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.