Cochrane-Metaloporfirinas TTO 2003

Metalloporphyrins for treatment of unconjugated
hyperbilirubinemia in neonates (Review)

Suresh G, Martin CL, Soll R
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2003, Issue 1
http://www.thecochranelibrary.com
Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 1 Severe hyperbiliribunemia. .
Analysis 1.2. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 2 Phototherapy. . . . . .
Analysis 1.3. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 3 Exchange transfusion. . .
Analysis 1.4. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 4 Cutaneous photosensitivity rash.
Analysis 1.5. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 5 Local reaction at site of
intramuscular injection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.6. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 6 Abnormal liver function tests.
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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1
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7
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[Intervention Review]
Metalloporphyrins for treatment of unconjugated

hyperbilirubinemia in neonates
Gautham Suresh1 , Christine L Martin2 , Roger Soll3
1 Department of Pediatrics, Neonatal Division, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. 2 College of Medicine,
University of Vermont College of Medicine, Burlington, Vermont, USA. 3 Division of Neonatal-Perinatal Medicine, University of
Vermont, Burlington, Vermont, USA
Contact address: Gautham Suresh, Department of Pediatrics, Neonatal Division, Dartmouth-Hitchcock Medical Center, One Medical
Center Drive, Lebanon, NH, 03576-001, USA. gautham.suresh@hitchcock.org.
Editorial group: Cochrane Neonatal Group.
Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.
Review content assessed as up-to-date: 13 November 2002.
Citation: Suresh G, Martin CL, Soll R. Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates. Cochrane
Database of Systematic Reviews 2003, Issue 1. Art. No.: CD004207. DOI: 10.1002/14651858.CD004207.
ABSTRACT
Background
Metalloporphyrins are heme analogues that inhibit heme oxygenase, the rate-limiting enzyme in the catabolism of heme to bilirubin.
By preventing the formation of bilirubin, they have the potential to reduce the level of unconjugated bilirubin in neonates and thereby
reduce the risk of neonatal encephalopathy and long term neurodevelopmental impairment from bilirubin toxicity to the nervous
system.
Objectives
1. To determine the efficacy of metalloporphyrins in reducing bilirubin levels, reducing the need for phototherapy or exchange
transfusion and reducing the incidence of bilirubin encephalopathy in neonates with unconjugated hyperbilirubinemia when compared
to placebo, phototherapy or exchange transfusion.
2. To determine the nature and frequency of side effects of metalloporphyrins when used to treat unconjugated hyperbilirubinemia in
neonates.
Search methods
We searched Medline (1966 - January 2003) and the Cochrane Controlled Trials Register (CCTR) from the Cochrane Library (2003,
issue 1). We hand-searched the articles cited in each publication obtained. We hand searched the abstracts of the Society for Pediatric
Research (USA) (published in Pediatric Research) for the years 1985 - 2002.
Selection criteria
We included only randomized controlled studies, in which preterm or term neonates (age 28 days of life or less) with unconjugated
hyperbilirubinemia due to any cause were randomly allocated to receive a metalloporphyrin in the treatment arm(s), and to receive a
placebo or a conventional treatment (phototherapy or exchange transfusion) or no treatment for hyperbilirubinemia in the comparison
arm(s). Any preparation of metalloporphyrin could be used, in any form, by any route, at any dose.
Data collection and analysis

Two authors extracted data independently. Data were entered into Revman by one author and checked by a second author. Prespecified
subgroup analyses were planned in term versus preterm infants, hemolytic versus non-hemolytic causes of jaundice and according to
the type of metalloporphyrin used.
Main results
Three small studies, enrolling a total of 170 infants, were eligible for inclusion in this review. None blinded intervention or outcome
assessment. In all three studies some patients were excluded after randomization. Metalloporphyrin-treated infants appeared to have
short-term benefits compared to controls, including a lower maximum plasma bilirubin level in one study, a lower frequency of severe
hyperbilirubinemia in one study, a decreased need for phototherapy, fewer plasma bilirubin measurements and a shorter duration of
hospitalization. None of the enrolled infants required an exchange transfusion in the two studies that described this outcome. None
of the studies reported on neonatal kernicterus, death, long-term neurodevelopmental outcomes or iron deficiency anemia. Though a
small number of metalloporphyrin-treated as well as control infants developed a photosensitivity rash, the trials were too small to rule
out an increase in the risk of photosensitivity or other adverse effects from metalloporphyrin treatment. No subgroup analyses were
possible due to the small number of included trials.
Authors conclusions
Treatment of neonatal unconjugated hyperbilirubinemia with metalloporphyrins may reduce neonatal bilirubin levels and decrease the
need for phototherapy and hospitalization. There is no evidence to support or refute the possibility that treatment with a metalloporphyrin decreases the risk of neonatal kernicterus or of long-term neurodevelopmental impairment due to bilirubin encephalopathy.
There is no evidence to support or refute the possibility that cutaneous photosensitivity is increased with metalloporphyrin treatment.
Routine treatment of neonatal unconjugated hyperbilirubinemia with a metalloporphyrin cannot be recommended at present.
PLAIN LANGUAGE SUMMARY

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates
Metalloporphyrins may reduce very high levels of jaundice in newborn babies, but more research is required on safety and to compare
it with other treatments. Jaundice is very common in newborn babies, and is caused by the liver producing too much bilirubin, a
yellow-coloured bile substance. A very high level of bilirubin can damage the developing brain, and is treated with phototherapy (light
therapy) or exchange transfusions. Metalloporphyrins are drugs that can prevent the formation of bilirubin, but they might also cause
photosensitivity (sensitivity to light) and anaemia (decreased hemoglobin levels in the blood). The review of trials found some evidence
that metalloporphyrins might be able to reduce bilirubin, but more research is needed on short and long-term effects and to compare
it with other treatments.
BACKGROUND
Unconjugated hyperbilirubinemia is a common problem in the
neonatal period, occurring in 30-50% of term newborns (Kivlahan
1984). It is the most common cause of readmissions to the hospital
after early hospital discharge of term neonates (Catz 1995, Brown
1998). It is more common in preterm infants than in term infants,
mainly because of a delay in the expression of hepatic glucuronyl
transferase, the enzyme that conjugates bilirubin (Gartner 1994).
There are many pathologic conditions leading to an elevated un-
conjugated bilirubin level in neonates and these can be broadly

