Recruitment of youth health care regions

Participating CHCs were recruited by coordination of youth healthcare doctors, who were informed about the EGS by the research team. In the Netherlands the Youth Health Care (YHC) is responsible for monitoring and promoting the health of newborn children up to 18 years. The YHC is situated in approximately 880 Children’s Healthcare Centres (CHCs) under the responsibility of Municipal Health Services in 257 municipals, healthcare organizations (10), foundations (21), municipals (3), or a combination of above (51) [11].

Recruitment and participant eligibility criteria

Children were recruited after visiting participating CHCs in the Netherlands, as part of screening for general health disorders and vaccinations. Parents of children aged 7 and 14 months received a brochure with information about the EGS. The brochure was available in different languages: Arabic, Dutch, English, German, Polish, and Turkish. Staff members of CHCs were not permitted by their employer to recruit, so recruitment consisted of scanning a QR-code from stickers, brochures or banners in participating CHCs, linked to a web-based registration-form.

After recruitment, parents were contacted by telephone by the research team for additional information and oral check of in- and exclusion criteria. Included were: children who could be examined between age ≥ 12 and < 18 months, born after 36 weeks gestation, registered at one of the participating CHCs, with voluntary consent for participation by both parents or legal representative or guardian and their willingness of complying with the study procedures. Excluded were: children who were not able to undergo the Entry Orthoptic Examination between age 12–18 months, children born prematurely or with perinatal birth damage, congenital syndromes, psychomotor retardation, known hereditary defects, cardiac disease, neurological disease, severe comorbidity, known ophthalmic diseases. Children who met the inclusion criteria and did not meet exclusion criteria were enrolled, and an appointment for the Entry Orthoptic Examination was made by the research orthoptist. It could happen that parents declined participation when an appointment would be made. Additional exclusion criteria could apply after the Entry Orthoptic Examination, as described below.

Entry orthoptic examination

All parents of enrolled children were required to provide written consent by both parents or legal representative or guardian prior to the Entry Orthoptic Examination. The Entry Orthoptic Examination was performed by research orthoptists. Date of birth, country of birth of participating children as well as from their parents, place of residence, language class of the parents (Class 1: does not speak Dutch or English; Class 2: can make themselves poorly understood; Class 3: sufficiently understood; Class 4: accent; Class 5: fluent) and their self-reported level of education, according to the International Standard Classification of Education (ISCED; Low: ISCED 0–2, medium: ISCED 3–4, high: ISCED 5–8; Supplement 1) were recorded. For socioeconomic status (SES), mean SES of citizens in the cities and regions with participating CHCs was determined.

At the Entry Orthoptic Examination family history of amblyopia, strabismic amblyopia, strabismus, ptosis, cataract or other ophthalmic diseases were recorded. A full orthoptic examination was performed, including inspection, quality of eye pursuit, motility and pupillary reflex, corneal reflex and cover test to detect strabismus, and the 15-prism-diopter prism test for ocular dominance. Retinoscopy was performed at least 30 min after installing a drop of cyclopentolate hydrochloride 1% twice in each eye with at least 10 min in between. Finally fundoscopy was performed for assessment of the posterior retina and the optic nerve of the eye.

When amblyopia, strabismus, ptosis, cataract, nystagmus or other ophthalmic diseases were found, children were excluded after the Entry Orthoptic Examination and referred to an ophthalmologist and/or orthoptist (the “treating orthoptist” in the following). In case no preference of fixation was found, no dominance was found with the 15-prism-diopter prism test and monocular pursuit movements were adequate and symmetric, amblyopia was not considered to be present [12]. Children with excessive refractive error, higher than the Criteria twofold (spherical equivalent (SE) of >  + 7D, > 3D astigmatism, > 2D oblique astigmatism (10°-80°), and > 3D anisometropia), were excluded for randomization and referred as well, as it was considered unethical to leave these children without glasses. All findings of the Entry Orthoptic Examination were saved in Castor version 2023.1.1.1 (Castor Electronic Data Capture) and were reported to the CHCs. In addition, parents received a copy of the findings to hand over to the general practitioner of their child.

