presents the study cohort. Six of the 117 (5.1%) eligible study infants who were alive at 35 weeks PMA were not successfully tested; 4/36 (11.1%) were from center A and 2/81 (2.5%) were from center B. Five infants were in the aggressive phototherapy treatment arm (three at center A and two at center B). Four infants (two from each site), including an infant in the conservative phototherapy treatment arm, were discharged or transferred prior to their test date without informing the personnel doing the BAER testing. An administrative error and unsuccessful testing due to poor recording conditions after two attempts accounted for the other two missed tests.
The number of study infants who were eligible, consented, randomized, died before the target test age (35 weeks postmenstrual age), and successfully tested.
Of the 111 eligible infants successfully tested according to protocol, the median age at testing was 35 weeks and 1 day PMA (interquartile range = 3 days); 106 (95.5%) infants were tested within 1 week of 35 weeks. Three infants were tested 14, 12, and 10 days prior to 35 weeks because they were going to be transferred to another hospital. The other two infants were retested at 36 weeks 1 day because of poor recording conditions at 35 weeks.
Demographic and baseline characteristics of the successfully tested study infants are listed in and . There were few imbalances in the baseline variables across the two treatment conditions within the two centers. Gender was somewhat of an exception. Males were more prevalent in the conservative (11/19 = 58%) compared to the aggressive (4/13 = 31%) phototherapy treatment conditions at center A. Males were more equally distributed in the conservative (18/41 = 44%) and aggressive (19/38 = 50%) conditions at center B.
Demographic and baseline characteristics of the study infants from center A
Demographic and baseline characteristics of the study infants from center B
There were center differences in demographic and baseline characteristics ( and ). Center A infants were mostly black (88%), with a small percentage (12%) of white infants. In contrast, 44% of center B infants were black, 30% were white, 24% were Hispanic, and one was Asian. Center A infants were significantly older at birth (27.1 ± 0.4 weeks vs. 26.2 ± 0.2 weeks), less likely to be outborn (6% vs. 25%), more likely to be ventilated (81% vs. 62%), and less likely to be on continuous positive airway pressure at 24 h (0% vs. 34%).
Effectiveness of the Intervention
presents bilirubin exposure and phototherapy treatment duration means and 95% CIs. As expected from the study design, infants in the conservative phototherapy condition had significantly higher average TSB levels for the first 14 days after initiating phototherapy (P < 0.001), higher peak TSB levels (P < 0.001), and shorter duration of phototherapy (P < 0.001) than infants in the aggressive phototherapy treatment arm. The 751–1,000 g birth-weight infants had significantly higher average TSB levels for the first 14 days after initiating phototherapy (P = 0.002) and higher peak TSB levels (P = 0.002) than the 501–750 g birth-weight infants (P < 0.001), although the latter result was moderated by treatment condition and center (i.e., there was a phototherapy by center by birth-weight stratum interaction, P < 0.001). Average TSB levels for the first 14 days after initiating phototherapy (P < 0.001) and peak TSB levels (P < 0.001) were significantly higher at center A than at center B. The duration of phototherapy in both treatment conditions was significantly longer at center A (P < 0.001).
Bilirubin measurements as a function of phototherapy condition, center, and birth-weight stratum
Reliability of the BAER Scoring
The two scorers agreed that waves III and V from each ear were present for nearly the entire sample (95.5–96.4% of the 111 infants recorded). Those measurements were scored within 0.2 ms of each other 89.6%–94.4% of recordings. Most of the few times that one scorer scored wave III or V as absent, the other did as well (4/4 times for the left ear and 3/5 times for the right ear for wave III and 4/5 times for both ears for wave V).
Wave I was the only measurement scored more reliably at one site than the other (100% agreement that wave I was present for both ears at center A vs. 51% for the left and 48% for the right ear at center B). The noninverting electrode was placed higher on the head at center B than center A to avoid CPAP tubes and nasal cannulae negatively affecting the recording of wave I. As a consequence, wave I was less prominent and often confused with wave II. For nearly 40% of the recordings, either both scorers or at least one scored II and also IV as absent.
Treatment Effects on the BAER
presents mean (95% CI) differences in BAER latencies calculated from regression models for infants in the aggressive and conservative treatment conditions by center and birth-weight stratum. The results presented in are averaged over the two ears.
