Bilirubin Neurotoxicity (BN) and Neurodevelopmental Impairment (NDI) in Extremely Preterm (EP) Infants: Avoidable by Reducing the Usual Intravenous Lipid (UL) Administration
Phase: PHASE2
Conditions: Bilirubin Encephalopathy
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-20-0916 
IRB APPROVAL DATE: 07/28/2023 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin Neurotoxicity (BN) and Neurodevelopmental Impairment (NDI) in 
Extremely Preterm (EP) Infants: Avoidable by Reducing the Usual Intravenous Lipid 
(UL) Administration? 
 
NCT04584983 
 
Version Date: 07/28/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB NUMBER: HSC-MS-20-0916 
IRB APPROVAL DATE: 07/28/2023 
 
Bilirubin Neurotoxicity (BN) and Neurodevelopmental Impairment (NDI) in 
Extremely Preterm (EP) Infants: Avoidable by Reducing the Usual 
Intravenous Lipid (UL) Administration? 
Lindsay Fleig, MD, Cody Arnold, MD, MSc, MPH, Alan Kleinfeld, PhD, Amir Khan, MD, 
Eric Reynolds, MD, Emily Stephens, RN, 
Claudia Pedroza, PhD, and Jon Tyson, MD, MPH 
 
Rationale. Extremely premature infants have very limited caloric reserves. Because of the 
pressing need to at least meet maintenance caloric requirements, early aggressive parenteral 
nutrition with glucose, protein, and lipids has been recommended for preterm infants, 
particularly those born before 27-28 wks.1 Intralipid, the most commonly used parenteral fat 
preparation, is commonly initiated starting 1-2 days after birth. However, the optimal age for 
administration is unclear as the most recent systematic review of the Cochrane Collaboration 
found no statistically significant benefits of “early” administration of lipids (<5 days after birth) 
from later introduction.2 Whether a relatively high caloric intake from lipids is better than a 
relatively low intake is also unclear. The dose of Intralipid is commonly increased from 1 g/kg/d 
on the day that it is started to 2 g/kg/d on the following day to 3 g/kg/d on the next day. The 
dose is usually limited to a maximum of 3 g/kg/d, partly to avoid potential dose-related adverse 
effects including chronic lung disease, increase in pulmonary vascular resistance, impaired 
pulmonary gas diffusion, sepsis, free radical stress and bilirubin neurotoxicity. 
 
Free fatty acids (FFA) compete with bilirubin for albumin binding sites. There is a long-standing 
concern that infusion of Intralipid may increase FFA sufficiently to displace bilirubin from 
albumin and increase serum unbound bilirubin (UB) that passes into the brain and causes 
bilirubin neurotoxicity.3 This concern was heightened by a 2017 report that Intralipid doses of 2- 
3 g/kg/d were associated with an increase in unbound free fatty acids (uFFA) and UB among 
infants <28 weeks gestation.4 Whether these increases resulted in bilirubin neurotoxicity or 
neurodevelopmental impairment (NDI) was not determined. In the commentary5 prompted by 
that report, Amin, Maisels, and Watchko, each a widely respected authority on neonatal 
hyperbilirubinemia concluded, “The current observations suggest that a more tempered 
approach to early lipid infusion in neonates ≤28 weeks gestation should be considered, until we 
have a better understanding of the risks and benefits.” 
 
Comparative effectiveness research is thus needed to compare usual with more reduced lipid 
administration in extremely premature infants during the first 1-2 weeks after birth when these 
infants are at risk for bilirubin neurotoxicity. A persisting problem in evaluating this issue has 
been the lack of a reliable, well validated, and commercially available method to assess UB. 
The study noted above involved a new method that avoids limitations of prior methods but is not 
yet commercially available. In the proposed study we will use that method to assess UB among 
extremely premature infants randomized to either our usual prescribed Intralipid dose (UL) or to 
a prescribed dose which is half that of the usual dose (reduced intralipid, RL). We will also 
measure uFFA profiles, brain stem auditory-evoked responses (BAERs) at 34-36 weeks 
postmenstrual age (PMA), and neurodevelopmental impairment (NDI) status at 22-26 months 
postnatal age. BAERs will be assessed because a prolonged wave V latency is a sensitive 
indicator of even transient bilirubin neurotoxicity.6,7,8 It is unknown which summary UB 
measurement, either single UB peak level per patient or repeated measures per patient with a 
mean UB, area under the curve or proportion of values, is most predictive of NDI outcomes. In 
Hegyi et al4, phototherapy was found to reduce both total serum bilirubin (TSB) and UB in all 
infants, but when evaluating the infants <28 weeks separately, TSB was reduced but UB was 
not, suggesting that UB may be a more preferred method to measure bilirubin toxicity. 