grouped into hemolytic and non-hemolytic conditions. Under certain circumstances unconjugated bilirubin can be toxic to the central nervous system, resulting in encephalopathy and neurologic
impairment (Gourley 1997). Factors influencing bilirubin toxicity to the brain cells of newborn infants are complex and incompletely understood; they include those that affect the serum albumin concentration and those that affect the binding of bilirubin
to albumin, the penetration of bilirubin into the brain, and the
vulnerability of brain cells to the toxic effects of bilirubin. It is

not known at what bilirubin concentration or under what circumstances significant risk of brain damage occurs or when the risk of
damage exceeds the risk of treatment (AAP 1994). Currently the
standard therapies for hyperbilirubinemia include phototherapy
and exchange transfusion. These therapies aim to reduce high levels of unconjugated bilirubin or prevent the development of such
high levels, and are usually instituted at different levels of bilirubin
in different categories of infants, based on the recommendations
of experts (AAP 1994, Gartner 1994).
In recent years, various metalloporphyrins have become available that show potential for the prevention and treatment of hyperbilirubinemia. They act by competitively inhibiting the enzyme microsomal heme oxygenase, the rate limiting enzyme in
the catabolism of heme to bilirubin. In this manner, metalloporphyrins decrease the production of bilirubin, in contrast to all
other current methods of therapy for unconjugated hyperbilirubinemia, which act by increasing the excretion of bilirubin after it
is formed. Metalloporphyrins are natural or synthetic heme analogues comprised of a porphyrin moiety such as a deuteroporphryin, protoporphyrin, mesoporphyrin or a bisglycol derivate and
a metal moiety such as tin, zinc, chromium, manganese, copper,
nickel or magnesium (Stevenson 1989, Vreman 2001). Based on
these structural differences, several varieties of metalloporphyrins
have been described, such as zinc protoporphyrin, zinc mesoporphyrin, tin protoporphyrin and tin mesoporphyrin. Various
metalloporphyrins have been reported to decrease naturally occurring or experimentally induced hyperbilirubinemia in animals
and in humans ( Cornelius 1984, Chernick 1989, Drummond
1981, Galbraith 1992, Kappas 1984, Kappas 1988, Kappas 1995a,
Labbe 1999, Martinez 1999, Valaes 1994, Valaes 1998, Vallier
1993, Vreman 1991).
Heme oxygenase is present not only in the liver but also in the
spleen, brain, testis and kidney. Therefore it is important to consider potential effects on the functioning of these other organs
when using metalloporphyrin therapy. Bilirubin is reported to be
a naturally occurring antioxidant in the human body (McDonagh
1990) and decreasing its production in a neonate by using metalloporphyrin therapy can theoretically expose the infant to tissue damage from free oxygen radicals. Adverse effects of metalloporphyrins reported in human studies include photosensitivity
causing cutaneous erythema (Valaes 1994, Galbraith 1992) and,
on prolonged administration, anemia due to the decreased uptake
of iron from the intestine consequent to inhibition of intestinal
heme oxygenase (Galbraith 1992).
In clinical trials metalloporphyrins have been used for the prevention as well as the treatment of neonatal unconjugated hyperbilirubinemia. The use of metalloporphyrins for the prevention of
neonatal unconjugated hyperbilirubinemia will be discussed in a
separate systematic review. In this systematic review we aimed to
evaluate and summarize the evidence on the use of metalloporphyrins for treatment of hyperbilirubinemia in neonates (infants
aged 28 days or less). Treatment with a metalloporphyrin is defined as its use in neonates who have already developed a moderate
or high level of serum bilirubin.
OBJECTIVES
1. To determine the efficacy of metalloporphyrins in reducing bilirubin levels, reducing the need for phototherapy or exchange transfusion and reducing the incidence of bilirubin encephalopathy and long term neurodevelopmental impairment in
neonates with unconjugated hyperbilirubinemia when compared
to placebo, phototherapy or exchange transfusion.
2. To determine the frequency and nature of side effects of metalloporphyrins when used to treat unconjugated hyperbilirubinemia in neonates.
METHODS
Criteria for considering studies for this review
Types of studies
We included only randomized controlled studies, where subjects
were randomly allocated to receive a metalloporphyrin in the treatment arm(s), and to receive a placebo or a conventional treatment
(phototherapy or exchange transfusion) or no treatment for hyperbilirubinemia in the comparison arm(s).
Types of participants
We included studies done in preterm and term neonates, who have
already developed unconjugated hyperbilirubinemia, due to any
cause.
Types of interventions
We included studies in which any preparation of metalloporphyrin
was administered in the neonatal period (up to and including 28
days of life), in any form, by any route, at any dose and its effects
were compared to those of a placebo or a conventional therapy
(such as phototherapy or exchange transfusion) or no treatment
for unconjugated hyperbilirubinemia . Infants treated with metalloporphyrin could, in addition, be treated with phototherapy
either simultaneously or subsequently (but not prior to the use of
metalloporphyrin).

Types of outcome measures

Outcomes to be assessed in the included trials were:
1. Maximum plasma unconjugated bilirubin levels
2. Severe hyperbilirubinemia
3. Decrease in unconjugated bilirubin levels over time
4. Treatment with phototherapy
5. Duration of phototherapy
6. The number of plasma bilirubin measurements
7. Treatment with exchange transfusion
8. Number of exchange transfusions
9. Neonatal encephalopathy (i.e., any abnormality in sensorium,
muscle tone or cry; or occurrence of involuntary movements; or
seizures in association with hyperbilirubinemia in the neonatal period, in the absence of another known cause of neurologic abnormality)
10. Length of hospital stay
11. Neonatal mortality.
12. Presence of neurodevelopmental sequelae (i.e., any sensory,
motor, cognitive, psychologic or behavioral impairment reported
on follow-up any time after the neonatal period)
13. Degree of such neurodevelopmental impairment (expressed as
mean or median scores on tests of neurodevelopmental function
performed any time after the neonatal period)
Adverse effects to be assessed in the included trials were:
1. Cutaneous photosensitivity rash
2. Iron deficiency
3. Local reaction at the site of intramuscular injection
4. Abnormal liver function tests and
5. Neonatal diseases in which free oxygen radicals are thought
to play a role in causation, namely, chronic lung disease, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, severe intraventricular hemorrhage (grade
3 - 4 ), patent ductus arteriosus, retinopathy of prematurity and
necrotizing enterocolitis.
Of all the outcomes and adverse effects mentioned above, the following were not pre-specified in the protocol: severe hyperbilirubinemia, the number of plasma bilirubin measurements, local reaction at the site of intramuscular injection and abnormal liver
function tests. In addition, the outcome cutaneous photosensitivity rash represents a combination of two pre-specified outcomes,
photosensitivity and skin rash. In the results below, length of jaundice-related hospitalization, rather than the length of hospital stay
(which was the pre-specified outcome) is described.
Search methods for identification of studies

