Objective. The religious convictions of parents who are Jehovah’s Witness adherents lead them to reject the use of exchange transfusions as therapy for severe hyperbilirubinemia in newborns in whom intensive phototherapy has failed to control this problem. Consequently, physicians caring for such infants may be obliged to initiate legal action to compel use of the procedure when severe hyperbilirubinemia not sufficiently responsive to phototherapy warrants an exchange transfusion. Our goal was to determine if we could use the potent inhibitor of bilirubin production, Sn-Mesoporphyrin (SnMP), to resolve the troubling medical-legal issues in such situations in 2 infants with hemolytic disease of the newborn who required exchange transfusions for severe hyperbilirubinemia but whose Jehovah’s Witness parents rejected the procedure. SnMP was administered in a single dose, as in previous studies, at the time when exchange transfusion would have been initiated and plasma bilirubin levels were monitored at close intervals thereafter.
Methods. SnMP is a potent inhibitor of heme oxygenase, the rate-limiting enzyme in catabolism of heme to bilirubin. We found in earlier studies that in single doses of 6 μmol/kg birth weight, SnMP is extremely effective in moderating the course of hyperbilirubinemia and in eliminating the need for supplemental phototherapy in jaundiced newborns. In the 2 cases described, a single dose of SnMP (6 μmol/kg birth weight) was administered intramuscularly to severely jaundiced infants with immune hemolysis at a time when clinical circumstances dictated the need for exchange transfusion.
Case 1. This patient was a preterm male infant (gestational age: 35 5/7 weeks; birth weight: 2790 g) whose plasma bilirubin concentration (PBC) at 1 hour after birth was 5.0 mg/dL. Despite intensive phototherapy with 3 banks of lights and 1 biliblanket, the PBC increased steadily with no diminution in the rate of increase for 75 hours. In view of the problems of immune hemolysis, and prematurity, and the inability of phototherapy to stop progression of hyperbilirubinemia, a decision to carry out an exchange transfusion was made; the decision was, however, rejected by the Jehovah’s Witness parents. Pending legal action to compel use of the procedure, a request to this (Rockefeller) laboratory for SnMP was made; its use was approved by the Food and Drug Administration; and the inhibitor was delivered to the physician-in-charge (D.P.M.) in Sioux Falls, South Dakota. The single dose of SnMP was administered to the infant at 75 hours after birth; the course of hyperbilirubinemia before and after the use of the inhibitor is shown in Fig 1.
Case 2. This female term infant (gestational age: 38–39 weeks; birth weight: 4140 g) with immune hemolysis was delivered by cesarean section and because of problems related to meconium aspiration required helicopter transfer to the Special Care Nursery in Abilene, Texas, where 10 hours after birth the first PBC was determined to be 18.0 mg/dL. Double-bank phototherapy plus a biliblanket was initiated; a third bank of lights was later ordered. The PBC fluctuated in the ensuing 2 days between 13.8 to 25.8 mg/dL during which suggestive clinical signs of possible bilirubin encephalopathy became manifest. In view of the clinical circumstances and the continued severe hyperbilirubinemia, permission for a double-exchange transfusion was requested. The parents, who were Jehovah’s Witness adherents, refused the procedure. While preparing legal action to compel use of the exchange, a request was made to this (Rockefeller) laboratory for use of SnMP to attempt control of hyperbilirubinemia. With FDA approval, the SnMP was delivered to the attending neonatologist (J. R. M.) in Abilene and administered in a single dose (6 μmol/kg birth weight) at 56 hours after birth when the PBC was 19.5 mg/dL. The course of bilirubinemia before and after SnMP use is shown in Fig 2.
Results and Conclusions. The use of SnMP to moderate or prevent the development of severe hyperbilirubinemia in newborns (preterm, near-term, term with high PBCs [15–18 mg/dL], ABO-incompatibility; glucose-6-phosphate dehydrogenase deficiency) has been extensively studied in carefully conducted clinical trials the results of which have been reported earlier. This inhibitor of bilirubin production has demonstrated marked efficacy in moderating the course of hyperbilirubinemia in all diagnostic groups of unconjugated neonatal jaundice. The 2 cases described in this report confirmed the efficacy of SnMP in terminating progression of hyperbilirubinemia in infants in whom phototherapy had failed to sufficiently control the problem and whose parents, for religious reasons, would not permit exchange transfusions. Interdiction of severe hyperbilirubinemia by inhibiting the production of bilirubin with SnMP can be an effective alternative to the use of exchange transfusion in the management of severe newborn jaundice that has not responded sufficiently to light treatment to ease concern about the development of bilirubin encephalopathy.
We report here the effective use of the inhibitor of bilirubin production, Sn-Mesoporphyrin (SnMP), to interdict progression of severe hyperbilirubinemia associated with immune hemolysis in 2 Jehovah’s Witness newborns in whom phototherapy did not sufficiently control the problem and for whom the use of exchange transfusion was rejected by parents on religious grounds. In both cases, administration of a single dose of SnMP was followed by sustained regression of plasma bilirubins to levels that ended concern about the development of bilirubin encephalopathy and eliminated the need for legal action to force the use of exchange transfusions in the infants.
