**Background:** The increasing survival of preterm infants has highlighted the need to improve long-term outcomes associated with preterm birth. Antenatal and perinatal insults impact not only mortality but also long-term disability, and preterm infants in the intensive care nursery are exposed to stressors that lead to cognitive deficits. Optical coherence tomography (OCT) is a powerful imaging modality recently adapted for infants, providing noninvasive, high-resolution, cross-sectional imaging of the infant eye at the bedside with low stress. This review discusses associations between preterm systemic health factors and OCT-based retinal findings, and their potential as non-invasive biomarkers for infant health and retinopathy of prematurity (ROP).
**Methods:** The authors review their own and others' work using handheld OCT systems (both commercial spectral-domain and investigational swept-source) to image preterm infants in the intensive care nursery. They describe the imaging protocol: infants are swaddled, eyelids held open gently, and pacifiers/sucrose used for calming. OCT does not require pupil dilation, though dilation facilitates peripheral imaging. The review covers findings from multiple IRB-approved protocols, including the prospective longitudinal BabySTEPS study (NCT02887157) initiated in 2016, which evaluates normal and abnormal microanatomic features of the developing retina in very preterm infants at risk for ROP. Retinal layer thicknesses are measured using semiautomatic segmentation (DOCTRAP software). Key measurements include inner retina (RNFL, GCL, IPL), macular edema (INL thickness), outer retina (OPL to RPE), choroidal thickness (Bruch's membrane to choroid-scleral junction), and peripapillary RNFL thickness (1.5 mm from optic nerve center in papillomacular bundle).
**Key Results:**
- **Fovea and inner retina:** Gestational age is the most critical factor affecting inner retinal thickness at the fovea. Extremely preterm infants (<28 weeks GA) have arrested foveal development with thicker inner retina. At 36 weeks PMA, thicker inner retina is associated with lower gestational age and lower birth weight. Higher ROP stages (0–2) are associated with increased inner retinal thickness, but no association with plus disease was found at 36 weeks. Eyes treated with laser photocoagulation for ROP are less likely to have all inner retinal layers present at the fovea compared to those treated with intravitreal bevacizumab.
- **Macular edema:** Incidence ranges from 19% to 79%. Edema appears as hyporeflective spaces in the inner nuclear layer, often bilateral and symmetric. It is detected as early as 30 weeks PMA. In 53 preterm infants, presence of macular edema was associated with poor language and motor skills on Bayley Scales at 2 years. Association with ROP severity remains controversial; in BabySTEPS, edema did not reach statistical significance with ROP stage or plus disease, but INL thickness was thicker with higher ROP stages. Edema is rare in term infants except in those with systemic disease (e.g., hypoxic ischemic encephalopathy, neonatal hemochromatosis).
- **Outer retina and photoreceptors:** Outer retinal thickness increases over time at the fovea in preterm infants, attributed to elongation of photoreceptor outer segments. The ellipsoid zone (EZ) band is not visible at 36 weeks PMA and appears around 40–42 weeks PMA. Severity of prematurity and ROP impact outer retinal development and visual acuity. Infants treated with laser photocoagulation are less likely to have the EZ band at the fovea.
- **Choroid:** Thinner choroid is independently associated with use of supplemental oxygen and slower postnatal growth velocity. Pulmonary conditions (bronchopulmonary dysplasia, pulmonary interstitial emphysema) are common systemic factors linked to thinner choroid. Higher FiO2 at 30 weeks is independently associated with choroidal thinning. Slower growth velocity (grams/kg/day) is also associated with thinner choroid. Plus disease, rather than ROP stage, impacts choroidal thickness in BabySTEPS. Choroidal growth rate is 14.8 µm/week from 30 to 38.4 weeks PMA, then slows to 0.3 µm/week from 38.4 to 60 weeks.
- **Optic nerve and RNFL:** Birth weight is the only independent factor influencing RNFL thickness at 36 weeks PMA, with an estimated 5.2 µm increase per 250 g increase in birth weight. Low infant weight at OCT imaging and sepsis/necrotizing enterocolitis (NEC) are independently associated with thinner RNFL. RNFL thickness follows a biphasic pattern: increases at 1.8 µm/week from 30 to 37.8 weeks PMA, then decreases at −0.3 µm/week from 37.8 to 60 weeks PMA. Thinner RNFL correlates with brain abnormalities on MRI (higher global brain lesion burden index) and worse cognitive and motor skills on Bayley Scales. In infants with hypoxic ischemic encephalopathy, RNFL thinning is seen within days of birth.
**Clinical Implications:** OCT imaging provides a noninvasive, low-stress bedside tool to assess retinal neurovasculature in preterm infants. Retinal markers such as inner retinal thickness, macular edema, choroidal thickness, and RNFL thickness are associated with systemic health factors (gestational age, birth weight, oxygen supplementation, growth velocity, sepsis/NEC) and with ROP severity. These markers may serve as early biomarkers for neurodevelopmental outcomes and for monitoring disease progression and treatment response. The ability to differentiate retinal schisis from detachment on OCT is valuable for surgical decision-making in advanced ROP. Longitudinal studies like BabySTEPS and BabySTEPS 2 (NCT04995341) aim to validate these findings and integrate OCT into clinical care for preterm infants, potentially improving both ocular and systemic outcomes.