See: Collaborative Review Group search strategy. We used the
standard search method of the Cochrane Neonatal Review Group
1. Published manuscripts: We searched Medline (1966 - January
2003) and the Cochrane Controlled Trials Register (CCTR) from
the Cochrane Library (2003, issue 1). We did not limit the search
to any language. We used the following search terms: {metalloporphyrin OR protoporphyrin OR mesoporphyrin}, limited to humans and further limited to the age group of newborn infants (infant, newborn). From the resulting studies we manually extracted
randomized controlled studies that fulfilled the inclusion criteria mentioned above. To identify long term neurodevelopmental
sequelae, we performed a search using the following keywords:
(outcome OR sequelae OR follow-up OR mental retardation OR
cerebral palsy OR hearing OR visual OR motor OR mental OR
psychological ) AND (metalloporphyrin OR protoporphyrin OR
mesoporphyrin) not limited to any age group or language. We also
searched the list of articles cited in each publication obtained, in
order to identify additional relevant articles.
2. Published abstracts: We hand searched the abstracts of the Society for Pediatric Research (USA) (published in Pediatric Research)
for the years 1985 - 2002. For this purpose we used the following key words: {metalloporphyrin OR protoporphyrin OR mesoporphyrin} AND {jaundice or hyperbilirubinemia}. For abstract
books that did not include keywords we limited the search to relevant sections such as hematology, gastrointestinal disorders and
neonatology.
Data collection and analysis

We used the standard method for the Cochrane Collaboration
which is described in the Cochrane Collaboration Handbook.
Selection process: We included randomized controlled trials fulfilling the selection criteria described in the previous section. Two
investigators separately selected the studies for inclusion. They resolved any disagreement by discussion.
Criteria for assessing the methodological quality of the studies:
We used the standard method of the Cochrane Neonatal Review
Group. We assessed the methodological quality of the studies by
assessing the risk for four types of bias (selection, performance,
attrition and detection). Two reviewers separately assessed each
study. They resolved any disagreement by discussion.
Data extraction and entry: Two investigators extracted, assessed
and coded separately all data for each study, using a form that was
designed specifically for this review. We replaced any standard error
of the mean by the corresponding standard deviation. We resolved
any disagreement by discussion. For each study, final data were
entered into RevMan by one reviewer (GKS) and then checked by
a second reviewer (CM).
Statistical analysis: We used the standard method of the Cochrane
Neonatal Review Group, using a fixed effect model. In assessing
the treatment effects for dichotomous outcomes we used the relative risk and risk difference, with 95% confidence intervals. For
outcomes measured on a continuous scale we used the weighted
mean difference, with 95% confidence intervals.
Planned subgroup analyses: We intended to perform analyses in
subgroups of term versus preterm (<37 completed weeks of ges-

tation) infants, hemolytic versus non-hemolytic causes of hyperbilirubinemia and type of metalloporphyrin used.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
We identified seven studies on metalloporphyrin use in neonatal
hyperbilirubinemia. We excluded four of them from this review.
We excluded Kappas 1988 and Valaes 1994 because these randomized trials tested the preventive use of a metalloporphyrin.
We excluded Kappas 2001 because it used historical controls for
comparison with metalloporphyrin-treated infants. We excluded
Valaes 1998 because it compared two different strategies of using a
metalloporphyrin (preventive versus therapeutic use). We included
three randomized trials in which a metalloporphyrin was used to
treat neonates with moderate to high levels of plasma bilirubin
(Kappas 1995a, Kappas 1995b, Martinez 1999). Two of the trials (Kappas 1995a and Kappas 1995b) were reported in a single
publication. Details of these studies are provided in the Table of
included studies. All three compared tin mesoporphyrin in a single
intramuscular dose of six micromoles per kilogram body weight
to phototherapy. In two studies all controls received phototherapy
and in one controls received phototherapy if the plasma bilirubin
rose above pre-defined levels. In all three studies metalloporphyrin
treated patients could receive phototherapy if the plasma bilirubin
rose above pre-defined levels.
Participants
All three studies were single center studies. In the three studies
combined, a total of 84 infants were treated with metalloporphyrin and there were 86 controls. The studies by Kappas 1995a
and Kappas 1995b were conducted in Greece and the study by
Martinez 1999 was conducted in Argentina. Kappas 1995a and
Martinez 1999 studied healthy term neonates. Kappas 1995a included only male neonates aged 36 - 84 hours who were breast and
formula fed. In this study 22 neonates received tin mesoporphyrin
and there were 22 controls. Kappas 1995b included male and female neonates with a gestation of 245 - 265 days (35 weeks to 37
weeks, 6 days) who were 36 - 96 hours of age. In this study 22
neonates received tin mesoporphyrin and there were 20 controls.
Neonates in Martinez 1999 were of both sexes, fully breast fed
and 48 - 96 hours of age. In this study 40 neonates received tin
mesoporphyrin and there were 44 controls. All three studies excluded neonates with congenital anomalies, congenital infection
and birth asphyxia. Additional exclusion criteria used by Kappas
1995a and Kappas 1995b were admission to the neonatal intensive
care unit and G6PD deficiency. Kappas 1995a excluded neonates
with Coombs positive hemolytic disease whereas Kappas 1995b
permitted the inclusion of neonates with ABO incompatibility.