The SnMP solution (20 mg/mL [26.5μmol/mL]), in single-dose vials, was delivered to the Sioux Valley Hospital and University Medical Center, Sioux Falls, South Dakota, and the Abilene Regional Medical Center Special Care Nursery, Abilene, Texas, through the services of the Jehovah’s Witness organization based in New York City. The Food and Drug Administration (FDA) gave approval for use of the inhibitor in the infants on a compassionate need basis (investigational new drug numbers 59 340 and 60 816, respectively). Institutional Review Board approval and parental informed consent for use of SnMP in the 2 infants was obtained at each of the hospitals involved. At the times noted in the case reports, a single dose of SnMP (6 μmol/kg birth weight) was administered intramuscularly to the infant and postinjection plasma bilirubin levels were monitored as the clinical situation warranted.
The patient was a preterm male infant born by induced delivery (gestational age [GA]: 35 weeks; birth weight 2790 g) at the Sioux Valley Hospital and University Medical Center, Sioux Falls, South Dakota, on June 21, 2000. The parents were Jehovah’s Witness adherents. The mother’s blood type was O negative; the infant’s blood type was O positive. The mother displayed rising anti-D titers at 31 weeks. Serial delta OD 450s by amniocentesis increased from mid-to-high zone 2. She was induced for delivery because of the concern for rising titers with her Rh problem. After delivery, light treatment consisted of the use of blue phototherapy banks with 8 tubes (Phillips-F2-OT12BB) that maximized the blue range of light and 1 fiberoptic blanket. The biliblanket, or white fiberoptic light, was maintained for the first 75 hours, and the blue phototherapy was used for a total of 129½ hours. The intensity of blue light irradiance was at least 30 μW/cm2/nm and that of the biliblanket, 10 μW/cm2/nm.
The cord blood bilirubin level was 5.0 mg/dL as was the plasma bilirubin concentration (PBC) 1 hour after birth. The hematocrit was 42 at birth; dropped to 34 at 9 days postpartum, and reached a low of 24 before discharge. The hematocrit at 3 months of age was 32; the hemoglobin level was 10.4 g/dL. Height, weight and head size were at the 90th percentile and the child was normal neurologically and developmentally.
Twelve PBC determinations were made in the first 75 hours after birth (Fig 1). These showed a steady increase in PBCs with no diminution in the rate of increase. In view of the hemolytic process and the prematurity of the infant, it was anticipated that progressive hyperbilirubinemia would ensue and that the infant would ultimately require exchange transfusion. When intensive phototherapy failed to stop the progression of hyperbilirubinemia, permission to carry out exchange transfusion was requested. The exchange was rejected on religious grounds by the parents. Pending legal action to force use of the procedure, contact was made with this (Rockefeller) laboratory concerning availability of SnMP to inhibit bilirubin production. The SnMP dose was prepared, FDA approval was secured, and delivery to the Sioux Valley Hospital was made by the Jehovah’s Witness organization. Based on the clinical circumstances of the infant, the attending neonatologist administered the inhibitor at 75½ hours after birth; the PBC was 17.7 mg/dL at 75 hours. The PBC increased to 18.2 mg/dL in the succeeding 4½ hours, but decreased to 13.6 mg/dL in the next 12 hours, and decreased steadily thereafter. There was no rebound hyperbilirubinemia. At the time of administration of SnMP, use of the biliblanket was discontinued, but blue light phototherapy was maintained until 129½ hours. A very mild, short-lasting erythema developed on light-exposed skin surfaces shortly after administration of SnMP, but subsided without sequelae despite continued phototherapy. The infant was discharged home on June 30, 2000. Anemia subsided with the use of iron supplementation. Subsequent follow-ups have shown the infant to be normal in growth and development.
