In a randomized controlled trial, we will establish whether early glasses for high refractive error at age one reduce the development of amblyopia between age one and four. As a secondary outcome early literacy will be compared in groups with and without glasses.

Background of the study:

Amblyopia (prevalence approx. 3.4%) develops in early childhood when the child's eyes have severe refractive error, when they squint, or both. It can effectively be treated with glasses and patching the better eye, but treatment should start before age 6 to be effective. Therefore, visual acuity should be measured in all children aged 4-5 to detect amblyopia early enough. In an effort to prevent the development of amblyopia all together, in some countries devices are being used to measure refractive error in toddlers and, when refractive error is severe, fit them glasses before amblyopia develops. In Flanders, the measurement of refractive error in 1- and 2.5-year-olds began in 2012, in addition to regular vision screening with measurement of the visual acuity at the age of 3, 4 and 5. Between 2012 and 2017 the percentage of 4-year-old glasses wearing children had risen from 4.7% to 6.4%, but it was unknown how many cases of amblyopia had been prevented from developing. A prospective comparison seems warranted between this new method and the current national vision screening program in the Netherlands.

Objective of the study:

To investigate whether treating children with high refractive errors at age one with glasses prevents the development of amblyopia.

Study design:

We will perform an interventional prevention study comparing the effect of prescribing glasses to children with high refractive error at age 1 (intervention) versus no prescription of glasses (control) on the prevalence of amblyopia at age 4. 12-18-months-old children will be recruited by the study physician after visiting the children's healthcare centers (CHCs) at 11 or 14 months. Refractive error will be determined by retinoscopy in cycloplegia in all children. Children with refractive error exceeding the AAPOS 2003 criteria (Donahue et al. 2003) are considered to have high refractive error in this study. We anticipate that 8% of all children will have high refractive error according to these criteria. These children will be randomized to the intervention group or the control group, and will be followed up until final examination at age 4 with visual acuity serving as primary outcome. In case amblyopia or strabismus develops during the course of the study, children will be referred for immediate treatment, and visual acuity at the moment of referral will be used as primary outcome. In all children in the intervention group compliance with wearing spectacles will be measured electronically. At age 4 pre-literacy skills will be measured in the intervention group and the control group.

The majority of children, approximately 92%, will have mild or no refractive error at age one. After the first examination, these children will continue regular vision screening at the CHCs. They will have their visual acuity measured at the age of 4 as part of standard vision screening in the Netherlands at the CHCs, which will serve as secondary outcome. If there is uncertainty about the visual outcome at the CHC, the child will receive a supplementary examination. Children with amblyopia or strabismus at the age of one will be excluded from this study and referred for immediate treatment. Due to ethical considerations, children with severe refractive error at the age of one, i.e. exceeding the AAPOS 2003 criteria twofold, will also be excluded from this study and referred for immediate treatment with glasses. Due the nature and design of the study, blinding of the researchers on site and of participants will not be possible.

Study population:

For this study we will recruit an estimated 2000-4000 healthy children aged 12-18 months after visiting one of the participating CHCs, located in different regions of the Netherlands: Utrecht, Harderwijk/Ermelo/Putten, Tiel/Geldermalsen/Culemborg,Roermond/Venlo and Eindhoven. It is estimated that approximately 8% of all included children will have high refractive error.

Intervention (if applicable):

Children assigned to the intervention group will be examined by the study orthoptist one to three times yearly until final examination, and will be fitted with glasses, based on accurate determinations of refractive error by retinoscopy in cycloplegia. Children with high refractive error assigned to the control group will be examined by the study orthoptist one to three times yearly until final examination, but will not be fitted with glasses.

Primary study parameters/outcome of the study:

The occurrence of amblyopia at the final examination, stratified according to visual acuity of the amblyopic eye in the intervention group and in the control group. The final examination will take place at the age of 4, unless children have been referred to an orthoptist and/or ophthalmologist before, for example when amblyopia or strabismus are suspected before the age of 4.

Secondary study parameters/outcome of the study:

• Prevalence of amblyopia at age 1;
• Type and severity of refractive error at age 1;
• Occurrence of amblyopia at the final examination, stratified according to visual acuity of the amblyopic eye in the children without high refractive error at age 1;
• Pre-literacy skills in the intervention and control group at age 4;
• Occurrence of strabismus, determined at the final examination in all groups.

Other outcome measures:

• Electronically measured compliance with spectacles wearing;
• The evolution of refractive error between age 1 and 4;
• Gender;
• Family history for ocular disease;
• Ethnicity;
• Parental level of education, social economic status and language skill.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

The expected burden and risks associated with participation can be considered minimal. In order to measure refractive error accurately, retinoscopy will be done by study orthoptists after the instillation of cycloplegic eye drops, as happens daily in clinical practice of orthoptists and pediatric ophthalmologists. We will install 1 eyedrop of cyclopentolate 1% in each eye, which we will repeat after 10 minutes. Cyclopentolate can cause sleepiness in rare cases: children are difficult to awaken for several minutes, but can be awoken thereafter, which is without sequelae without exception.

Inclusion Criteria:

• Registered at one of the participating CHCs;
• 12-18 months of age;
• Voluntary approval for participation by the parents or legal representative/guardian with provided written informed consent;
• Willingness of the parents/guardian(s) to comply with the study procedures

Exclusion Criteria:

• Congenital syndromes;
• Psychomotor retardation;
• Known hereditary defects;
• Known cardiac disease;
• Severe comorbidity;
• Children's whose parents do not agree to cyclopegia with the use of cyclopentolate 1% eye drops for orthoptic examination (retinacopy) by the study orthoptist;
• Refractive error higher than the AAPOS criteria twofold (i.e. hyperopia >7 dioptres, anisometropia >3 dioptres and astigmatism of >3 dioptres at 90º or 180º and >2 dioptres in oblique axis (>10º eccentric to 90º or 180º);
• Strabismus;
• Amblyopia;
• Ptosis;
• Cataract or other media opacity;
• Other ophthalmic disease requiring immediate referral;

The outcome assessor will only have access to coded data, which cannot be traced back to the individual participants, from the electronic Case Report Forms in Castor, a cloud-based clinical data management platform.