IRB NUMBER: HSC-MS-20-0916 
IRB APPROVAL DATE: 07/28/2023 
 
 
We expect to see some difference between treatment groups in UB levels in the first 1-2 weeks 
after birth but not their BAERs at 34-36 weeks postmenstrual age (PMA) (the earliest PMA that 
BAERs are likely to be reliably assessed in a neonatal ICU setting) or in rates of NDI at 22-26 
months postnatal age. This expectation is based in part on the absence of discernible BAER 
evidence of neurotoxicity with the usual Intralipid doses administered in our center (3 g/kg/d 
maximum) and the TSB levels reached during our recent trial of cycled versus continuous 
phototherapy (PT).9 Nor did we identify evidence of bilirubin neurotoxicity in BAERs performed 
in our center using the same maximum Intralipid dose even with the relatively high TSB levels 
reached with more conservative use of PT in the prior NICHD Neonatal Research Network 
(NRN) Trial of aggressive vs. conservative PT.10 
 
While bilirubin neurotoxicity with overt encephalopathy does occur, it is rare and currently 
unpredictable.11 To improve our understanding of the relationship of UB to BAERs and NDI, we 
will request mothers who decline consent to randomize their infants to different Intralipid 
regimens to include their infants with those in the trial in an observational analysis relating their 
UB levels to their BAERs and neurodevelopmental findings (with and without adjustment for 
potential confounding variables). 
 
We will also assess the clinical findings in all these infants in an effort to better understand their 
relationship to TSB and UB and the paradoxical findings reported by Oh and colleagues12 that 
peak total bilirubin levels at 5 days age were inversely related to death or adverse 
neurodevelopmental outcomes in stable infants (a quite unexpected finding) although directly 
related to these outcomes in unstable infants (as expected). It is possible that because of 
bilirubin’s antioxidant properties that higher TSB levels are protective in preventing death or 
from any cause providing the infants have not been exposed to factors that may predispose 
infants them to bilirubin neurotoxicity (e.g., sepsis, hypoxic ischemic episodes, severe acidosis, 
low albumin levels) and that the risk of bilirubin neurotoxicity with elevated TSB is over- 
estimated in these infants. Infants who were considered unstable in that study include all 
receiving mechanical ventilation at that age, and the need for mechanical ventilation at 5 days 
might simply be associated with factors that cause bilirubin neurotoxicity or that the need for 
mechanical ventilation is an effect of bilirubin neurotoxicity already present at that age. Informed 
consent will be obtained for each infant as approved by the IRB. 
 
Hypotheses. 
 
1. Among infants <27 weeks gestation or <750 g birth weight, the usual prescribed intralipid 
(UL) regimen and a reduced prescribed intralipid (RL) regimen (consisting of half the UL 
regimen) during the first two weeks after birth will result in somewhat higher mean unbound free 
fatty acids and mean UB values but similar BAERs, and in infants less than 27 weeks 
gestational age rates of death or impairment at 2 years postnatal age. 
 
2. Any infants with clear evidence of bilirubin neurotoxicity on BAERs and NDI at 22-26 months 
(including all infants in observational analyses) will have A) moderate to increased mean and 
peak UB levels in combination with one or more other factors thought increase their 
susceptibility to bilirubin neurotoxicity; B) a lower peak TSB to UB level (as expected if albumin 
levels are low or bilirubin is displaced from albumin); C) will have a greater need for mechanical 
ventilation at 5 days than expected from baseline measures (a potential indicator of bilirubin 
neurotoxicity at 5 days). 

IRB NUMBER: HSC-MS-20-0916 
IRB APPROVAL DATE: 07/28/2023 
 
Methods. 
 
Population. Inborn infants <27 weeks’ gestation by best obstetric estimate or <750 g birth 
weight who has no major congenital anomaly or overt nonbacterial infection who has not 
received Intralipid and whose mother has consented to inclusion of the infant for the NRN 
Cycled Phototherapy Trial (which warrants higher priority based partly on stipulations in joining 
the NRN). Mothers of infants <27 weeks gestational age who refuse consent for this 
randomization control lipid trial may also be approached for consent in the observational arm of 
this lipid study. 
 
