Pregnancy amplifies neurovascular vulnerability: longitudinal retinal high-resolution OCT imaging reveals early, treatment-specific neurodegeneration in gestational and pre-conceptional diabetes

Gestational diabetes mellitus (GDM) and pre-conceptional diabetes are linked to increased long-term risk of type 2 diabetes (T2D) and microvascular complications. However, the earliest signs of neurovascular damage during pregnancy remain elusive. Here, we report the first longitudinal analysis of circumpapillary retinal nerve fiber layer thickness (cpRNFLT) using high-resolution 768-A-scan spectral-domain OCT in a population-based cohort of 591 pregnant women, including healthy pregnancies (HPC), diet-treated (dGDM) and insulin-treated GDM (iGDM), and pre-conceptional diabetes (T1D/T2D). We reveal divergent, treatment-specific neuroretinal trajectories: dGDM exhibited early thinning in the temporal-inferior sector (up to −20 µm), while iGDM showed progressive thickening in the temporal-superior sector (up to +22 µm), correlating with insulin exposure duration. Notably, women with pre-conceptional diabetes displayed profound and sustained thinning (up to −30 µm), exceeding levels seen in non-pregnant diabetic individuals. Using Euclidean nested case-control matching, these differences were confirmed after rigorous adjustment for confounders. Our findings demonstrate that glucose dysregulation during pregnancy induces measurable neuroretinal changes at an earlier stage than previously recognized, suggesting that the retina may serve as a non-invasive window into systemic metabolic vulnerability. These results position cpRNFLT as a potential biomarker for early detection of long-term diabetes risk, with implications for prenatal screening and preventive strategies.