Martinez 1999 excluded, in addition to neonates with the three
conditions mentioned above, neonates with complications such
as respiratory distress syndrome, birth weight less than 10th percentile or greater than the 90th percentile, maternal phenobarbitone therapy, venous hematocrit > 65%, significant bruising, large
cephalhematoma, hemolytic disease (rhesus or ABO incompatibility and a positive Coombs test or a serum bilirubin rising by
greater than 0.5 mg/dl per hour.
Plasma bilirubin criteria
Kappas 1995a and Kappas 1995b included neonates who had a
baseline plasma bilirubin value within a defined range on a chart
depicting time on the X axis and bilirubin levels on the Y axis. The
upper and lower limits of this range rose progressively between 3684 hours and were approximately 7 - 10 mg/dl at 36 hours of life,
11 - 15 mg/dl at 60 hours of life and 14 - 20 mg/dl at 84 hours
of life. Neonates with the onset of jaundice < 36 hours and those
with a plasma bilirubin above the defined range were excluded.
Martinez 1999 included neonates who had a plasma bilirubin of
15 - 18 mg/dl 48 - 96 hours after birth.
Interventions
The experimental intervention in all three trials was tin mesporphyrin in a single dose of six micromoles per kilogram body
weight, given intramuscularly. None of the trials used a placebo
in the control group. In Kappas 1995a and Kappas 1995b, all
neonates in the control group received phototherapy per study
protocol and there was no statistical difference between experimental and control neonates in the mean age at enrollment or in
the mean plasma bilirubin at enrollment. In Martinez 1999, phototherapy was initiated in both intervention and control neonates
if the plasma bilirubin rose to 19.5 mg/dl or higher.
Outcomes
The following outcomes were reported in one or more of the three
studies: maximum plasma bilirubin level attained, severe hyperbilirubinemia (Defined by Kappas 1995 as bilirubin > 23 mg/dl
after 84 hours age or above predefined level on bilirubin chart at
36 - 84 hours and by Martinez 1999 as bilirubin above 19.5 mg/
dl after 48 hours of life), phototherapy, number of plasma bilirubin measurements, exchange transfusion, jaundice-related hospitalization past day 4 of life, cutaneous erythema or photosensitivity, local reactions at the site of intramuscular injection and abnormal liver function tests. None of the three studies described
the presence or absence of the following outcomes: decrease in
unconjugated bilirubin levels over time, neonatal encephalopathy,
neonatal mortality, neurodevelopmental sequelae, iron deficiency,
chronic lung disease, bronchopulmonary dysplasia, patent ductus
arteriosus, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis and retinopathy of prematurity.
Risk of bias in included studies

All three trials had methodologic deficiencies. Full details are provided in the Table.
Method of subject allocation: In Kappas 1995a and Kappas 1995b
eligible infants were randomized in pairs within strata. Allocation
to treatment or control group within each pair was blinded by
using a random numbers table and placing the assignment codes
in serially numbered sealed envelopes. A series of sealed envelopes
was created for each stratification category. Martinez 1999 used
a table of random numbers for randomization. Whether or not
treatment allocation was blinded could not be assessed in this
study.
Masking of caregivers: This was not done in any of the three trials.
Completeness of outcome assessment: In the analyses, infants were
excluded after randomization in all three trials. In Kappas 1995a
and Kappas 1995b, neonates who were found to have G6PD deficiency after randomization were excluded (removed from the analyses) and replaced in their respective pairs by the next eligible infant of the same stratification group. In Kappas 1995a, three infants in the tin-mesoporphyrin group and two in the phototherapy
group were replaced in this manner. In Kappas 1995b one infant
in the tin-mesoporphyrin group was replaced. All such exclusions
were done after the initiation of therapy. Martinez 1999 excluded
infants after randomization if they met the exclusion criteria or
if bilirubin level measurements were not made according to the
study protocol (10 out of 94 infants were excluded after randomization and only the remaining were analyzed). It is not clear if
these exclusions occurred after the administration of the intervention.
Masking of outcome assessment: This was not done in any of the
three trials
Effects of interventions
The maximum plasma unconjugated bilirubin level attained: This
outcome was not described in Kappas 1995a and Kappas 1995b.
In Martinez 1999, the maximum plasma bilirubin values (medians, minimum and maximum values in parentheses) were 16.4
(15 - 19) mg/dl and 17.7 (15 - 24) mg/dl respectively in the metalloporphyrin and control groups (p .0043).
Severe hyperbilirubinemia (defined by Kappas 1995 as bilirubin
> 23 mg/dl after 84 hours age or above predefined level on bilirubin chart at 36 - 84 hours and by Martinez 1999 as bilirubin
above 19.5 mg/dl after 48 hours of life): None of the neonates
in Kappas 1995a or Kappas 1995b developed severe hyperbilirubinemia. In Martinez 1999, 27% of neonates in the control group
developed severe hyperbilirubinemia and were treated with phototherapy whereas none of the metalloporphyrin-treated infants
developed severe hyperbilirubinemia. For this outcome, the summary RR was 0.04 (95% CI 0.00, 0.72) and the summary RD was
-0.13 (95%CI -0.21, -0.06). The estimate of RD for this outcome
demonstrated marked heterogeneity across the three studies.
Decrease in unconjugated bilirubin levels over time: None of the

three studies described this outcome.
Phototherapy: In Kappas 1995a and Kappas 1995b all control
infants received phototherapy per study protocol and none of
the metalloporphyrin treated infants received phototherapy. In
Martinez 1999, none of the metalloporphyrin treated infants and
27% of control infants received phototherapy. For this outcome,
the summary RR was 0.04 (95% CI 0.00, 0.72) and the summary
RD was -0.13 (95%CI -0.21, -0.06).
Duration of phototherapy: The mean duration of phototherapy
provided to control infants was 33.2 hours in Kappas 1995a and
48.6 hours in Kappas 1995b. In neither study did the metalloporphyrin-treated infants receive phototherapy. Standard deviations
were not provided in the publication. This outcome was not reported by Martinez 1999.
The number of plasma bilirubin measurements: This was not a
pre-specified outcome but was described in all three studies. This
number was lower in the metalloporphyrin group than in the
control group in all three studies (mean of 1.6 vs 2.8, p<.001
in Kappas 1995a; mean of 2.5 vs 4.1 in Kappas 1995b p <.003;
median, minimum and maximum of 3, 1 and 9 vs 5, 3 and 11, p
<.0001 in Martinez 1999).
Exchange transfusion: None of the infants (metalloporphyrin or
control group) in Kappas 1995a and Kappas 1995b required an
exchange transfusion. Martinez 1999 did not describe this outcome in their publication.
Neonatal encephalopathy: None of the three studies described the
presence or absence of this outcome.
Length of hospital stay: Jaundice-related hospitalization past day
four of life, the routine discharge day, (excess days) was described
by Kappas 1995a and Kappas 1995b but not by Martinez 1999.
In both, the metalloporphyrin group had fewer excess days than
the control group (5 vs 26 days in Kappas 1995a and 24 vs 42
days in Kappas 1995b).
Neonatal mortality: None of the three studies described the presence or absence of this outcome.
Presence of neurodevelopmental sequelae: None of the three studies described the presence or absence of this outcome.
Degree of neurodevelopmental impairment: None of the three
studies described the presence or absence of this outcome.
Cutaneous photosensitivity rash: This outcome was specifically
looked for in all three studies. In Kappas 1995a, cutaneous erythema developed in one neonate in the metalloporphyrin group
after exposure to direct sunlight while in his mothers room and in
one neonate in the control group after phototherapy. In Kappas
1995b, no neonate in the metalloporphyrin group and one in the
control group developed cutaneous erythema. In all cases the erythema subsided without blistering, desquamation or other sequelae. In Martinez 1999, none of the infants (metalloporphyrin or
control) developed cutaneous erythema or photosensitivity. For
this outcome the summary RR was 0.58 (95% CI 0.08, 4.13) and
the summary RD was -0.01 (95% CI -0.06, 0.04).