This female term infant (GA: ≈38–39 weeks; birth weight: 4140 g) was delivered by cesarean section (because of a previous cesarean, and the existence of placenta praevia) on April 15, 2001, at the Rolling Plains Memorial Hospital, Sweetwater, Texas. Hemoglobin was 12.9 g/dL. Meconium aspiration was diagnosed, and she was mechanically ventilated. Because of her difficult clinical condition, transfer by helicopter was made to the Abilene Regional Medical Center Special Care Nursery, Abilene, Texas, where she was noted to be quite jaundiced, with hypertonic extremities. A direct Coombs test was positive; mother’s and newborn’s blood types were O, Rh positive; anti-c antibody was identified in the infant. The initial PBC at 10 hours of age was 18.0 mg/dL. Phototherapy was initiated with overhead lights and biliblanket. Irradiance from the overhead lights averaged 28 μW/cm2/nm and for the biliblanket, 11 μW/cm2/nm during the period of light treatment. Seizures developed and the decision was made to carry out a double-volume exchange transfusion. However, the parents, who were Jehovah’s Witness adherents, rejected the exchange transfusion. While preparing to secure legal permission for the procedure, the attending neonatologist sought use of SnMP from this (Rockefeller) laboratory. With FDA approval and the help of the Jehovah’s Witness organization the inhibitor was delivered to Abilene on the same day. Nine PBC determinations were made in the first 56 hours after birth. The initial PBC, at 10 hours after birth was, as noted, 18.0 mg/dL; the lowest value in the subsequent series of determinations before SnMP administration was 13.4 mg/dL at 23 hours of life. Of all PBC determinations made in the first 56 hours of life, 6 reached a level of 18.4 mg/dL or greater with the highest value being 25.8 mg/dL at 36 hours. At 50 hours the PBC was 19.0 mg/dL; because of concern about neurologic symptomatology and the fact that the PBC appeared to be increasing again, the SnMP dose was administered at 56 hours when the PBC was 19.5 mg/dL. The PBC increased further to 21.6 mg/dL over the next 4 hours, before decreasing rapidly to 14.2 mg/dL 4 hours later. A brief rebound to 18.1 mg/dL occurred, but thereafter PBC’s decreased steadily. The PBC decreased to <8.0 mg/dL within 27 hours after SnMP treatment. The course of bilirubinemia over the entire period of observation is depicted in Fig 2. No erythema or other side effects of administration of SnMP were noted in the infant. The hemoglobin had increased to 13.8 g/dL with use of Epogen and iron supplementation and the infant was discharged to home from the Special Care Nursery on May 15, 2001, having required prolonged care for pulmonary problems related to meconium aspiration, but without displaying neurologic sequelae.
SnMP is a potent inhibitor of heme oxygenase, the rate-limiting enzyme in the catabolism of heme to bilirubin.1,2 The compound has proved effective in controlling all induced or naturally occurring forms of jaundice studied in experimental animals and has been shown, in extensive protocol-based clinical trials, to be highly effective in moderating or preventing the development of severe postnatal jaundice in human newborns.3,4,5,6,7 The 2 cases described in this report provided unusual circumstances in which the efficacy of SnMP in moderating threatening levels of hyperbilirubinemia could be examined in newborns in whom phototherapy did not sufficiently control the problem and whose parents, for religious reasons, would not permit exchange transfusions.
The patterns of bilirubinemia in each infant, before and after administration of SnMP, are shown in Figs 1 and 2, and detailed in the case reports. Because it was obviously not possible to undertake properly controlled trials in the medical situations with which the attending neonatologists were presented, it is useful to evaluate the observations reported here against the background of extensive clinical experience with SnMP that has been accrued in newborns. The results of 5 carefully controlled, protocol-based clinical trials in newborns that have been reported earlier have demonstrated the efficacy of SnMP in moderating the course of bilirubinemia in all diagnostic groups of unconjugated neonatal jaundice.3,4,5,6,7 Of the 443 newborns studied in these groups a single dose of SnMP eliminated entirely the need for supplemental light treatment to manage the problem of hyperbilirubinemia in 430 infants. The 13 newborns who required supplemental phototherapy were all preterm infants of 210 to 251 days’ GA.3
Of special interest is the fact that in >50% of the glucose-6-phosphate dehydrogenase-deficient term newborns treated preventively (approximately 24 hours after birth) with SnMP, the PBC at the time of administration of the inhibitor proved to be the highest plasma bilirubin level reached during the infant’s postnatal course.7 Additionally, of the 80 term, breastfed newborns with preexisting high (15–18 mg/dL) levels of plasma bilirubin whom we have treated with SnMP (Martinez et al6 and unpublished data), none progressed to a PBC (19.5 mg/dL) dictating initiation of phototherapy. These data provide strong evidence that a single dose of SnMP results in a prompt and significant inhibition of bilirubin formation and greatly moderates development of hyperbilirubinemia in jaundiced infants.
In the 2 cases described here, the PBC increased slightly (0.5–2.1 mg/dL) after SnMP administration, but within 4 to 12 hours began a sustained decline to levels that eased concern about the development of bilirubin encephalopathy and resolved the troubling medical-legal issues raised by the religious convictions of the parents. These responses conform in all respects to those observed in the SnMP-treated, jaundiced infant populations studied earlier.3,4,5,6,7 It is reasonable to conclude, therefore, that SnMP interdiction of bilirubin production played a key role in terminating progression of hyperbilirubinemia in the infants reported here and in eliminating the need for exchange transfusions to control this problem in them.
This study was supported by the National Institute of Child Health and Human Development (Contract NO1-HD-5-3234).
- Received August 1, 2001.
- Accepted September 18, 2001.
Reprint requests to (A.K.) Rockefeller University, 1230 York Ave, New York, NY 10021.
- ↵Valaes T, Petmezaki S, Henschke C, Drummond GS, Kappas A. Control of jaundice in preterm newborns by an inhibitor of bilirubin production: studies with tin-mesoporphyrin. Pediatrics.1994 ;93:1–11
- ↵Kappas A, Drummond GS, Henschke CI, 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
- ↵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(5):. Available at: http://www.pediatrics.org/cgi/content/full/101/5/e1
- ↵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
- ↵Kappas A, Drummond GS, Valaes T. A single dose of Sn-mesoporphyrin prevents development of significant hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient newborns. Pediatrics.2001 ;108:25–30
- American Academy of Pediatrics