Possibility of inclusion of two other major centers. With the protected time and funding 
provided by a KL2 award, I hope to add two centers to increase the sample size and 
generalizability of this pilot study. These centers are 1) the University of Alabama which 
generally has the largest enrollment in NRN trials and is led by Wally Carlo, MD and 
2) Stanford where Cody Arnold, MD is Visiting Professor and David Stevenson, MD, an 
international leader in studies of bilirubin and PT studies, are based. Both Drs. Carlo and 
Stevenson have expressed serious interest in joining the pilot. 
 
Enrollment and Randomization. Patients will be approached for informed consent after 
informed consent has been given or refused for the NRN Cycled PT Trial. Infants for whom 
informed consent is obtained for this lipid study will be randomized using a variable block size 
stratified by study site and phototherapy use (continuous or cycled which may affect UB level) to 
either UL or RL using a web-based computerized program (REDCap). Lipid and phototherapy 
use are concurrent. Mothers who refuse consent infants for this lipid trial will be asked if they 
would consent for their infant to be included in the observational component of this study so that 
UB levels can be related to BAERs and 2-year outcomes. In the observational component 
Intralipid infusions will be at the attending physician’s discretion and care would be altered only 
by collection of the small amount of blood (<2 mL total) as for participants randomized to UL or 
RL. 
 
Treatment Regimen. 
UL regimen: Intralipid will be started at 1 g/kg/day and routinely advanced by 1 g/kg/day each 
day to a max of 3 g/kg/day as per usual clinical practice. 
RL regimen: Intralipid will be started at 0.5 g/kg/day and routinely advanced by 0.5 g/kg/day 
each day to a max of 1.5 g/kg/day (half rate of usual clinical practice). 
 
The assigned treatment regimen (UL or RL) will remain in effect for a minimum of 7 days and a 
maximum of 14. On postnatal day 8-14, the Intralipid preparation and dosage maybe changed 
at the discretion of the clinical team if phototherapy has been off for >48 hours (TSB <5 mg/dL). 
(After that point, the Intralipid preparation and dosage maybe changed at the discretion of the 
clinical team). Throughout the study period, the infusion rates for both regimens may be 
decreased, and advances may be delayed for reason of lipid intolerance providing the 
justification is documented in the daily progress note. (Each study site should strive to 
standardize criteria for lipid intolerance so as to minimize the likelihood of using different criteria 
for the treatment groups). Intralipid infusions will be routinely initiated on specified day after the 
birthday as per the routine in the study site; this will be the first day after the birthday in 
Houston. The dates and times of start, stop, and changes in infusion rates will be recorded. 
 
Cointerventions. As appropriate for a pragmatic trial, the protein and glucose components of 
parenteral nutrition (PN) will be prescribed by the clinical team following usual care prescribing 

IRB NUMBER: HSC-MS-20-0916 
IRB APPROVAL DATE: 07/28/2023 
 
guidelines and will likely differ between study groups. The quantities of macronutrients will be 
recorded during the intervention period (parenteral and enteral, g/kg/day). 
 
Study Assessments. Blood samples for the study will be obtained with blood draws for clinical 
measurement of TSB levels such that the study will not require additional interventions for blood 
sampling. The first study blood sample will be obtained on the morning when the newborn is 4 
days old (postnatal day 5). Age in days is defined as 0 days old at birth, and 1 day old at 
midnight on the birthday. Postnatal day 1 is until midnight of the birthday, and postnatal day 2 at 
midnight on the birthday, etc. Blood samples numbers 2-7 will be obtained on each subsequent 
morning through postnatal day 14 when a total bilirubin is obtained for clinical purposes as 
ordered by the clinical team. Bedside nurses collect blood using BD red-top microtainers at the 
same time that blood is sampled to measure total bilirubin for clinical purposes. A total of up to 6 
study blood samples will be obtained within the first 2 weeks from birth, to not exceed total study 
blood volume of 2mL. (See sample schedule below). 
 