Iron deficiency: None of the three studies described the presence

or absence of this outcome.
Local reactions at the site of intramuscular injection: Kappas 1995a
and Kappas 1995b did not describe the presence or absence of this
outcome. Martinez 1999 looked for this outcome and did not find
it to occur in any of the infants treated with metalloporphyrin (n=
40) or controls (n=44).
Abnormal liver function tests: Kappas 1995a and Kappas 1995b
did not describe the presence or absence of this outcome. Martinez
1999 looked for this outcome and did not find it to occur in any
of the infants treated with metalloporphyrin (n=40) or controls
(n=44).
Neonatal diseases in which free oxygen radicals are thought to
play a role in causation, namely, chronic lung disease, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular
leukomalacia, severe intraventricular hemorrhage (grade 3 - 4 ),
patent ductus arteriosus, retinopathy of prematurity and necrotizing enterocolitis: None of the three studies described the presence
or absence of these conditions.
DISCUSSION
The purpose of treatment of unconjugated hyperbilirubinemia is
the prevention of a neonatal encephalopathy that has variously
been labeled as kernicterus, bilirubin encephalopathy and bilirubin-induced neurologic dysfunction (BIND) (Johnson 2002). The
long-term goal of the management of neonatal unconjugated hyperbilirubinemia is the avoidance of neurodevelopmental sequelae
that can result from the toxicity of bilirubin to the immature nervous system. The modern management of neonatal unconjugated
hyperbilirubinemia consists of phototherapy and, in cases with extreme elevations of unconjugated bilirubin, exchange transfusion.
Phototherapy is widely available and has been used for many years.
In this review we have summarized the results of three trials in
which a metalloporphyrin was used to treat neonates with moderate to high levels of plasma bilirubin. The outcomes reported in
all three trials were short-term intermediate outcomes and no outcomes addressing long-term neurodevelopmental status of treated
and control infants are available. Metalloporphyrin-treated infants
appeared to have short-term benefits compared to controls, including a lower maximum plasma bilirubin level in one study, a
lower frequency of severe hyperbilirubinemia in one study, a decreased need for phototherapy, fewer bilirubin measurements and
a shorter duration of hospitalization. There was marked heterogeneity in the estimate of risk difference for severe hyperbilirubinemia across the three studies. This is likely to be the result of
differences in criteria for institution of phototherapy in the control
groups. In Kappas 1995a and Kappas 1995b phototherapy was
instituted in all controls at enrollment whereas in Martinez 1999
it was instituted only at a bilirubin level of 19.5 mg/dl.
In the study by Martinez 1999 the threshold used for initiating phototherapy was higher than the level recommended by the
American Academy of Pediatrics (AAP 1994). This limits the generalizability of the results of this study. However, there is no evidence to support or refute the possibility that treatment with a
metalloporphyrin decreases the risk of neonatal kernicterus, exchange transfusion or the risk of long term neurodevelopmental
impairment. A small number of metalloporphyrin-treated as well
as control infants developed a photosensitivity rash. The trials were
too small to rule out an increase in the risk of photosensitivity or
other adverse effects from metalloporphyrin treatment.
Of the metalloporphyrins, tin mesoporphyrin has been most commonly used in clinical trials on humans, including neonates. Early
neonatal studies of tin mesoporphyrin used doses varying from
one to six micromoles per kilogram body weight. The dose of tin
mesoporphyrin used in all recent studies has been six micromoles
per kilogram body weight. This is the dose that is likely to be used
if this compound were to be come into routine clinical use.
Before metalloporphyrin treatment of neonatal unconjugated hyperbilirubinemia can be considered for routine use, further studies with masking of interventions and outcome assessment are required to compare the safety and efficacy of metalloporphyrins
and phototherapy. Subsequently, the convenience and cost-effectiveness of metalloporphyrin therapy and phototherapy can be
compared and parental preferences can be incorporated to make
decisions about clinical usage. Randomized control trials are required to test whether the use of metalloporphyrins can prevent
the need for an exchange transfusion in neonates with levels of
unconjugated bilirubin that are rising toward the threshold for
exchange transfusion. In such trials the use of a metalloporphyrin
either alone or in conjunction with phototherapy can be compared against phototherapy alone with exchange transfusion and
bilirubin encephalopathy serving as the primary outcomes. If an
exchange transfusion can be prevented, the benefits of metalloporphyrins are likely to outweigh the risks, especially in healthcare settings where donor blood carries the risk of viral and other
infections. In addition to their use in treatment of unconjugated
hyperbilirubinemia, metalloporphyrins also have the potential for
use in its prevention. The use of metalloporphyrins for prevention
will be reviewed in a separate systematic review.
AUTHORS CONCLUSIONS
Implications for practice
The evidence from randomized controlled trials on the effects of
metalloporphyrins on clinically important outcomes is insufficient
at present.
Implications for research

