MEMORANDUM

DATE: May 14, 2003

TO: Pediatric Subcommittee of the Anti-Infective Drugs Advisory
Committee

FROM: Division of Pediatric Drug Development

SUBJECT: Briefing Document for June 11 Open Session of the Pediatric
Advisory

> Committee on Hyperbilirubinemia and Drug Development in the Term
>
> and Near -- Term Newborn Infant

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Introduction

Jaundice occurs in about 60% of all newborns. The management of
hyperbilirubinemia in the healthy term and near-term newborn has long
been controversial. Central to the controversy is the need to find a
balance between the risk of the rare but devastating occurrence of
kernicterus and the potential adverse consequences of therapeutic
interventions to prevent it. Eleven years ago, Newman and Maisels
highlighted this controversy proposing that jaundiced infants without an
underlying illness were at low-risk for bilirubin toxicity and that "the
risks and costs of identifying and treating high bilirubin levels may
exceed the benefits"(1). In 1994, the American Academy of Pediatrics
(AAP) issued its first practice parameter on the management of
hyperbilirubinemia in healthy newborns. It was defined as otherwise
healthy, non-isoimmunized newborns of at least 37 weeks of gestation who
did not exhibit jaundice in the first 24 hours of life (2).

Subsequent reports have suggested an increase in the frequency of
kernicterus in this population, thus raising concerns that the treatment
pendulum has swung too far with serious hyperbilirubinemia in healthy
newborns going untreated and significant neurotoxicity in the form of
kernicterus the result (3, 4). In 2001, the AAP Subcommittee on Neonatal
Hyperbilirubinemia issued a commentary that identified the common
clinical risk factors for severe hyperbilirubinemia and the root causes
for new cases of kernicterus. It emphasized key recommendations for
management of jaundice from the 1994 practice parameter and identified
areas in need of further research (5). In addition, the commentary
mentioned that the AAP treatment recommendations were undergoing
revision.

In preparation for these revised guidelines, the AAP requested the U.S.
Agency for Healthcare Research and Quality (AHRQ) to commission an
evidence review of several key questions about neonatal
hyperbilirubinemia. This report (herein referred to as the AHRQ Report)
was issued in January 2003. The AHRQ Report examined the relationship
between severe hyperbilirubinemia and neurodevelopment (adjusting for
the role of effect modifiers), the efficacy of phototherapy, the
reliability of various strategies for predicting hyperbilirubinemia, and
the accuracy of transcutaneous bilirubin measurements (6). Various
aspects of the diagnosis, management, and consequences of
hyperbilirubinemia in the term and near-term newborn are summarized
below.

Descriptors of Jaundice and Hyperbilirubinemia

There are no standardized definitions for neonatal hyperbilirubinemia
and there is limited gestational age adjusted data on the distribution
of bilirubin in the newborn period. Criteria for describing
hyperbilirubinemia refer to absolute levels of bilirubin measured at any
age in the neonatal period, and specific bilirubin levels linked to
infant age in hours. "Physiologic jaundice" is a commonly used term
implying that the bilirubin level is within the normal range for age, is
not due to a pathologic risk factor such as hemolysis, and has
traditionally not required medical intervention. The 1994 AAP Guidelines
define jaundice present in the first 24 hours of life to be "pathologic"
(2).

Predicting Risk for Severe Hyperbilirubinemia and Kernicterus

Several authors define "severe hyperbilirubinemia" as levels of
bilirubin that are greater than the 95^th^ percentile for chronological
age. Clinical risk factors for that condition in term and near term
infants include: jaundice in the first 24 hours of life; visible
jaundice before hospital discharge; previous jaundiced sibling;
gestational age of 35-38 weeks at birth; exclusive breastfeeding; East
Asian race; bruising and/or cephalohematoma; maternal age of 25 years or
more; and male gender (5)(7).

