Home > Health & Research > Health Education Campaigns & Programs > Cochrane Neonatal Review > Metalloporphyrins for treatment of unconjugated hyperbilirubinemia

Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates

Skip sharing on social media links
Share this:

Authors

Suresh GK, Martin CL, Soll RF

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


Dates

Date edited: 26/02/2003
Date of last substantive update: 14/11/2002
Date of last minor update: / /
Date next stage expected / /
Protocol first published: Issue 3, 2000
Review first published: Issue 2, 2003

Contact reviewer

Dr Gautham GKS Suresh

Department of Pediatrics
University of Vermont College of Medicine
A-121 Medical Alumni Building
Burlington
VT USA
05405-0068
Telephone 1: +1-802-847-0024
Facsimile: +1-802-847-5225

E-mail: gautham.suresh@vtmednet.org

Contribution of reviewers

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.

Intramural sources of support

  • None noted.

Extramural sources of support

  • None noted.

What's new

Date / Event Description

History

Date / Event Description

Synopsis

  • Synopsis pending

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 strategy

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 & 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.

Reviewers' 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.

[top]

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 unconjugated 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.

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 strategy 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.

[top]

Methods of the review

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 gestation) infants, hemolytic versus non-hemolytic causes of hyperbilirubinemia and type of metalloporphyrin used.

Description of 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 36-84 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.

Methodological quality of 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

[top]

Results

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 mother's 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.

Reviewers' 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 metalloporphyrin 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 high-risk neonates may be targeted in future trials.

Acknowledgements

  • None noted.

Potential conflict 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.

[top]

Characteristics of studies

Characteristics of Included Studies

Study Methods Participants Interventions Outcomes Notes Allocation concealment
Kappas 1995a 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. 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. Tin mesoporphyrin 6 micromoles/kg birth weight intramuscularly (N=22). All controls received phototherapy (N=22). 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. This is an equivalency trial in term neonates (mesoporphyrin versus phototherapy) Follow up at 18 months described in the methods but no results provided. A
Kappas 1995b 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. 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 pre-defined level, congenital anomalies, suspected congenital infection, birth asphyxia, admission to neonatal intensive care unit. Tin mesoporphyrin 6 micromoles/kg birth weight intramuscularly (N=22). All controls received phototherapy (N=20). 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. 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. A
Martinez 1999 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. 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 greater than/or equal to 65% and hemolysis. Ten patients excluded after randomization, one because of hemolytic disease, one because of infection and eight because of protocol violation. 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 less than/or equal to 13 mg/dl Number of newborns requiring phototherapy, maxium plasma bilirubin concentration, number of bilirubin determinations, hours between enrollment and closure of case, adverse effects. Study conducted in Argentina. Phototherapy threshold higher than recommended by American Academy of Pediatrics in its guideline. B

Characteristics of excluded studies

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)

[top]

References to studies

Included studies

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;95:468-474.

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;95:468-474.

Martinez 1999

{published data only}

Martinez JC, Garcia HO, Otheguy LE, Drummond GS, Kappas A. Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. Pediatrics 1999;103:1-5.

Excluded studies

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 Coombs-positive ABO incompatibility. Pediatrics 1988;81:485-497.

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 dehydrogenase-deficient newborns. Pediatrics 2001;108:25-30.

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;93:1-11.

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;101:1-7.

* indicates the primary reference for the study

Other references

Additional references

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;94:558-565.

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. Pediatr Res 1998;43:168A.

Catz 1995

Catz C, Hanson JW, Simpson L, Yaffe SJ. Summary of workshop: early discharge and neonatal hyperbilirubinemia. Pediatrics 1995;96:743-745.

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;10:365 - 369.

Cornelius 1984

Cornelius CE, Rodgers PA. Prevention of neonatal hyperbilirubinemia in rhesus monkeys by tin-protoporphyrin. Pediatr Res 1984;18:728-730.

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;78:6466-6470.

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, tin-mesoporphyrin. Pediatrics 1992;89:175-182.

Gartner 1994

Gartner LM. Neonatal jaundice. Pediatr Rev 1994;15:422-432.

Gourley 1997

Gourley GR. Bilirubin metabolism and kernicterus. Adv Pediatr 1997;44:173-229.

Johnson 2002

Johnson LH, Bhutani V, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002;140:396-403.

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;4:336-341.

Kivlahan 1984

Kivlahan C, James EJ. The natural history of neonatal jaundice. Pediatrics 1984;74:364-370.

Labbe 1999

Labbe RF, Vreman HJ, Stevenson DK. Zinc protoporphyrin: a metabolite with a mission. Clin Chem 1999;45:2060 - 2072.

McDonagh 1990

McDonagh AF. Is bilirubin good for you? Clin Perinatol 1990;17:359-369.

Stevenson 1989

Stevenson DK, Rodgers PA, Vreman HJ. The use of metalloporphyrins for the chemoprevention of neonatal jaundice. Am J Dis Child 1989;143:353-356.

Vallier 1993

Vallier HA, Rodgers PA, Stevenson DK. Inhibition of heme oxygenase after oral vs intraperitoneal administration of chromium porphyrins. Life Sci 1993;52:L79 - 84.

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;302:335 - 341.

Vreman 2001

Vreman HJ, Wong RJ, Stevenson DK. Alternative metalloporphyrins for the treatment of neonatal jaundice. J Perinatol 2001;21:S108-S113.

[top]

Data and analyses

01 Tin mesoporphyrin versus use of phototherapy

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
01.01 Severe hyperbiliribunemia 3 170 Relative Risk [Fixed] [95% CI] 0.04 [0.00, 0.72]
01.02 Phototherapy 3 170 Relative Risk [Fixed] [95% CI] 0.04 [0.00, 0.72]
01.03 Exchange transfusion 2 86 Relative Risk [Fixed] [95% CI] Not Estimable
01.04 Cutaneous photosensitivity rash 3 170 Relative Risk [Fixed] [95% CI] 0.58 [0.08, 4.13]
01.05 Local reaction at site of intramuscular injection 1 84 Relative Risk [Fixed] [95% CI] Not Estimable
01.06 Abnormal liver function tests 1 84 Relative Risk [Fixed] [95% CI] Not Estimable

Additional tables

  • None noted.

Amended sections

None selected

Contact details for co-reviewers

Ms Christine L Martin, MPH

Medical Student
University of Vermont College of Medicine

Dr Roger F Soll, M.D.

Professor of Pediatrics
Division of Neonatal-Perinatal Medicine
Fletcher Allen Health Care
Burgess 426
111 Colchester Ave.
Burlington
Vermont USA
05401
Telephone 1: +1-802-847-2392
Facsimile: +1-802-847-5225

E-mail: Roger.Soll@vtmednet.org


This review is published as a Cochrane review in The Cochrane Library, Issue 2, 2003 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent recent version of the review.