Sample 
Number 
Postnatal Day 
to Collect 
Age (days) 
Blood 
Volume* 
* 
1 (birthday) 
0 
0 
* 
2 
1 
0 
* 
3 
2 
0 
1 
4 
3 
0.25mL 
2 
5 
4 
0.25mL 
3 
6 
5 
0.25mL 
4 
7 
6 
0.25mL 
5 
8 
7 
0.25mL 
6 
9 
8 
0.25mL 
Total Blood Vol. 
<2 mL 
*All samples will be 0.25mL with the exception of the morning after the lipid infusion is 
advanced to the peak infusion rate (usual group 3 g/kg/day or reduced group 
1.5g/kg/day). On this day ONLY, the blood sample volume will be 0.5mL. 
 
Blood Volume and Measurements. 
A 0.5 ml will be obtained on the morning after the lipid infusion has been advanced to the peak 
infusion rate (1.5 or 3.0 g/kg/d). 
The priority for measurements for 0.5 ml sample will be: 
1. UB [10ul serum] in duplicate [20 ul serum] 
2. Albumin [10ul serum] in duplicate [20 ul serum] 
3. Unbound FFA complete (60ul serum) in duplicate (120ul serum) 
This includes FFA blended estimate 
On other days, 0.25 ml blood will be obtained each morning (up to 6 samples). 
The priority for measurements for the 0.25 ml samples will be: 
1. UB [10ul serum] in duplicate [20 ul serum] 
2. Albumin in duplicate [10ul serum] in duplicate [20 ul serum] 
3. Unbound FFA blended estimate [5ul serum] (#1) 
4. Unbound FFA complete [60ul serum] (#1) 
5. Unbound FFA blended estimate [5ul serum] (#2) 
6. Unbound FFA complete [60ul serum] (#2) 
 
The nurse or person obtaining blood for routine TSB levels will collect whole blood at the same 
time in study-provided red-top microtainer and immediately place the microtainer in a pre- 

IRB NUMBER: HSC-MS-20-0916 
IRB APPROVAL DATE: 07/28/2023 
 
labeled amber plastic bag provided by the research team. The amber bag containing the sample 
will be placed in the specified location in the research refrigerator (4 degrees Celcius) as soon 
as feasible. A member of research team will pick up the specimen within 12 hours, transport the 
specimen to the UT-Houston McGovern Medical School. In the laboratory space at UT Houston 
McGovern Medical School, a centrifuge will be used to separate serum which will be labeled 
and frozen at minus 80 degrees Celsius until samples are shipped in batch to Fluoresprobe 
Sciences in San Diego, California. 
 
Measurands in each whole blood sample will include concentrations of UB, albumin, total 
unbound free fatty acids (uFFA), and a uFFA profile, which includes concentrations of specific 
uFFA. These results will not be available with the bedside clinician and will not affect direct 
patient care. These will be linked with any of the following measurands from the same blood 
sample measured in the hospital laboratory: TSB, indirect bilirubin, direct bilirubin, albumin, 
triglyceride, glucose, serum bicarbonate. Additionally, if a blood gas is obtained within 4 hours of 
this blood draw, the pH from that blood gas will be linked to the sample, providing no intervening 
ventilator changes were made prior to the blood draw. Other data reflecting general status and 
severity of illness and/or potentially influencing UB levels will be abstracted from the medical 
record, including baseline variables such as sex, gestation, anthropometrics, multiple gestation, 
delivery information, Apgar scores, SNAP-II scores, Z scores at birth, 28 days of life, and 36 
weeks postmenstrual age, etc. 
 
Data Management. Data will be entered and stored in a secure UTH REDCap database. Paper 
logs of data will be secured in a locked cabinet or room. 
 
Outcome Measures. To be compared by treatment group: 
Primary outcomes: 
• 
Area under the UB curb with UB concentration >40 nM/L 
• 
BAER wave V latency at 34-36 weeks post menstrual age (or as soon as feasible if the 
infants if an artifact free BAER cannot be obtained at 34-36 weeks) 
Secondary outcomes: 
• 
Mean UB concentration and proportion of measurements >40 nM/L, peak UB 
• 
Peak UB concentration 
• 
Area under the total unbound FFA (uFFA) concentration – time curve; mean FFAu and 
peak uFFA 
• 
Peak total serum bilirubin (TSB) 
• 
Direct bilirubin > 1.5 mg/dL before discharge 
• 
Macronutrients prescribed (parenteral and enteral protein, fat and carbohydrate, 
g/kg/day) 
• 
Weight change (g/kg/day) and Z score change from birth through day 28 and at 36 
weeks postnatal age 
• 
Relevant data abstracted from the medical record and stored in the existing databases: 
o Serial FiO2 and ventilator settings (routinely collected generic data) 
o Bronchopulmonary dysplasia (oxygen requirement at 36 weeks PMA) 
o Perinatal and hospital acquired sepsis episodes 
o Other clinical findings potentially related to signs of or susceptibility to bilirubin 
neurotoxicity 
o Death or NDI as assessed at 24 months PMA 
o Death or hearing loss at 24 months PMA 
o Death or cerebral palsy at 24 months PMA 