Underlying etiologies for severe hyperbilirubinemia include active
hemolysis and inborn errors of metabolism. A recent case review by the
AAP Subcommittee on Neonatal Hyperbilirubinemia identified the following
root causes for kernicterus (5):

-   Hospital discharge before 48 hours of life, with no early follow up
    (especially for infants born at 35 to 37 weeks gestational age);

-   Failure to check the bilirubin level in an infant noted to be
    jaundiced in the first 24 hours;

-   Failure to recognize the presence of risk factors for
    hyperbilirubinemia;

-   Underestimating the severity of jaundice by clinical (visual)
    assessment;

-   Lack of concern regarding the presence of jaundice;

-   Delay in measuring serum bilirubin despite marked jaundice; and

-   Failure to respond to parental concern regarding jaundice, poor
    feeding, or lethargy.

A recent study evaluated whether the level of total serum bilirubin
(TSB) collected prior to hospital discharge could be used to model
subsequent risk of clinically significant hyperbilirubinemia. The model
assigned three levels of risk to postnatal age in hours specific TSB
(8).

Screening and Diagnosis

The first screening method for jaundice is visual inspection of the
infant's skin. Jaundice is usually visible when the total serum
bilirubin level reaches 6 mg per deciliter (mg/dL) serum or more.
Limitations of visual inspection include inter-observer variability,
dark skin pigmentation in the infant that obscures the yellow hue, and
infrequent physical examinations. In term and near term infants, peak
bilirubin levels commonly occur in the second half of the first week of
life, usually after hospital discharge. This peak may occur later in
breast-fed infants and pre-term infants.

Early hospital discharge reduces the opportunity for frequent physical
assessments. Discharge before 48 hours of age is now common among
newborns delivered via an uncomplicated vaginal delivery and these
infants may have only one physical examination before going home. The
AAP and the American College of Obstetrics and Gynecology (ACOG) now
recommend one physical examination within 24 hours of birth and a second
within 24 hours prior to discharge -- both of which should include an
observation for jaundice (9). In addition, if an infant is discharged at
less than 48 hours of age, the AAP and ACOG recommend a similar
evaluation within 48 hours of discharge. In cases where there is no
second inpatient exam and/or timely outpatient follow-up, progressive
hyperbilirubinemia may escape recognition.

Quantification of total serum bilirubin (TSB) is the current standard
for diagnosing hyperbilirubinemia. Methods for assessing TSB include the
following: bilirubin oxidase; 2.5.dichlorophenyldiazonium
tretrafluoroborate diazo; direct spectrophotometry; high performance
liquid chromatography (HPLC); and reflectance spectrophotometry (10).
Methods differ in their ability to fractionate bilirubin, effects of the
pH of the sample on the test result, and utility of the test based on
the postnatal age of the infant. All tests are subject to impact of
serum sample collection, due to the breakdown of bilirubin when it is
exposed to light. Additionally, availability of these tests and turn
around time for receiving results vary across the United States.
Furthermore, intra- and even greater inter-laboratory variability exists
(11).

Transcutaneous bilirubinometry (TcB) measurement has emerged as a
non-invasive screening method that may reduce the number of blood
collections needed to monitor change in TSB. The FDA has cleared the
following devices to measure TcB: Abbott Nbil; Air Shields JM-102
Jaundice Meter; Air Shields JM-103 Jaundice Meter; Chromatics Colormate
III; Chromatics Colormate TLC Bilitest; Ingram Icterometer;
Instrumentation Laboratory Synthesis; Minolta Hill-Rom Air shields
Bilirubinometer; Respironics Bilichek Non-Invasive Bilirubin Analyzer;
and the SpectRx Bilicheck TM. The AHRQ Report found that the correlation
coefficients for TcB compared to TSB in these devices ranged from 0.84
to 0.96. Factors such as the skin assessment site, the actual level of
TSB, the degree of skin pigmentation, and hemoglobin level may influence
the strength of correlation between TcB and TSB (6).

