MEMORANDUM
DATE:
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
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 95th 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
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
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
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).
Age in hours
|
Total Serum
Bilirubin Level, in mg/dL
|
|||
|
|
Consider
phototherapy
|
Phototherapy
|
Exchange
transfusion if intensive phototherapy fails
|
Exchange
Transfusion and intensive phototherapy
|
< 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
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
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
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.