Randomized clinical trials are required that compare metallopor-

phyrin treatment to placebo and that report on important outcomes such as severe hyperbilirubinemia, neonatal kernicterus,
exchange transfusion and long term neurodevelopmental impairment. Future trials should be designed so that selection, performance, attrition and detection bias are minimized. Measurement
of bilirubin values should be done by high pressure liquid chromatography to minimize inter and intralaboratory variation in
bilirubin measurement that has been described with other methods of bilirubin measurement. Adequate sample sizes are required
to rule out an increased risk of adverse events with metalloporphyrin treatment. Such trials are likely to be difficult to conduct
due to the rarity of these outcomes. Therefore the conduct of such
trials should be considered in high-risk neonates such as those with
hemolysis or those that have rising bilirubin levels approaching
the threshold for exchange transfusion. Also useful will be observational studies that lead to the identification of reliable risk factors for severe hyperbilirubinemia and kernicterus, so that highrisk neonates may be targeted in future trials.
REFERENCES
References to studies included in this review
Additional references
Kappas 1995a {published data only}

Kappas A, Drummond GS, Henschke C, Valaes T.
Direct comparison of Sn-mesoporphyrin, an inhibitor
of bilirubin production and phototherapy in controlling
hyperbilirubinemia in term and near-term newborns.
Pediatrics 1995;95:468474.
AAP 1994
American Academy of Pediatrics, Provisional Committee
for Quality Improvement and Subcommittee on
Hyperbilirubinemia. Practice parameter: management of
hyperbilirubinemia in the healthy term newborn. Pediatrics
1994;94:55865.
Kappas 1995b {published data only}

Kappas A, Drummond GS, Henschke C, Valaes T.
Direct comparison of Sn-mesoporphyrin, an inhibitor
of bilirubin production and phototherapy in controlling
hyperbilirubinemia in term and near-term newborns.
Pediatrics 1995;95:468474.
Brown 1998
Brown AK, Damus K, Harper R, King K, Kim MH. Factors
relating to readmission of term and near-term neonates in
the first two weeks. Pediatric Research 1998;43:168A.
Martinez 1999 {published data only}

Martinez JC, Garcia HO, Otheguy LE, Drummond GS,
Kappas A. Control of severe hyperbilirubinemia in fullterm newborns with the inhibitor of bilirubin production
Sn-mesoporphyrin. Pediatrics 1999;103:15.
References to studies excluded from this review

Kappas 1988 {published data only}
Kappas A, Drummond GS, Manola T, Petmezaki S,
Valaes T. Sn-protoporphyrin use in the management of
hyperbilirubinemia in term newborns with direct Coombspositive ABO incompatibility. Pediatrics 1988;81:485497.
Kappas 2001 {published data only}
Kappas A, Drummond GS, Valaes T. A single dose
of Sn-mesoporphyrin prevents development of severe
hyperbilirubinemia in glucose-6-phosphate dehydrogenasedeficient newborns. Pediatrics 2001;108:2530.
Valaes 1994 {published data only}
Valaes T, Petmezaki S, Henschke C, et al.Control of
jaundice in preterm newborns by an inhibitor of bilirubin
production: studies with tin-mesoporphyrin. Pediatrics
1994;93:111.
Valaes 1998 {published data only}
Valaes T, Drummond GS, Kappas A. Control of
hyperbilirubinemia in glucose-6-phosphate dehydrogenase
deficient newborns using an inhibitor of bilirubin
production, Sn-mesoporphyrin. Pediatrics 1998;101:17.
Catz 1995
Catz C, Hanson JW, Simpson L, Yaffe SJ. Summary of
workshop: early discharge and neonatal hyperbilirubinemia.
Pediatrics 1995;96:7435.
Chernick 1989
Chernick RJ, Martasek P, Levere RD, Margreiter R,
Abraham NG. Sensitivity of human tissue heme oxygenase
to a new synthetic metalloporphyrin. Hepatology 1989;10:
3659.
Cornelius 1984
Cornelius CE, Rodgers PA. Prevention of neonatal
hyperbilirubinemia in rhesus monkeys by tinprotoporphyrin. Pediatric Research 1984;18:72830.
Drummond 1981
Drummond GS, Kappas A. Prevention of neonatal
hyperbilirubinemia by tin protoporphyrin IX, a potent
competitive inhibitor of heme oxidation. Proc Natl Acad Sci
USA 1981;78:646670.
Galbraith 1992
Galbraith RA, Drummon GS, Kappas A. Suppression
of bilirubin production in the Crigler-Najjar type I
syndrome: studies with the heme oxygenase inhibitor, tinmesoporphyrin. Pediatrics 1992;89:17582.
Gartner 1994
Gartner LM. Neonatal jaundice. Pediatr Rev 1994;15:
422432.
Gourley 1997
Gourley GR. Bilirubin metabolism and kernicterus. Adv
Pediatr 1997;44:173229.