Utility of the end-tidal carbon monoxide measurement (Natus CO-STAT
analyzer) in combination with a single TSB has also been investigated in
order to potentially improve the predictive value of TSB measured in the
first days of life (12).

Kernicterus

Kernicterus, or bilirubin encephalopathy, is a rare though serious
complication of severe hyperbilirubinemia, occurring in fewer than 1 in
250,000 live births (19). In the acute phase, infants with kernicterus
are lethargic with low tone and a poor suck. Infants with kernicterus
may go on to develop clinical findings that include hypertonia,
high-pitched cry, choreo-athetoid cerebral palsy, dental dysplasia,
paralysis of upward gaze, and cognitive and other disabilities. The
mortality rate for kernicterus is at least 10 percent, and long term
morbidity at least 70 percent. The concentration and the exposure
duration of bilirubin in the brain are determinants of bilirubin
neurotoxicity (13). However, correlation between serum bilirubin
concentration and encephalopathy is weak in infants without active
hemolysis (13). The AHRQ Report found that the preponderance of
kernicterus cases occurred in infants with serum bilirubin levels above
20 mg/dl. Whether that association is causal is not clear. This report
further concludes that a single TSB was not sufficient to predict
long-term behavioral or neurodevelopmental outcomes for
hyperbilirubinemia.

As mentioned earlier, recent reports suggest that the frequency of
kernicterus has increased in the last decade. However, no long-term
population-based surveillance systems currently exist in the United
States to answer that question. Efforts to establish kernicterus
surveillance are ongoing through the Centers for Disease Control and
Prevention National Center for Birth Defects and Developmental
Disabilities.

Management

The 1994 AAP Management guidelines provide recommendations for
intervention based on an infant's age in hours and total serum bilirubin
(see Table below).

## 

##  

## **Table. Management of Hyperbilirubinemia in the Healthy Term Newborn (2)**

+-------------+-------------+-------------+-------------+-------------+
| # *Ag       | # *Total    |             |             |             |
| e in hours* |  Serum Bili |             |             |             |
|             | rubin Level |             |             |             |
|             | , in mg/dL* |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| #           | #           | # P         | # Exchange  | # Exc       |
|             |  Consider p | hototherapy |  transfusio | hange Trans |
|             | hototherapy |             | n if intens | fusion and  |
|             |             |             | ive phototh | intensive p |
|             |             |             | erapy fails | hototherapy |
+-------------+-------------+-------------+-------------+-------------+
| # \< 24     | #           | #           | #           | #           |
+-------------+-------------+-------------+-------------+-------------+
| # 25-48     | # \>12      | # \> 15     | # \> 20     | # \>25      |
+-------------+-------------+-------------+-------------+-------------+
| # 49-72     | # \> 15     | # \> 18     | # \>25      | # \> 30     |
+-------------+-------------+-------------+-------------+-------------+
| # \> 72     | # \> 17     | # \>20      | # \> 25     | # \> 30     |
+-------------+-------------+-------------+-------------+-------------+

#  

Phototherapy has been the standard of care for treatment of neonatal
hyperbilirubinemia for approximately 40 years. Phototherapy acts by
converting bilirubin to compounds that can avoid the hepatic conjugation
system and be eliminated in the urine or the bile without further
metabolism. Phototherapy is usually administered in the hospital setting
during the post-partum stay, but also upon hospital re-admission.
Phototherapy may also be used in the home setting.

Potential adverse effects of phototherapy -- which include, but are not
limited to, skin rash overheating, and dehydration -- are usually mild
if appropriate precautions are taken to assure proper thermal control,
hydration, and covering of the eyes. The constraints imposed by the
administration of phototherapy may reduce the opportunity for
maternal-infant interaction, especially if the infant remains in the
hospital after the mother is discharged. When administered in the home,
phototherapy can be disruptive to the family/s adjustment to its new
member. There is no evidence to suggest that phototherapy has any
adverse long-term effect (6)(9).

