscopy (LenStar 900, Haag Streit, Köniz, Switzerland) were assessed in both eyes. Corneal and anterior segment tomography was measured using a rotating Scheimpflug camera (Pentacam HR, Oculus Optikgeräte GmbH, Wetzlar, Germany) that allows the three-dimensional examination from the anterior corneal surface to the posterior lens surface. For optimal alignment, corneal tomography was performed while participants had to fixate on a light source. The Scheimpflug camera captures 25 images within 2 s. All corneal thickness measurements were controlled and excluded if a measurement artifact was suspected based on the raw Scheimpflug images. The following corneal parameters were included in the present analysis: corneal thickness at the pupil center (CCT), corneal thickness at the apex (Dapex), minimal corneal thickness (Dmin), and circles around Dmin with 2 mm (D2mm), 4 mm (D4mm), 6 mm (D6mm), 8 mm (D8mm), and 10 mm (D10mm) diameter.

Medical history data was assessed from medical records in the UMCM including GA (weeks), BW (kg), ROP and stage, ROP treatment with laser or cryotherapy, history of intraventricular hemorrhage, bronchopulmonal dysplasia, necrotizing enterocolitis, maternal placental insufficiency, maternal smoking during pregnancy, maternal preeclampsia and breastfeeding. Perinatal adverse events were defined in congruence with the German query for quality control of the neonatal clinics30 as an occurrence of intraventricular haemorrhage (at least grade 3 or parenchymal haemorrhage), necrotising enterocolitis and moderate or severe broncho-pulmonary dysplasia. BW percentile was calculated according to Voigt et al..31

The covariates were selected based on literature review and clinical plausibility21,32-34 including age,33 gender,32 mean corneal radius,21 and white-to-white distance.21 The following parameters were also considered GA (weeks), BW (kg), BW percentile, ROP (yes), ROP treatment (yes).

The main outcome measures were the corneal thickness at the apex, the pupil center, and in circles around the thinnest position. Absolute and relative frequencies were calculated for the dichotomous parameters, mean and standard deviation were calculated for approximately normally distributed data, otherwise median and interquartile range. Linear regression analysis with general estimating equations (GEE) was applied to assess associations and account for correlations between corresponding eyes. First, univariate analyses between the main outcome measure and sex (female), age (years), mean corneal radius (mm), white-to-white distance (mm), GA (weeks), BW (kg), BW percentile, ROP (yes), and ROP treatment (yes), were computed, then, a multivariable model included all these parameters except BW due to the high correlation between gestational age and BW. This is an explorative study so there was no adjustment for multiple testing. All statistical analyses were performed using commercial software (IBM SPSS 20.0; SPSS, Inc., Chicago, IL, USA).

In total, 390 participants (754 eyes) with a mean age of 29.7±  8.7 years (224 females) were included in this study. There were 253 eyes of 131 participants with a GA ≥37 weeks (group 1), 241 eyes of 124 participants with a GA between 33 and 36 weeks without ROP (group 2), 159 eyes of 82 participants with a GA between 29 and 32 weeks without ROP (group 3), 27 eyes of 14 participants with GA ≤28 weeks without ROP (group 4), 62 eyes of 31 participants with GA between 24 and 32 weeks with untreated ROP (group 5), and 12 eyes of 8 participants with GA between 24 and 32 and postnatal treatment for ROP (group 6). Of the ROP treated group, 4 participants (6 eyes) had laser coagulation, while 4 participants (6 eyes) had cryocoagulation. The effective recruitment efficacy proportion for each group is presented in Supplementary Figure 1. Overall, 60 participants were excluded because Scheimpflug imaging was not possible, or the scan quality was low (Table 1) or they had a history of corneal surgery.

Corneal thickness measurements at different anatomic regions by GA and ROP status are displayed in Table 2. Participants born preterm with a GA between 33 and 36 weeks had a thinner corneal thickness than the control group and like the group with previous treated ROP, had a very low mean BW percentile. Fig. 1 provides the scatterplots of BW percentile, BW, and GA with minimal corneal thickness, showing that a lower BW percentile was associated with a thinner central corneal thickness.

Fig. 1.

Relationship of minimal corneal thickness of all participants with a) birth weight percentile, b) birth weight, c) gestational age in the Gutenberg prematurity eye study (n = 390). The line presents the Loess (Locally Weighted Scatterplot Smoothing) curve.

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A lower BW percentile was associated with a thinner corneal thickness at the apex (B = 0.20 [95% CI: 0.07; 0.34] µm per percentile increase; p = 0.003), the center of the pupil (B = 0.19 [95% CI: 0.05; 0.32] µm; p = 0.007), minimal corneal thickness (B = 0.20 [95%-CI: 0.06; 0.33] µm; p = 0.005), and in the 2-mm (B = 0.19 [95% CI: 0.05; 0.32] µm; p = 0.007) and 4-mm diameter circles around the corneal minimum (B = 0.16 [95% CI: 0.02; 0.29] µm; p = 0.024) after adjustment for age, sex, corneal radius, and white to white distance (Table 3). These effects diminished towards the corneal periphery and there was no association between the BW percentile and corneal thickness in circles with a diameter of 6 mm, 8 mm, and 10 mm. Gestational age, ROP occurrence, and treatment were not associated with the corneal thickness (Table 3).