Johnson 2002
Johnson LH, Bhutani V, Brown AK. System-based approach
to management of neonatal jaundice and prevention of
kernicterus. J Pediatr 2002;140:396403.
Stevenson 1989
Stevenson DK, Rodgers PA, Vreman HJ. The use of
metalloporphyrins for the chemoprevention of neonatal
jaundice. Am J Dis Child 1989;143:353356.
Kappas 1984
Kappas A, Drummon GS, Simionatto CS, et al.Control of
heme oxygenase and plasma levels of bilirubin by a synthetic
heme analogue, tin-protoporphyrin. Hepatology 1984;4:
336341.
Vallier 1993
Vallier HA, Rodgers PA, Stevenson DK. Inhibition of heme
oxygenase after oral vs intraperitoneal administration of
chromium porphyrins. Life Sci 1993;52:L7984.
Kivlahan 1984
Kivlahan C, James EJ. The natural history of neonatal
jaundice. Pediatrics 1984;74:364370.
Labbe 1999
Labbe RF, Vreman HJ, Stevenson DK. Zinc protoporphyrin:
a metabolite with a mission. Clin Chem 1999;45:
20602072.
McDonagh 1990
McDonagh AF. Is bilirubin good for you?. Clin Perinatol
1990;17:359369.
Vreman 1991
Vreman HJ, Lee OK, Stevenson DK. In vitro and in vivo
characteristics of a heme oxygenase inhibitor: ZnBG. Am J
Med Sci 1991;302:33541.
Vreman 2001
Vreman HJ, Wong RJ, Stevenson DK. Alternative
metalloporphyrins for the treatment of neonatal jaundice.
Journal of Perinatology 2001;21:S10813.
Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Kappas 1995a
Methods
Sequential analysis. Four strata used, based on age (36-60 hours, 61 - 84 hours) and ABO incompatibility
status (compatible, incompatible). Infants randomized in pairs within each stratum. Concealment of
randomization - yes; blinding of treatment - no; complete follow up - yes; blinding of outcome assessment
- no. Infants excluded after randomization if found to be G6PD deficient, and replaced by the next eligible
infant of the same stratification group
Participants
Healthy term breast fed newborns age 36 - 84 hours; only male infants; breast and formula fed, bilirubin
within a pre-defined range (e.g., 7 - 10 mg/dl at 36 hours, 11 - 15 mg/dl at 60 hours, 14 - 20 mg/dl at 84
hours). Exclusions: Coombs positive hemolytic anemia, G6PD deficiency, female infants, jaundice within
36 hours, plasma bilirubin level above a pre-defined level, congenital anomalies, suspected congenital
infection, birth asphyxia, admission to neonatal intensive care unit
Interventions
Tin mesoporphyrin 6 micromoles/kg birth weight intramuscularly (N=22). All controls received phototherapy (N=22)
Outcomes
Number needing phototherapy, mean age at closure of case (hours), mean plasma bilirubin at closure
(mg/dl), mean hours in study, excess days of hospitalization (>4 days) related to jaundice
Notes
This is an equivalency trial in term neonates (mesoporphyrin versus phototherapy) Follow up at 18 months
described in the methods but no results provided
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
A - Adequate
Kappas 1995b
Methods
Sequential analysis. Four strata used, based on age (36-60 hours, 61 - 96 hours) and gestation (245 - 255
days, 256 - 265 days). Infants randomized in pairs within each stratum. Concealment of randomization
- yes; blinding of treatment - no; complete follow up - yes; blinding of outcome assessment - no. Infants
excluded after randomization if found to be G6PD deficient, and replaced by the next eligible infant of
the same stratification group
Participants
Neonates 245 - 265 days gestation, both sexes, age 36 - 84 hours; ABO incompatibility permitted, bilirubin
within a pre-defined range (e.g., 7 - 10 mg/dl at 36 hours, 11 - 15 mg/dl at 60 hours, 14 - 20 mg/dl at
84 hours). Exclusions: G6PD deficiency, jaundice within 36 hours, plasma bilirubin level above a predefined level, congenital anomalies, suspected congenital infection, birth asphyxia, admission to neonatal
intensive care unit

10
Kappas 1995b
(Continued)
Interventions
Tin mesoporphyrin 6 micromoles/kg birth weight intramuscularly (N=22) . All controls received phototherapy (N=20)
Outcomes
Number needing phototherapy, mean age at closure of case (hours), mean plasma bilirubin at closure
(mg/dl), mean hours in study, excess days of hospitalization (>4 days) related to jaundice
Notes
This is an equivalency trial in near term neonates (mesoporphyrin versus phototherapy) Follow up at 18
months described in the methods but no results provided
Risk of bias
Item
Authors judgement
Description
Yes
A - Adequate
Martinez 1999
Methods
Concealment of randomization - Cannot tell; blinding of treatment - no; complete follow up - yes;
blinding of outcome assessment - no; infants excluded after randomization if they met exclusion criteria
Participants
Single centre; healthy neonates 38 - 41 weeks gestation, born after uncomplicated pregnancy, fully breast
fed, plasma bilirubin concentration 15 to 18 mg/dl 48 to 96 hours after birth, mothers instructed not to
expose infants to sunlight. Exclusions: maternal phenobarbital in last month of pregnancy, infants with
congenital anomalies, congenital infection, neonatal complications such as asphyxia, birth weight less
than 10th percentile or greater than 90th percentile, venous hematocrit > or = 65% and hemolysis. Ten
patients excluded after randomization, one because of hemolytic disease, one because of infection and
eight because of protocol violation
Interventions
Tin mesoporphyrin six micromoles / kg intramuscularly (N = 40). Controls received standard management
(N= 44). Phototherapy started in either group if bilirubin reached 19.5 mg/dl. Closure reached when
plasma bilirubin decreased to < or = 13 mg/dl
Outcomes
Number of newborns requiring phototherapy, maxium plasma bilirubin concentration, number of bilirubin determinations, hours between enrollment and closure of case, adverse effects
Notes
Study conducted in Argentina. Phototherapy threshold higher than recommended by American Academy
of Pediatrics in its guideline
Risk of bias
Item
Authors judgement
Description
Unclear
B - Unclear

11
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Kappas 1988
This is a study of the preventive use of a metalloporphyrin
Kappas 2001
This study compares infants treated with tin mesoporphyrin (for prevention) with historical controls
Valaes 1994
This is a study of the preventive use of a metalloporphyrin
Valaes 1998
This study compares two different strategies of using a metalloporphyrin (preventive versus therapeutic)

12
DATA AND ANALYSES
Comparison 1. Tin mesoporphyrin versus use of phototherapy
Outcome or subgroup title
No. of
studies
No. of
participants
3
3
2
3
1
170
170
86
170
84
Risk Ratio (M-H, Fixed, 95% CI)

0.04 [0.00, 0.72]

0.04 [0.00, 0.72]
Not estimable
0.58 [0.08, 4.13]
Not estimable
84
Not estimable
1 Severe hyperbiliribunemia
2 Phototherapy
3 Exchange transfusion
4 Cutaneous photosensitivity rash
5 Local reaction at site of
intramuscular injection
6 Abnormal liver function tests
Statistical method
Effect size
Analysis 1.1. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 1 Severe
hyperbiliribunemia.
Review:
Comparison: 1 Tin mesoporphyrin versus use of phototherapy

Outcome: 1 Severe hyperbiliribunemia
Study or subgroup
Metalloporphyrin
Control
n/N
n/N
Risk Ratio
Risk Ratio
Kappas 1995a
0/22
0/22
0.0 [ 0.0, 0.0 ]
Kappas 1995b
0/22
0/20
0.0 [ 0.0, 0.0 ]
Martinez 1999
0/40
12/44
0.04 [ 0.00, 0.72 ]
Total (95% CI)
84
86
0.04 [ 0.00, 0.72 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI
Total events: 0 (Metalloporphyrin), 12 (Control)

Heterogeneity: Chi2 = 0.0, df = 0 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 2.19 (P = 0.028)
0.002
0.1
Favours treatment

10
500
Favours control
13
Analysis 1.2. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 2 Phototherapy.
Review:

Outcome: 2 Phototherapy
Study or subgroup
Metalloporphyrin
Control
n/N
n/N
Risk Ratio
Risk Ratio
Kappas 1995a
0/22
0/22
0.0 [ 0.0, 0.0 ]
Kappas 1995b
0/22
0/20
0.0 [ 0.0, 0.0 ]
Martinez 1999
0/40
12/44
0.04 [ 0.00, 0.72 ]
Total (95% CI)
84
86
0.04 [ 0.00, 0.72 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

0.002
0.1
Favours treatment
10
500
Favours control
Analysis 1.3. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 3 Exchange
transfusion.
Review:

Outcome: 3 Exchange transfusion
Study or subgroup
Metalloporphyrin
Control
n/N
n/N
Risk Ratio
Risk Ratio
Kappas 1995a
0/22
0/22
0.0 [ 0.0, 0.0 ]
Kappas 1995b
0/22
0/20
0.0 [ 0.0, 0.0 ]
Total (95% CI)
44
42
0.0 [ 0.0, 0.0 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%
Test for overall effect: Z = 0.0 (P < 0.00001)
0.1 0.2
0.5
Favours treatment

10
Favours control
14
Analysis 1.4. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 4 Cutaneous
photosensitivity rash.
Review:

Outcome: 4 Cutaneous photosensitivity rash
Study or subgroup
Metalloporphyrin
Control
n/N
n/N
Risk Ratio
Risk Ratio
Kappas 1995a
1/22
1/22
1.00 [ 0.07, 15.00 ]
Kappas 1995b
0/22
1/20
0.30 [ 0.01, 7.07 ]
Martinez 1999
0/40
0/44
0.0 [ 0.0, 0.0 ]
Total (95% CI)
84
86
0.58 [ 0.08, 4.13 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

0.01
0.1
10
Favours treatment
100
Favours control
Analysis 1.5. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 5 Local reaction at
site of intramuscular injection.
Review:

Outcome: 5 Local reaction at site of intramuscular injection
Study or subgroup
Metalloporphyrin
Control
n/N
n/N
Risk Ratio
Risk Ratio
Martinez 1999
0/40
0/44
0.0 [ 0.0, 0.0 ]
Total (95% CI)
40
44
0.0 [ 0.0, 0.0 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Heterogeneity: not applicable
0.1 0.2
0.5
Favours treatment

10
Favours control
15
Analysis 1.6. Comparison 1 Tin mesoporphyrin versus use of phototherapy, Outcome 6 Abnormal liver
function tests.
Review:

Outcome: 6 Abnormal liver function tests
Study or subgroup
Metalloporphyrin
Control
n/N
n/N
Risk Ratio
Risk Ratio
Martinez 1999
0/40
0/44
0.0 [ 0.0, 0.0 ]
Total (95% CI)
40
44
0.0 [ 0.0, 0.0 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Heterogeneity: not applicable
0.1 0.2
0.5
Favours treatment
10
Favours control
WHATS NEW
Last assessed as up-to-date: 13 November 2002.
Date
Event
Description
30 October 2008
Amended
Converted to new review format.
HISTORY
Protocol first published: Issue 3, 2000
Review first published: Issue 2, 2003
Date
Event
Description
14 November 2002
New citation required and conclusions have changed
Substantive amendment

16
CONTRIBUTIONS OF AUTHORS
Gautham Suresh wrote the protocol, performed the literature search, extracted study data, entered the data into Revman, wrote the
review and compiled the other references.
Christine Martine performed an independent literature search, extracted study data, checked the data entered into Revman by Gautham
Suresh and assisted in compilation of the other references
Roger Soll contributed toward framing the questions for the protocol, revising the drafts of the protocol and the review, provided
guidance in selecting outcomes of interest, structuring subgroup analyses, selection of studies, and in revising the discussion and
conclusions.
DECLARATIONS OF INTEREST
Dr. Suresh has been a collaborator with Dr.Kappas (a leading researcher in the field of metalloporphyin therapy), on a website and a
publication on Crigler-Najjar syndrome.
INDEX TERMS
Medical Subject Headings (MeSH)
Hyperbilirubinemia [ drug therapy]; Infant, Newborn; Metalloporphyrins [ therapeutic use]; Randomized Controlled Trials as Topic
MeSH check words

Humans

17

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Metalloporphyrins for treatment of unconjugated

hyperbilirubinemia in neonates (Review)

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Metalloporphyrins for treatment of unconjugated

Data collection and analysis

PLAIN LANGUAGE SUMMARY

conjugated bilirubin level in neonates and these can be broadly

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Criteria for considering studies for this review

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Types of outcome measures

Search methods for identification of studies

Data collection and analysis

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

permitted the inclusion of neonates with ABO incompatibility.

Risk of bias in included studies

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Decrease in unconjugated bilirubin levels over time: None of the

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Iron deficiency: None of the three studies described the presence

Implications for research

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

References to studies included in this review

Kappas 1995a {published data only}

Kappas 1995b {published data only}

Martinez 1999 {published data only}

References to studies excluded from this review

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Indicates the major publication for the study

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Characteristics of included studies [ordered by study ID]

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Characteristics of excluded studies [ordered by study ID]

Reason for exclusion

This is a study of the preventive use of a metalloporphyrin

This is a study of the preventive use of a metalloporphyrin

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

DATA AND ANALYSES

Comparison 1. Tin mesoporphyrin versus use of phototherapy

Outcome or subgroup title

Risk Ratio (M-H, Fixed, 95% CI)

0.04 [0.00, 0.72]

Risk Ratio (M-H, Fixed, 95% CI)

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates

Comparison: 1 Tin mesoporphyrin versus use of phototherapy

0.0 [ 0.0, 0.0 ]

0.0 [ 0.0, 0.0 ]

0.04 [ 0.00, 0.72 ]

Total (95% CI)

0.04 [ 0.00, 0.72 ]

Total events: 0 (Metalloporphyrin), 12 (Control)

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates (Review)

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates

Comparison: 1 Tin mesoporphyrin versus use of phototherapy

0.0 [ 0.0, 0.0 ]

0.0 [ 0.0, 0.0 ]

0.04 [ 0.00, 0.72 ]

Total (95% CI)

0.04 [ 0.00, 0.72 ]

Total events: 0 (Metalloporphyrin), 12 (Control)

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates

Comparison: 1 Tin mesoporphyrin versus use of phototherapy