In a study cohort of almost 70,000 babies during 1992-1994,
rehospitalization for jaundice was associated with race/ethnicity
(Caucasian and Asian more likely than African-American and Hispanic);
primaparity; preterm birth; breast-feeding; and suspicion of jaundice
during the initial hospitalization (14). The median pre-admission TSB
was 20.6mg/dl, and almost 90% of the re-admitted babies received
phototherapy.

The AHRQ Report evaluated the ability of phototherapy to prevent the
serum bilirubin from exceeding 20mg/dl and the effect of this treatment
on neurodevelopmental outcome (6). The authors concluded that between
six and 10 healthy newborns with bilirubin levels above 15 mg/dl needed
to be treated with phototherapy, to prevent one occurrence of a
bilirubin level above 20mg/dl. Phototherapy combined with cessation of
breastfeeding and substitution with formula was found to be the most
efficient treatment protocol.

Use of exchange transfusion has decreased largely due to the prevention
of Rh iso-immunization and use of phototherapy interventions in infants
considered at high risk for developing kernicterus. Exchange transfusion
is utilized when phototherapy fails, and has become an uncommon
procedure in the U.S. Exchange transfusion to treat hyperbilirubinemia
is now rare in the U.S.

Metalloporphyrin Heme Oxygenase Inhibitors

There are no approved drugs for the treatment or prevention of neonatal
hyperbilirubinemia. Metalloporphyrin (Mps) heme oxygenase inhibitors
have been studied in animals and humans for these indications and act by
inhibiting the heme oxygenase enzyme, thereby limiting the conversion of
heme to bilirubin. Tin mesoporphyrin has been studied in preterm
infants, full term infants, and those with G-6-P-D deficiency
(15)(16)(17). Treated infants required less phototherapy compared to
controls. A transient erythematous rash was the most common adverse
event reported in human newborns receiving tin mesoporphyrin. In
addition, Mps are photosensitizers, suggesting a potentially harmful
interaction with phototherapy.

In animal models, the half-life for tin mesoporphyrin was at least nine
months, with long-term deposition of the drug in the
reticulo-endothelial system. In vitro studies demonstrate inhibition by
Mps of a variety of metabolic and enzymatic processes (18). The human
safety data base for tin mesoporphyrin is limited. Limitations of the
human safety data include the timing and duration of safety monitoring
and the specific safety assessment parameters collected and evaluated.
In addition, the safety monitoring to date has not addressed the
potential long-term safety signals present in the animal toxicology
literature. For example, it is unknown whether there is human health
impact from long-term deposition of this drug in the
reticulo-endothelial system.

**Closing Thoughts**

In summary, the management of hyperbilirubinemia in the term and
near-term newborn remains controversial, with a continuing need to find
an appropriate balance between the risk of the rare occurrence of
kernicterus and the potential adverse events of therapeutic
interventions to prevent it. The 1994 AAP guidelines strove for that
balance, yet subsequent reports suggested an increase in the frequency
of kernicterus -- a rare and serious life-long disability. Adding to
this complexity is the change in routine hospital discharge practices
for healthy newborn infants, with short hospital stays of 24 to 48 hours
becoming the norm. The consequences of earlier newborn discharge are
less frequent screening for jaundice and the potential for a newborn
infant with a rapidly rising bilirubin level to go unrecognized.

Following release of the 1994 AAP guidelines, a variety of research
efforts have attempted to address remaining controversies about the
description, screening, diagnosis, and treatment of hyperbilirubinemia
in the term and near-term newborn. The prospect for widespread
pharmacological treatment to prevent hyperbilirubinemia in this
population is one new development that raises many research and ethical
quandaries. These complex issues will be the substance of your
discussion on June 11th, 2003.

