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Cochrane Database of Systematic Reviews Protocol - Intervention

Prenatal phenobarbital to reduce neonatal jaundice after red cell isoimmunization

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To asses the efficacy of antenatal phenobarbital in red cell isoimmunized pregnancies in reducing the incidence of phototherapy and exchange transfusion for the neonate.

Background

Red cells in the human body express various antigens which are used in the ABO blood grouping system and Rhesus typing system. The Rhesus typing system stands for three specific antigens C, D and E. Of these, the D antigen is the one most often involved in Rhesus isoimmunization. Over the years various other antigens have also been described as being involved in red cell isoimmunization. A Rhesus negative women (with no D antigens) who has a partner who is homozygous for Rhesus positive (DD) will have a fetus who is heterozygous Rhesus positive (D). If the partner is Rhesus positive but heterozygous (D) the fetus could be either Rhesus negative (no D antigens) or heterozygous Rhesus positive (D).

Invariably in the course of the pregnancy there would be fetomaternal haemorrhages with Rh positive fetal red cells crossing into the maternal circulation. This causes the Rhesus negative maternal immune system to produce antibodies against the Rhesus positive red cells from the fetus. In subsequent pregnancies these antibodies to Rhesus positive red cells would cross over to the Rhesus positive fetus through the placenta and cause fetal red cell destruction causing anaemia in the fetus. If the anaemia is severe the fetus could develop cardiac failure leading to hydrops fetalis and eventually fetal death.

Nearly 15% of Caucasian women are Rhesus negative whereas about 8% of African Americans and 2% of Asians are Rhesus negative. Among the Caucasian population this results in about 10% of pregnancies being affected with red cell isoimmunization. The prevention of red cell isoimmunization has been facilitated with the use of prophylactic administration of Anti D antibodies to the pregnant mother so that the fetal cells that cross over to the maternal circulation are destroyed before they sensitize the mother to produce antibodies. Monitoring of mothers for sensitization during pregnancies, fetal surveillance and intrauterine fetal transfusions have been done to reduce the morbidity on the fetus (Gabbe 2002).

The natural destruction of red blood cells in the body results in accumulation of bilirubin. Bilirubin is a breakdown product of haemoglobin which carries oxygen in the red blood cells. Various enzyme systems in the liver conjugate bilirubin in the liver and is eventually excreted. In the newborn the liver takes time to conjugate all the bilirubin and this sometimes results in physiological jaundice. Physiologic jaundice usually is seen 48 to 72 hours after birth and often needs no intervention. This becomes pathologic in those babies where red cell destruction increases the load of bilirubin as in red cell isoimmunization or in preterm infants where the liver is too immature to deal with the normal load.

In neonates with high levels of bilirubin this can result in 'kernicterus' involving the basal ganglia in the brain. Bilirubin toxicity may result in brain damage. This has been associated with athetoid form of cerebral palsy, hearing loss, and developmental delays (AAP 2002). It is thus critical to keep the bilirubin levels low in the neonate. Pathological jaundice is usually seen within 24 hours of birth and needs phototherapy to increase the conjugation of bilirubin by skin. Occasionally high levels of bilirubin may indicate the need for exchange transfusion where the neonates blood is exchanged with fresh blood effectively removing bilirubin from circulation. Phenobarbital by a process of induction increases the amount of enzymes in the endoplasmic reticulum of the liver cells which results in larger volumes of bilirubin being conjugated (Katzung 1998; Price 1986). The use of phenobarbital for the purpose of inducing the hepatic microsomal enzyme system has been well established (Kawasaki 1982).

This mechanism can be used to induce hepatic microsomal enzyme system in the neonate to accelerate the hepatic conjugation of bilirubin. This would decrease neonatal hyperbilirubinaemia and consequently the need for phototherapy and or exchange transfusion. This rationale has lead to the antenatal use of phenobarbital just before birth in trying to induce the fetal hepatic microsomal enzyme system. Thomas reported a decrease in the incidence of significant jaundice. No significant complications resulted from the drug therapy, and the newborn infants demonstrated no adverse effects attributable to the phenobarbital. Mothers who were given prophylactic phenobarbital took their infants home earlier, brought infants back to the hospital for phototherapy less often, and spent fewer dollars for their total medical care than their control counterparts (Thomas 1976).

Rayburn et al reviewed their experience with maternal phenobarbital therapy and fetal bilirubin conjugation in the very premature fetus. Their conclusion was antenatal phenobarbital enhances bilirubin conjugation before delivery of a very low birthweight infant (Rayburn 1998). Wennberg reported positive correlation between the cord serum indirect bilirubin concentration and its subsequent rise in 19 infants who had received antenatal phenobarbital therapy, but this relationship was not observed in untreated infants. The phenobarbital‐treated infants had a slower postnatal rise of indirect bilirubin than did non‐treated controls (Wennberg 1978).

The fetus with red cell isoimmunization is at a much greater risk of neonatal jaundice and anaemia. In a retrospective analysis 106 women with red cell isoimmunization in the current pregnancy who met study criteria showed a significant difference in the need for exchange transfusion for the neonate between those who had received antenatal phenobarbital one week before delivery compared to those who had not (Trevett 2004).

The aim of this review is to systematically assess the available evidence from randomised and quasi‐randomised controlled trials for the antenatal use of phenobarbital in red cell isoimmunized women aimed at reducing the need for phototherapy and or transfusion in the neonate.

Objectives

To asses the efficacy of antenatal phenobarbital in red cell isoimmunized pregnancies in reducing the incidence of phototherapy and exchange transfusion for the neonate.