Mean (95% CI) differences in BAER latencies (ms) between the aggressive and conservative phototherapy treatment conditions
The 751–1,000 g birth-weight center A infants in the aggressive compared to the conservative phototherapy treatment condition had significantly shorter wave V latencies and also significantly shorter wave I and III latencies. Similar nonsignificant trends were recorded for the 501–750 g birth-weight center A infants. The small number of infants in the 501–750 g birth-weight stratum at center A limits the interpretation of those results. At center B, there were no significant differences in BAER latencies between treatment conditions.
There was little support for different phototherapy treatment effects in 501–750 g and 751–1,000 g infants. None of the three-way or two-way phototherapy treatment by birth-weight stratum interactions were significant. In contrast, there was some statistical support for different phototherapy treatment effects in the two centers (i.e., treatment by center interactions). Center differences in the phototherapy treatment effects were robust for wave III latencies (P = 0.032) but not for wave V (P = 0.239) and wave I (P = 0.174) latencies. Given the small sample size, nonsignificant interactions are not surprising.
Aggressive phototherapy treatment did not reduce brainstem transmission times as measured by the V–I, V–III, and III–I interwave latencies (see ). These results are consistent with a peripheral (i.e., the distal auditory nerve and/or the inner, middle, or outer ears) and not a brainstem site of lesion. Axonal vs. synaptic transmission was not significantly different in aggressive and conservative phototherapy-treated infants, with one exception. There was a significant phototherapy treatment by birth-weight stratum interaction (P
= 0.036) for the IV–III interwave latencies, indicating that aggressive phototherapy was associated with faster axonal transmission in the 501–750 g birth-weight infants. The last row of presents the II–I interwave latencies for the 94 infants whose latencies could be scored in at least one ear. The II–I latency interval also measures axonal transmission (5
). There was no support for phototherapy treatment differences for wave II–I interwave latencies, suggesting that the phototherapy treatment effect for the 501–750 g birth-weight infants for the IV–III interwave latencies may be a chance result.
Adjusting for the age at testing and each of the baseline and demographic variables listed in did not significantly alter the phototherapy treatment effects reported in . In addition, adjusting for possible mediators having their onset after the initiation of phototherapy but prior to the 35-week assessment (intraventricular hemorrhage grades 3 and 4, necrotizing enterocolitis, retinopathy of prematurity, patent ductus arteriosus, bronchopulmonary dysplasia, and late-onset sepsis) did not alter the recorded phototherapy treatment effects.
18- to 22-Month Outcomes
To further evaluate center differences, post hoc analyses were conducted comparing 18- to 22-month outcomes. Fewer aggressively treated center A infants (6/13 or 46%) died or had neurodevelopmental impairment at 18–22 months than conservatively treated center A infants (11/18 or 61%). In contrast, more aggressively treated center B infants (22/34 or 65%) died or had neurodevelopmental impairment at 18–22 months than conservatively treated center B infants (18/36 or 50%). These center differences were also observed for deaths and neurodevelopmental impairment analyzed separately.
Four infants had no scorable BAER waves despite valid recording conditions. All four of these infants were from center B: one in the 751–1,000 g stratum receiving conservative phototherapy and the other three in the 501–750 g stratum, one receiving conservative phototherapy and the other two receiving aggressive phototherapy. Three of these infants in this study were the only infants recorded as being deaf at the 18- to 22-month assessment. The other infant with no BAER died before the 18- to 22-month assessment.
Each of the four bilirubin variables was positively correlated with the BAER V, III, and I latencies but not the interwave intervals for the 751–1,000 g center A infants in the aggressive treatment arm. The regression coefficients were of similar magnitude for all three waves for these infants (V, III, and I latencies are highly correlated) and 8/12 (three waves by four bilirubin variables) were statistically significant at the 0.05 level. For wave V, there was a 0.05-ms (95% CI = −0.05, 0.16) latency increase for every mg/dl increase in 14-day TSB average, a 0.06-ms (95% CI = −0.04, 0.16) latency increase for every mg/dl increase in peak TSB over the 14-day treatment interval, a 0.09-ms (95% CI = 0.01, 0.18) latency increase for every 24-h increase in the age at peak TSB, and a 0.15-ms (95% CI = 0.02, 0.27) latency increase for every 24-h increase in the duration of phototherapy. For the 751–1,000 g center A infants, 11/12 correlations were positive in the conservative treatment arm, although only one was significant at the 0.05 level. There were only three significant positive correlations for infants in the 72 other combinations of center, birth-weight stratum, and phototherapy treatment.