Randomization

Examined children with a refraction exceeding the Criteria (SE of >  + 3.5D, > 1.5D astigmatism, > 1D oblique astigmatism or > 1.5D anisometropia), approximately 10%, were randomized in a 1:1 allocation ratio using block randomization to be fitted in glasses or not. Castor was used to perform the randomization procedure. Since signs of wearing glasses would be noticed by the research orthoptists, blinding was not feasible. The glasses were provided for free to the children assigned to the group with glasses.

Follow-up (Orthoptic) examination

All randomized children will receive Follow-up Orthoptic Examinations performed by the research orthoptist, biannually to age 45–48 months. If a child reaches a primary endpoint by developing amblyopia or strabismus or developing another ophthalmic disease, the child will be referred to the treating orthoptist for treatment. In children randomized into wearing glasses, glasses wearing will be monitored electronically during at least 1 week from age 2 years. Examined children who did not exceed the Criteria, approximately 90%, are followed-up by youth healthcare doctors and -nurses at CHCs as part of general screening to age 45–48 months. At that age VA is first measured in all children in the Netherlands and these data will be communicated to the study center while children with unclear outcome will be reexamined by research orthoptists.

Final orthoptic examination

All randomized children will receive a Final Orthoptic Examination and VA will be measured by the research orthoptist in presence of at least one other member of the research team, between age 45–48 months. Those who have reached a primary endpoint earlier during a Follow-up Orthoptic Examination and have been referred to the treating orthoptist will undergo a Final Orthoptic Examination and measurement of VA, between age 45–48 months, performed by the treating orthoptist, also attended by a member of the research team.

Final VA measurement

Children who did not exceed the Criteria will be followed up to age 45–48 months at CHCs as part of general screening. They receive a Final VA Measurement, performed by youth healthcare doctors or -nurses. This data will be communicated to the study center. In case the result of the Final VA Measurement is unclear or unsatisfactory, the youth healthcare doctors will be asked to clarify or the child will be reexamined. In case children have been referred to an ophthalmologist and/or orthoptist during follow-up at the CHC, the results of orthoptic examinations will be collected from the treating orthoptist.

Primary endpoints

The primary endpoints are development of accommodative esotropia or amblyopia before the age of 48 months. The VA measured from the worst eye will be used as a proxy for the degree of amblyopia.

Supplemental procedure for establishing the diagnosis of amblyopia and strabismus

A deficiency in the study protocol was uncovered when assessing the application of the exclusion criteria amblyopia and strabismus. The study protocol had not been foreseen that research- and treating orthoptist would not be in agreement about the presence of amblyopia or strabismus. On September 5th, 2023, a supplemental procedure for establishing the diagnosis of amblyopia or strabismus was decided upon, after plenary discussion with the EGS Study Group:

(1)

The diagnosis of amblyopia or strabismus should be founded on the judgement of all research- and treating orthoptists who have examined the child.

(2)

These judgements are subsequently presented to the EGS Study Group including research- and treating orthoptists and a plenary decision of diagnosis will be reached. (Supplement 2)

Statistics and mathematical

Baseline characteristics are presented as means of continuous variables and as counts (percentages) of categorical variables. Characteristics of recruited, enrolled, excluded, and randomized children are shown in tables and figures. Significance values were determined using a two-tailed t-test analysis, with a significance value of p < 0.05 used for all analyses. All analyses were performed using IBM SPSS Statistics, version 28.0.1.0.

Ethical approval

The study was approved by the Medical Ethics Review Committee (MERC) of the Erasmus University Medical Center on April 30th, 2021, and was carried out in accordance with the ethical conduct and juridical laws laid down in the Declaration of Helsinki, version 2013. First Entry Orthoptic Examination and randomization were on May 11th, 2021, and May 17th, 2021, respectively. Last child undergoing the Entry Orthoptic Examination and the last randomization took place on March 29th, 2023. The projected follow-up is approximately 3 years after the last Entry Orthoptic Examination. The study is registered at ClinicalTrials.gov, identifier: NCT04740593.