Currently, this research paradigm recommends the prophylactic use of
drugs to prevent hyperbilirubinemia and the need for phototherapy. This
approach inevitably will lead to treatment of individual healthy
newborns that in the past would receive no treatment at all for their
transient jaundice. In that research context, what knowledge about
safety, in both the short and long term, must be known about the drug
before clinical trials proceed? What safety issues should be addressed
during and after any clinical trial of a drug to prevent
hyperbilirubinemia? Since the major adverse consequence of severe
untreated hyperbilirubinemia remains kernicterus\--a condition that is
still so rare that its prevalence is difficult to estimate\--how does
one measure efficacy of any preventive drug therapy? Is prevention of
phototherapy an appropriate endpoint? Are there subpopulations that
might be at especially high risk for kernicterus and would be
appropriate candidates for a preventive drug therapy trial? These and
related issues will be the focus of our discussion on June 11th.

References

1.  Newman TB, Maisels MJ. Evaluation and treatment of jaundice in the
    term newborn: A kinder, gentler approach.Pediatr.1992;89:809-818

2.  AAP Provisional committee for Quality Improvement and Subcommittee
    on Hyperbilirubinemia. Practice parameter: Management of
    hyperbilirubinemia in the healthy term newborn. Pediatr 1994;
    94:558-562.

3.  Kernicterus in full-term infants-United States, 1994-1998.MMWR
    2001;50:491-494.

4.  Bhutani VK Johnson LH. Kernicterus: Lessons learned for the future
    from a current tragedy. Neo Reviews2003; 4:e30-32.

5.  AAP Subcommittee on Neonatal Hyperbilirubinemia. Neonatal Jaundice
    and Kernicterus. Pediatr. 2001; 108: 763-765.

6.  Agency for Healthcare Research and Quality. Management of Neonatal
    Hyperbilirubinemia. Evidence Report/Technology Assessment Number 65,
    January 2003. [**www.ahrq.gov**](http://www.ahrq.gov/)

7.  Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and
    prevention of Extreme neonatal hyperbilirubinemia in a mature health
    maintenance organization. Arch Pediatr Adolesc Med
    2000;154:1140-1147.

8.  Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a
    predischarge hour- specific serum bilirubin for subsequent
    significant hyperbilirubinemia in healthy term and near-term
    infants.Pediatrics 1999;103:6-14.

9.  AAP/ACOG. Guidelines for Perinatal care. 2002.

10. Maisels MJ. In Avery GB, Fletcher 869-873.MA, MacDonald MG, eds.
    Neonatology. Lippincott; 1999, p.800.

11. Vreman HJ, Verter J, Oh W, et al. Interlaboratory variability of
    bilirubin measure-ments. Clin Chem 1996;42(6,part 1 ): 869-873.

12. Stevenson DK, Vreman HJ. Carbon monoxide production in neonates.
    Pediatrics 1997; 100:252-257.

13. Dennery PA, Seidman DS, Stevenson DK. Neonatal Hyperbilirubinemia. N
    Eng J Med. 2001; 344:581-590.

14. Geiger AM, Petite DB, Yak JF. Rehospitalisation for neonatal
    jaundice: risk factors and outcomes.Paediatric and Perinatal
    Epidemiology 2001;15:352-358.

15. Martinez JC, Garcia HO, Otheguy LE, et al. Control of severe
    hyperbilirubinemia in full-term newborns with the inhibitor of
    bilirubin production Sn-Mesoporphyrin. Pediatr 1999; 103:1-5.

16. Valaes, Petmezaki S, Henschke C, et al. Control of jaundice in
    preterm newborns by an inhibitor of bilirubin production: studies
    with Tin-Mesoporphyrin, Pediatr 1994; 93:1-11.

17. ValaesT, Drummond GS, Kappas A. Control of hyperbilirubinemia in
    Glucose-6-phosphate dehydrogenase deficient newborns using an
    inhibitor of bilirubin production, Sn-mesoporphyrin. Pediatr
    1998;101:1-7.

18. Vreman HJ, Wong RJ, Stevenson DK. Alternative metalloporphyrins for
    the treatment of neonatal jaundice. J. Perinatology 2001; S108-113.

19. Nelson, K. Personal communication.