IRB NUMBER: HSC-MS-20-0916 
IRB APPROVAL DATE: 07/28/2023 
 
Cohort analyses (across study groups and any infants in the observational arm) Associations of 
interest will include: 
• 
UB and death or NDI, unadjusted and adjusted for potential confounders 
• 
UB and wave V latency, unadjusted and adjusted for potential confounders 
• 
Wave V latency and death or NDI, unadjusted and adjusted for potential confounders 
• 
uFFA measured by single probe and total uFFA measured as the sum of individual uFFA 
• 
uFFA and UB 
• 
Total uFFA and individual uFFA(s) 
 
Power and Sample Size. We plan to study sufficient infants at UTH to assess BAERs in 40 
infants in each treatment group and have more than 80% power at P < 0.05 to identify a 
difference between groups in wave V latency longer than 0.3 millisecond (SD = 0.5 millisecond). 
This sample size would also afford sufficient power to assess a clinically important difference in 
UB level. 
 
I have the opportunity to enroll more patients within the limitations of my funding period, 
scheduled to end June 2024. I have been successful at enrolling patients at an accelerated rate 
from the minimum needed for adequate power. My current enrollment rate is 4-5 patients per 
month, and my target is 3 patients per month. The greater than anticipated enrollment rate has 
occurred because of the significant and unanticipated increase in the census of tiny and 
premature babies. By increasing our sample size, this will allow me the opportunity to ensure 
adequate power for an important trial, not likely to ever be repeated, and provide a more narrow 
confidence interval for more precise results. If differences are appreciated this would provide 
pilot data to motivate a larger and multicenter trial to investigate an earlier measure for 
neurodevelopmental impairment, allowing for earlier interventions and treatment. I propose the 
largest feasible enrollment for the remainder of my funding period or n=175 infants (Enroll an 
average of 5 infants per month for 11 months remaining in funding). 
 
Data Analysis. Intention-to-treat analyses will be performed under the supervision of Claudia 
Pedroza. Generalized linear mixed models will be performed to analyze all outcomes and will 
include treatment group, PT type (continuous and cycled), as covariates with random effects for 
study site. Interaction will be assessed for treatment group and PT type. Bayesian analyses will 
be performed in evaluating differences in treatment effects overall and in different patient 
subgroups and centers. For the primary outcome and any other continuous outcome, a linear 
regression model will be used. Binary outcomes will be analyzed with a logistic regression and 
count data with a Poisson or negative binomial regression model. All priors will be neutral. 
For binary outcomes, all priors will be centered at RR of 1.0 (indicative of no difference between 
treatment groups with a 95% prior interval of 0.3-3.0 (in the log RR scale a Normal distribution 
with mean of 0 and variance of 0.50). A Normal (0,102) prior will be used for the intercept term 
and Normal (0,1) for all other variables in the model. For the standard deviation of the center 
random effect, a half-Normal (0,1) prior will be used. Similar neutral informative priors (based on 
previous NRN PT trial9 where possible) will be used for non-binary outcomes. We will report 
posterior medians and 95% credible intervals for group differences and relative risks. We will 
also report posterior probability of benefit/harm for each outcome. 
 
Similar analyses will be conducted for the cohort analyses (including infants in the observational 
arm). 
 
Data Interpretation. If UB is higher and BAER wave V latency is longer in the UL than the RL 
group, the findings would likely prompt changes to more conservative use of Intralipid use in the 

IRB NUMBER: HSC-MS-20-0916 
IRB APPROVAL DATE: 07/28/2023 
 
first 1-2 weeks after birth in extremely preterm infants. If values for UB and BAER wave V 
latency in the UL group are no higher than the RL group, the findings would support continue 
use of the UL regimen to provide somewhat greater caloric intake. If UB is higher with no 
discernible effect on wave V latency, the findings would suggest that the UB level were not high 
enough to cause bilirubin neurotoxicity with effects lasting to 34-36 weeks. However, findings at 
2 years would need to be scrutinized for evidence of adverse neurodevelopmental effects. 
 
