Conservative Phototherapy Research Articles

Phototherapy for preterm newborns—historical controversies and RCT evidence

: The Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight randomized controlled trial (A-v-C RCT), published in 2008, was designed to address two long standing intertwined controversies about bilirubin and phototherapy in preterm newborns. The older controversy, dating from the 1950s, was whether ‘low’ bilirubin levels might cause CNS injury in preterm newborns. The newer and less well-known controversy began when scrutiny of the 1974–1976 NICHD Collaborative Phototherapy Trial revealed that the results were consistent with increased mortality risk in the phototherapy arm for ELBW newborns: relative risk (RR) 1.49, 95% CI: 0.93, 2.40. The results of the A-v-C RCT fueled rather than settled the controversy regarding safety of phototherapy for ELBW newborns: mortality was higher with aggressive phototherapy in the 501–750 g stratum, but the strength of the association was not strong enough that the evidence of causation would be considered indisputable (RR 1.13, 95% CI: 0.96, 1.34). By contrast, the A-v-C RCT essentially proved that mean peak total serum bilirubin (TSB) levels ~10 mg/dL (~171 mmol/L) can cause lasting CNS injury in ELBW newborns: RR 0.86 (95% CI: 0.74, 0.99) for neurodevelopmental impairment (NDI) with aggressive phototherapy and mean peak TSB 7.0±1.8 mg/dL versus 9.8±2.1 mg/dL with conservative phototherapy (120±31 versus 168±36 mmol/L). For profound NDI, the RR was 0.68 (95% CI: 0.52, 0.89), and by Bayesian analysis the probability that aggressive phototherapy reduced profound NDI was 0.99. A recently begun large multicenter RCT evaluating cycled phototherapy as a means to reduce exposure to phototherapy in newborns with birth weight <751 g or gestational age <27 weeks could resolve the mortality risk controversy.

Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns?

ObjectiveAggressive phototherapy (AgPT) is widely used and assumed to be safe and effective for even the most immature infants. We assessed whether the benefits and hazards for the smallest and sickest infants differed from those for other extremely low birth weight (ELBW; (≤1000 g) infants in our Neonatal Research Network trial, the only large trial of AgPT.Study DesignELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12–36 hours. The effect of AgPT on outcomes (death; impairment; profound impairment; death or impairment [primary outcome], and death or profound impairment) at 18–22 months corrected age was related to BW stratum (501–750 g; 751–1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses.ResultsBaseline illness severity was well characterized using mechanical ventilation and FiO2 at 24 hours age. Among mechanically ventilated infants ≤750 g BW (n =684), a reduction in impairment and in profound impairment was offset by higher mortality (p for interaction <0.05) with no significant effect on composite outcomes. Conservative Bayesian analyses of this subgroup identified a 99% (posterior) probability that AgPT increased mortality, a 97% probability that AgPT reduced impairment, and a 99% probability that AgPT reduced profound impairment.ConclusionsFindings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing.

The effects of aggressive vs. conservative phototherapy on the brainstem auditory evoked responses of extremely-low-birth-weight infants

This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, ≤ 1,000 g). BAER latencies of 751-1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501-750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results. The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management. Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.

Is phototherapy exposure associated with better or worse outcomes in 501‐ to 1000‐g‐birth‐weight infants?

To compare risk-adjusted outcomes at 18- to 22-month-corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy. Outcomes at 18 to 22-month-corrected age included death, neurodevelopmental impairment (NDI) and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for centre and other potentially confounding variables. Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501- to 1000-g-BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI: 0.60-1.20), death or adverse neurodevelopmental endpoints. However, among infants 501-750 g BW, the rate of significant developmental impairment with MDI < 50 was significantly higher for NoPTx (29%) than PTx (12%) (p = 0.004). Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded because of bias from deaths before reaching conservative treatment threshold. The higher rate of MDI < 50 in the 501- to 750-g-BW NoPTx group is concerning and consistent with NRN Trial results.

Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight

Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight

Aggressive or Conservative Phototherapy in ELBW Infants

Inova Fairfax Hospital for Children, Falls Church, Virginia. Address correspondence to Laura A. Stokowski, RN, MS; [email protected]

Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight

Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight

Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight

Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight

A randomized trial of aggressive versus conservative phototherapy for hyperbilirubinemia in infants weighing less than 1500 g: Short- and long-term outcomes

Treatment regimens for hyperbilirubinemia vary for very low birth weight infants. The present study seeks to determine whether the initiation of conservative phototherapy is as effective as aggressive phototherapy in reducing peak bilirubin levels without increasing adverse effects. The present randomized, controlled study included infants with birth weights between 500 g and 1500 g, stratified into two birth weight groups. In one group, aggressive phototherapy was commenced by 12 h of age, while in the other group, conservative phototherapy was commenced if serum bilirubin levels exceeded 150 mumol/L. The primary outcome variables were peak serum bilirubin levels and hours of phototherapy. Secondary outcomes were age at peak bilirubin levels, number of infants with rebound hyperbilirubinemia, and number of adverse short- and long-term outcomes. Of 174 eligible infants, 95 consented to participate -49 in the conservative arm and 46 in the aggressive arm. Ninety-two infants completed the study. There was no significant difference in peak bilirubin levels except in infants who weighed less than 1000 g -171.2+/-26 mumol/L (conservative) versus 139.2+/-46 mumol/L (aggressive); P<0.02. There was no difference in duration of phototherapy or rebound hyperbilirubinemia. There were no differences in short-term adverse outcomes. Of the 87 infants who survived until hospital discharge, 82 (94%) had some follow-up and 75 (86%) attended follow-up until 18 months corrected age. The incidence of cerebral palsy, abnormal mental developmental index at 18 months corrected age, or combined outcome of cerebral palsy and death did not significantly differ between the two groups. In infants weighing less than 1000 g, peak bilirubin levels were significantly higher using conservative phototherapy regimens and there was a tendency for poor neurodevelopmental outcome.

