Nailfold Capillaroscopy: A Promising, Noninvasive Approach to Predict Retinopathy of Prematurity

Abstract

Objective: To test the hypothesis that nailfold capillaroscopy can noninvasively detect dysregulated retinal angiogenesis and predict retinopathy of prematurity (ROP) in infants born premature before its development.

Methods: In a cohort of 32 infants born <33 weeks of gestation, 1386 nailfold capillary network images of the 3 middle fingers of each hand were taken during the first month of life. From these, 25 infants had paired data taken 2 weeks apart during the first month of life. Images were analyzed for metrics of peripheral microvascular density using a machine learning-based segmentation approach and a previously validated microvascular quantification platform (REAVER vascular analysis). Results were correlated with subsequent development of ROP based on a published consensus ROP severity scale.

Results: In total, 18 of 32 (56%) (entire cohort) and 13 of 25 (52%) (2-time point subgroup) developed ROP. Peripheral vascular density decreased significantly during the first month of life. In the paired time point analysis, vessel length density, a key metric of peripheral vascular density, was significantly greater at both time points among infants who later developed ROP (15 563 and 11 996 μm/mm², respectively) compared with infants who did not (12 252 and 8845 μm/mm², respectively) (P < .001, both time points). A vessel length density cutoff of >15 100 at T1 or at T2 correctly detected 3 of 3 infants requiring ROP therapy. In a mixed-effects linear regression model, peripheral vascular density metrics were significantly correlated with ROP severity.

Conclusions: Nailfold microvascular density assessed during the first month of life is a promising, noninvasive biomarker to identify premature infants at highest risk for ROP before detection on eye exam.

Keywords: microvasculature; neonate.

Figure 1:. Capillary network from a 9-day-old 25 5/7-week GA infant who later developed ROP (ROP severity scale of 8 - stage 3 zone 2 without plus disease )(A, B, C)) contrasting with a network from a 8-day-old 27 2/7-week GA infant who did not develop ROP (ROP severity scale of 0) (C, D, E):

(A, D) High-definition capillaroscopy images (200x), showing in (A) a nailbed capillary network with relatively higher vascular length density (VLD) compared to (D). (B, E) Subsequent binarized images of A and D respectively. (C, F) Vascular centerline map produced from REAVER analysis of (B,E) respectively. VLD values shown for each respective image. (G) Picture of the capillaroscopy exam of a sleeping NICU ex-premature infant. LED light is off for demonstration purposes.

Figure 2:. Vascular Density Metrics (VLD, VBPD, VSC, VAF) correlates with ROP status at Timepoints 1 and 2:

Nailfold capillary images were obtained in a cohort of 25 premature infants < 33 weeks of GA within 2 weeks of birth [“First Timepoint” (T1)] and repeated 14 days later [“Second Timepoint” (T2)]. (A-D) Mean values of vascular density metrics (Vessel Length Density, VLD; Vessel Branchpoint Density, VBPD; Vessel Segment Count, VSC; and Vessel Area Fraction, VAF) were plotted for each exam and stratified by timepoint and ROP status: ROP (light orange) compared to no/minimal ROP (purple). ***: p < 0.001. **: p < 0.01. *:p<0.05. (E) VLD plotted over post-natal age (days) and colored for ROP severity according to the color scale on the right.

Figure 3 (on-line only):. Individual hands comparison stratified by ROP status:

Individual hands were compared for each timepoint for each group (ROP vs no/minimal ROP). For each violin plot, the left hand is on the left of the violin and the right hand is on the right. Each scatter plot depicts all image density values. The median is shown for each violin by a white dot, and the interquartile range is depicted by the bold dark lines for each violin.