Data Safety and Monitoring. Claudia Pedroza, PhD, the study statistician, will conduct 
an interim analysis of mortality when half the planned sample size has been discharged from 
the neonatal ICU. If there is a Bayesian posterior probability >99% (assuming a neutral prior 
probability), the study statistician (Claudia Pedroza, PhD), will notify the Dr. Amir Khan, Medical 
Director of the CMHH Neonatal ICU and the Director of the Neonatology Division. Unless there 
are important chance differences between treatment groups in baseline risk factors that 
are known to influence outcomes of extremely premature infants (birth weight, gestational age, 
sex, multiple births (twins, triplets), antenatal steroids, high ventilator settings) and that 
could account for differences in outcome, she would contact Amir Khan, MD. They would decide 
whether to halt enrollment in the study. 
 
Predischarge outcome date will of course be entered into the study database for each infant 
once he/she is discharged from the NICU. The rationale for the stopping guideline is that 
impairment is likely to be a persisting problem and that other neonatal outcomes short of death 
(IVH, NEC, BPD) are short term outcomes less important than impairment or death. Were we 
performing frequentist analysis, the stopping guideline would be based on a p<0.01 (two-tailed). 
References 
 
1 Hay WW. Aggressive nutrition of the preterm infant. Curr Pediatr Rep 2013;1:doi:10.1007/s40124-013- 
0026-4. 
 
2 Simmer K, Rao SC. Early introduction of lipids to parenterally-fed preterm infants. Cochrane Database 
Syst Rev. 2005 Apr 18;(2):CD005256. 
 
3 Effect of free fatty acids on bilirubin-albumin binding affinity and unbound bilirubin in premature infants. 
Amin SB.JPEN J Parenter Enteral Nutr. 2010 Jul-Aug;34(4):414-20 
 
4 Hegyi T, Kleinfeld A, Huber A, Weinberger B, Memon N, Shih WJ, Carayannopoulos M, Oh W Effects of 
Soybean Lipid Infusion on Unbound Free Fatty Acids and Unbound Bilirubin in Preterm Infants. J Pediatr. 
2017 May;184:45-50 
 
5 Amin SB, Maisels MJ, Watchko JF Early Lipid Infusions and Unbound Bilirubin in Preterm Neonates: A 
Cause for Concern?.J Pediatr. 2017 May;184:6-7 
 
6 Shapiro SM, Popelka GR. Auditory impairment in infants at risk for bilirubin-induced neurologic 
dysfunction. Semin Perinatol. 2011;35(3):162-170. 
 
7 Wennberg RP, Ahlfors CE, Bickers R, McMurtry CA, Shetter JL. Abnormal auditory brainstem response 
in a newborn infant with hyperbilirubinemia: improvement with exchange transfusion.J Pediatr. 
1982;100(4):624-626. 
 
8 Kuriyama M, Tomiwa K, Konishi Y, Mikawa H. Improvement in auditory brainstem response of 
hyperbilirubinemic infants after exchange transfusions. Pediatr Neurol. 1986;2(3):127-132. 

IRB NUMBER: HSC-MS-20-0916 
IRB APPROVAL DATE: 07/28/2023 
 
 
 
9 Arnold C, Tyson JE, Pedroza C, et al Cycled Phototherapy Dose-Finding Study for Extremely Low-Birth- 
Weight Infants: A Randomized Clinical Trial. JAMA Pediatr. 2020 Apr 27:e200559 
 
10 Lasky RE, Church MW, Orlando MS, et al The effects of aggressive vs. conservative phototherapy on 
the brainstem auditory evoked responses of extremely-low-birth-weight infants..Pediatr Res. 2012 
Jan;71(1):77-84. 
 
11 Watchko JF, Maisels MJ. The enigma of low bilirubin kernicterus in premature infants: why does it still 
occur, and is it preventable? Semin Perinatol. 2014;38(7):397-406 
 
12 Oh W, Stevenson DK, Tyson JE et al.Influence of clinical status on the association between plasma 
total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth 
weight infants. Acta Paediatr. 2010 May;99(5):673-8.