2 Neuro-Developmental Outcomes at 18 Months Corrected Age in Infants Weighing

The “safe” level of serum bilirubin in infants <1500 grams is controversial, but recent retrospective reviews show direct correlation between peak bilirubin level and adverse neuro-developmental outcome. Our recent randomized study showed that infants <1000 grams who received conservative phototherapy had higher peak bilirubin levels and that infants <1500 grams who received conservative phototherapy reached peak bilirubin levels earlier than those treated with aggressive phototherapy. The purpose of this study was to examine the 18 month neuro-developmental outcomes in infants <1500 grams who had been enrolled in our randomized trial of aggressive versus conservative phototherapy. This follow-up phase of an unmasked, randomized study included infants with birth weight <1500 grams who had no evidence of major anomaly or iso-immunization and for whom parental consent was obtained. Aggressive phototherapy was started by 12 hours of post-natal age, while conservative phototherapy was started when the serum bilirubin level exceeded 8.8 mg/dL (150 μmol/L). All surviving infants were enrolled in a comprehensive neuro-developmental follow-up program at 4, 8, 12, 18, 14 and 36-months corrected age. At each visit, a full neuro-developmental assessment was performed and information on growth, hospital readmission, interval health and medication use was collected. All children had hearing screens at the 12-month visit, regular vision screening, and Bayley Scales of Infant Development (BSID-III) at the 18 and 36 month visits, if cooperative. Of 95 patients enrolled in the original study, 87 (92%) survived until hospital discharge, of whom 82 (94% of survivors) attended for comprehensive neuro-developmental assessment until 12 months corrected age and 75 (86% of survivors) attended until 18 months corrected age. The incidence of cerebral palsy was higher in the conservative phototherapy group 7/41 (17%) vs 2/41 (5%), p=0.15, OR 4.01 [0.69, 41.50]. The combined outcome of CP/death was also higher in the conservative group at 12/46 (26%) vs 5/44 (11%), p=0.04, OR 3.44 [0.92, 15.82]. Two-thirds of the infants with CP were in the <1000 grams subgroup. An MDI <84 on 18-month corrected age BSID-III testing did not differ between the two groups being 6/38 (16%) in the conservative group and 8/37 (22%) in the aggressive group, p=0.52, OR 0.68 [0.17, 2.56]. Although the numbers in this study are too small to draw definitive conclusions, there is a worrisome trend for poor neuro-developmental outcome for infants receiving conservative phototherapy, particularly in the <1000 grams group. Further studies with long-term neuro-developmental outcome as the primary outcome are urgently required.

Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants.

To assess the association between peak total serum bilirubin (PSB) levels during the first 2 weeks of life and neurodevelopmental outcomes of extremely low birth weight (ELBW) infants at 18 to 22 months' postmenstrual age. A retrospective analysis was conducted of a cohort of ELBW infants (401-1000 g) who survived to 14 days of age in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 1, 1994, and December 31, 1997. Demographic and clinical risk factors and PSB levels during the first 14 days were analyzed with reference to death or adverse neurodevelopmental outcomes at 18 to 22 months' postmenstrual age. The neurodevelopmental variables considered were Psychomotor Developmental Index (PDI) <70, Mental Developmental Index (MDI) <70, moderate or severe cerebral palsy (CP), hearing impairment (needs hearing aids), and a composite category designated as neurodevelopmental impairment (NDI). The NDI is defined as infants with any 1 or more of the following: PDI <70, MDI <70, moderate to severe CP, bilateral blindness, or bilateral hearing impairment requiring amplification. The subjects of this cohort analysis are infants who were admitted to the Network centers during calendar years 1994-1997 and survived beyond 14 days and had PSB recorded during the 14-day period. From this cohort, 3246 infants survived at discharge, 79 died after discharge, and 592 were lost to follow-up. Thus, 2575 of 3167 infants were seen in the follow-up clinics with a compliance rate of 81%. Logistic regression analysis showed that various demographic and clinical variables are associated with poor neurodevelopmental outcomes. After adjustment for these risk factor, significant association were found between PSB (mg/dL) and death or NDI (odds ratio: 1.068; 95% confidence interval [CI]: 1.03-1.11); PDI <70 (R = 1.057; 95% CI: 1.00-1.12), and hearing impairment requiring hearing aids (odds ratio: 1138; 95% CI: 1.00-1.30). There was no significant association between PSB (mg/dL) and CP, MDI <70, and NDI. PSB concentrations during the first 2 weeks of life are directly correlated with death or NDI, hearing impairment, and PDI <70 in ELBW infants. The statistical association based on retrospective analysis of observational data and relatively small effect size should be interpreted with caution. Furthermore, because of the possibility of compounding effects of variables on outcome, the potential benefits of moderate hyperbilirubinemia and the potential adverse effects of phototherapy, a randomized, controlled trial of aggressive and conservative phototherapy is needed to address this controversial issue.