Methods

Criteria for considering studies for this review

Types of studies

All identified published and unpublished randomised and quasi‐randomised controlled trials will be considered for inclusion in this review.

Types of participants

All pregnant women who are established to have red cell antibodies in the current pregnancy identified by positive coombs test during their prenatal testing.

Types of interventions

Phenobarbital alone or in combination with other drugs with or without placebo controls given before delivery to women who are isoimmunized.

Types of outcome measures

(1) Total and direct bilirubin in the neonates:

  • at birth;

  • within 24 hours of birth;

  • after 24 hours of birth.

(2) Haemoglobin and retic counts:

  • at birth;

  • within 24 hours of birth;

  • after 24 hours of birth.

(3) Need for phototherapy:

  • within 24 hours of birth;

  • after 24 hours of birth.

(4) Need for transfusion:

  • within 24 hours of birth;

  • after 24 hours of birth.

(5) Duration of intensive care admission.

(6) Adverse neonatal outcomes in terms of

  • stillbirth;

  • neonatal death;

  • bilirubin encephalopathy/kernicterus;

  • longer‐term neurological outcomes.

(7) Maternal adverse effects.

(8) Cost of phenobarbital therapy.

Search methods for identification of studies

We will contact the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group Trials Register.

The Cochrane Pregnancy and Childbirth Group's trials register is maintained by the Trials Search Co‐ordinator and contains trials
identified from:
1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
2. monthly searches of MEDLINE;
3. handsearches of 30 journals and the proceedings of major conferences;
4. weekly current awareness search of a further 37 journals.

Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the 'Search strategies for identification of studies' section within the
editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are given a code (or codes) depending on the topic. The codes are linked to review topics. The Trials Search Co‐ordinator searches the register for each review using these codes rather than keywords.

Data collection and analysis

The three review authors will independently scan the titles and abstracts (when available) of all identified reports. For studies appearing to meet the inclusion criteria, or where there is insufficient information to make a clear decision, the full report will be obtained and the three authors will independently assess it to establish whether the studies met the inclusion criteria. Disagreements will be resolved by discussion, with an independent author consulted if resolution was not possible. All studies meeting the inclusion criteria will be assessed for quality and data will be extracted independently by the three authors. Studies rejected at this or subsequent stages will be entered in the 'Characteristics of excluded studies' table and reasons for exclusions recorded. There will be no blinding of authorship (Alderson 2004).

Assessment of selection bias will examine the process involved in the generation of the random sequence and the method of allocation concealment separately. The three authors will independently rate studies as adequate or inadequate using the criteria described in section six of the Cochrane Reviewers' Handbook (Alderson 2004):
A = adequate;
B = unclear;
C = inadequate.

We will examine performance and detection bias as to who was blinded in the trials, i.e. participant, caregiver, outcome assessor or data analyst. In many trials the caregiver, assessor and data analyst are the same party. We will specify who was blinded and seek details of the feasibility and appropriateness of blinding at all levels (recognising that for many of the interventions in these studies that blinding will be difficult).

In addition, we will document each trial regarding use of a placebo and the completeness of follow up as follows.

Use of placebo
(1) A ‐ placebo used;
(2) C ‐ no placebo;
(3) D ‐ unclear.

Completeness of follow up
(1) A ‐ less than 3% of participants excluded;
(2) B ‐ 3% to 9.9% of participants excluded;
(3) C ‐ 10% to 19.9% of participants excluded;
(4) D ‐ 20% or more excluded;
(5) E ‐ unclear.

We will include outcome data in the analyses if they meet the prestated criteria in 'Types of outcome measures'. We will process included trial data as described in the Cochrane Reviewers' Handbook (Alderson 2004). We will independently extract and enter data. We will resolve discrepancies by discussion. There will be no blinding of authorship.
Whenever possible, we will seek quality issues that were unclear and unpublished data from investigators.

We will perform statistical analyses using the Review Manager software (RevMan 2004). We will compare dichotomous data using relative risks and 95% confidence intervals (CI) and continuous data using weighted mean difference and 95% CI. We will test for statistical heterogeneity between trials using the I2 statistic, with I2 greater than 50% regarded as substantial heterogeneity. Results will be pooled using a random‐effects model. If heterogeneity is detected, possible causes will be explored and subgroup analyses for the main outcomes performed.

We will extract data from the trials on an intention‐to‐treat basis. Where this was not done in the original report, re‐analysis will be performed where possible. If missing data are such that they might significantly affect the results, we will exclude these data from the analysis. This decision rests with the authors and will be clearly documented. If missing data become available subsequently, they will be included in the analyses. Data will be double entered by the review authors.

A priori, we decided that all eligible trials would be included in the initial analysis and sensitivity analyses carried out to evaluate the effect of trial quality including aspects of selection, performance and attrition bias. This will be done by using the grading A to C for concealment of treatment allocation excluding quasi‐randomised trials and other sensitivity analyses will be based on the quality assessments we specified above.

Primary analyses will be limited to the prespecified outcomes and subgroup analyses. Studies with 20% or more participants lost to follow up or unable to be clarified after contacting the authors will be excluded from the analyses.

Subgroup analysis will be done based on:

  • gestational age at birth 24 to less than 28 weeks; 28 to less than 32 weeks; 32 to less than 36 weeks; 36 weeks and above;

  • premature preterm ruptured membranes; with suspicion of chorioamnionitis and with no suspicion of chorioamnionitis;

  • fetal therapy instituted ie fetal transfusions or maternal gammglobulin infusions;

Outcomes not prespecified will be clearly identified as such.