The relationship between patterns of intermittent hypoxia and retinopathy of prematurity in preterm infants

Abstract

Background: We have previously shown an increased incidence of intermittent hypoxemia (IH) events in preterm infants with severe retinopathy of prematurity (ROP). Animal models suggest that patterns of IH events may play a role in ROP severity as well. We hypothesize that specific IH event patterns are associated with ROP in preterm infants.

Methods: Variability in IH event duration, severity, and the time interval between IH events (≤80%, ≥10 s, and ≤3 min) along with the frequency spectrum of the oxygen saturation (SpO2) waveform were assessed.

Results: Severe ROP was associated with (i) an increased mean and SD of the duration of IH event (P < 0.005), (ii) more variability (histogram entropy) of the time interval between IH events (P < 0.005), (iii) a higher IH nadir (P < 0.05), (iv) a time interval between IH events of 1-20 min (P < 0.05), and (v) increased spectral power in the range of 0.002-0.008 Hz (P < 0.05), corresponding to SpO2 waveform oscillations of 2-8 min in duration. Spectral differences were detected as early as 14 d of life.

Conclusion: Severe ROP was associated with more variable, longer, and less severe IH events. Identification of specific spectral components in the SpO2 waveform may assist in early identification of infants at risk for severe ROP.

Figure 1

Both A) mean SpO2 and B) baseline SpO2, excluding IH events, were significantly lower in the severe ROP group (p<0.05 and p<0.01, respectively). open circle, No or Mild ROP, black square, Severe ROP, solid line, covariate adjusted models. m±SEM.

Figure 2

There was an increase in event severity with increasing age in both infant groups. Infants with severe ROP had less severe events, as defined by a higher nadir, after 14 days of life (p<0.05). open circle, No or Mild ROP, black square, Severe ROP, solid line, covariate adjusted models. m±SEM.

Figure 3

The A) mean, B) standard deviation, and C) histogram (Hist) entropy of the duration of IH events decreased with increasing postnatal age in the No or Mild ROP group. In contrast, these parameters remained relatively constant in the severe ROP group, after the first week of life, with a longer mean (p<0.05), higher standard deviation (p<0.05) and higher histogram entropy (p<0.0001) when compared to the No or Mild ROP group. Histogram entropy may be a more sensitive marker with earlier differences identified between groups at ≥14 days of life (p<.05) followed by mean duration ≥ 21 days of life (p<0.005) and standard deviation of IH event durations at ≥ 28 days of life (p=0.004). open circle, No or Mild ROP, black square, Severe ROP, solid line, covariate adjusted models. m±SEM.

Figure 4

Stratification of events by a time interval of A) <1min, B) 1–20 minutes and C) >20 minutes. A) A substantial number of events occurred <1min apart, however, there were no differences between infant groups. B) A higher number of IH in the severe ROP group was associated with a time interval of 1–20 minutes between IH events with a significant difference at 28 days of life (p<0.05) and a trend towards a higher frequency of events at 21 and 35 days (both p=0.064). C) Relatively few IH events occurred with a time interval of >20 min between IH events with no overall difference between infant groups. open circle, No or Mild ROP, black square, Severe ROP, solid line, covariate adjusted models. m±SEM.

Figure 5

There was an increase in Sample Entropy with increasing postnatal age in both infant groups. Although there was a slightly higher Sample Entropy in the ROP group there was no significant difference between groups. open circle, No or Mild ROP, black square, Severe ROP, solid line, covariate adjusted models. m±SEM.

Figure 6

Wavelet analysis of the SpO₂ waveform. At the higher frequencies levels, A) D1: 0.125–0.250Hz, B) D2: 0.063–0.125Hz, and C) D3: 0.031–0.063hz, the severe ROP infant group had significantly lower spectral power from 21–49 days of life at level D1 (p<0.05) and ≥14 days of life at levels D2 and D3 (all p<0.05). There were no differences between groups at mid frequencies D) D4: 0.016–0.031Hz, and E) D5: 0.008–0.016Hz. At the two lowest frequency levels F) D6: 0.004–0.008Hz and G) D7: 0.002–0.004Hz) there was a shift towards a significantly higher spectral power in the severe ROP group from 21 to 28 days of life at level D6 (p<0.05) and from 21 to 35 days of life at D7 (p<0.05). open circle, No or Mild ROP, black square, Severe ROP, solid line, covariate adjusted models. m±SEM.