Control of jaundice in preterm newborns by an inhibitor of bilirubin production: studies with tin-mesoporphyrin.

BACKGROUND: Studies in vitro, in animal models, and in adult and newborn humans have demonstrated that certain tin(Sn)-porphyrins that competitively inhibit the activity of heme oxygenase, the rate-limiting enzyme in heme catabolism, reduce production of bilirubin and can thereby substantially diminish plasma levels of the bile pigment. OBJECTIVES: To assess the effectiveness of increasing doses of the heme oxygenase inhibitor, Sn-mesoporphyrin (SnMP), in moderating the development of significant hyperbilirubinemia and thus the requirements for phototherapy in preterm newborns. METHODS: In five randomized, blinded, placebo-controlled trials, SnMP in increasing doses from 1 mumol to 6 mumol/kg body weight was administered intramuscularly in the first 24 hours of life in preterm newborns of 210 to 251 days gestational age. "Special blue" lamps (Phillips F20T12/BB) were used for phototherapy in newborns exceeding a predetermined plasma bilirubin concentration, irrespective of study group. RESULTS: A total of 517 newborns were randomized in the five trials carried out sequentially over a 4-year period. SnMP in a dose-related manner significantly ameliorated the course of hyperbilirubinemia in the treated newborns of all gestational ages. With a SnMP dose of 6 mumol/kg body weight, the mean peak incremental plasma bilirubin concentration was reduced by 41% and the phototherapy requirements were decreased by 76% compared to control subjects. Erythema observed in a few SnMP-treated newborns who required phototherapy was mild, transient, and without sequelae. No other untoward effects were observed during hospitalization or at a follow-up at post-term age of 3 and 18 months. CONCLUSIONS: SnMP, by inhibiting the production of bilirubin, substantially moderates the development of hyperbilirubinemia in preterm newborns. This compound and similarly acting enzyme inhibitors merit further clinical study as agents for controlling neonatal hyperbilirubinemia, particularly in neonatal populations for whom other treatment modalities are not available.

Alpha-fetoprotein in congenital hypothyroidism.

alpha-Fetoprotein (alpha-FP) was measured in dried blood spots from normal, congenital hypothyroid (CH) and transient hyperthyrotropinemic (TH) newborns as well as in serum from CH and TH babies together with thyroxine, triiodothyronine and thyrotropin. The half-life of alpha-FP had a median value of 12 days in the CH cases and 4.9 days in the TH cases. alpha-FP was significantly higher in the CH group before treatment and showed a significant rise after discontinuation of thyroxine therapy. It would appear that thyroid hormones influence alpha-FP metabolism and that a hypothyroid environment results in increased alpha-FP levels.

Sn-protoporphyrin use in the management of hyperbilirubinemia in term newborns with direct Coombs-positive ABO incompatibility.

In two separate studies, in which two different treatment regimens of Sn-protoporphyrin were used, a total of 69 control and 53 treated infants were studied to determine whether this potent inhibitor of the enzyme, heme oxygenase, could ameliorate the severity of the hyperbilirubinemia which develops in term babies with direct Coombs-positive ABO incompatibility. The results indicate that Sn-protoporphyrin can, in appropriate doses, moderate the postnatal rate of increase of plasma bilirubin levels and diminish the intensity of hyperbilirubinemia in treated babies. In addition, a decreased use of phototherapy in Sn-protoporphyrin-treated infants was observed. No rebound hyperbilirubinemia was detected during the six- to eight-day period after Sn-protoporphyrin administration. The plasma clearance (t1/2) of Sn-protoporphyrin was much faster in newborns than in adults (approximately 1.6 hours v 3.5 hours, respectively). The incidence of clinical side effects in the 53 Sn-protoporphyrin-treated infants was limited to the development of transient erythema during the use of concurrent phototherapy in two babies. In both infants this reaction subsided completely without sequelae. The use of Sn-protoporphyrin or related synthetic heme analogues to diminish the severity of hyperbilirubinemia in newborn infants merits further study because inhibition of the rate-limiting enzyme in the catabolism of heme to bilirubin may prove to be a useful therapeutic approach in the clinical management of neonatal hyperbilirubinemia, especially in settings in which, for social or economic reasons, other treatment modalities are not available.

Effectiveness and safety of prenatal phenobarbital for the prevention of neonatal jaundice.

The effect of 100 mg of phenobarbital (PB) at bedtime for the last few wk of pregnancy on the incidence and severity of neonatal hyperbilirubinemia was studied. No effect was observed in the newborns of mothers who took less than ten tablets. In the 1310 newborns of adequately treated mothers (PB greater than or equal to 1.0 g), the incidence of marked jaundice (bilirubin > 16.0 mg/dl) and the need to perform an exchange transfusion were reduced by a factor of six in relation to the incidence in 1553 control infants. A randomly selected group of 415 children (182 control, 233 PB) were reexamined at 61 to 82 months of age. There was no difference in the overall morbidity and mortality between the control and treatment group. A detailed neurologic assessment failed to reveal any differences between the two groups. In the VisuoMotor Integration test, the PB group scored significantly better than the control group. In the Draw-A-Woman and the Verbal Intelligence Test, the difference was in the same direction but was not statistically significant. The degree of jaundice was not found to significantly influence the performance in the neurological examination and the intelligence tests. Sensorineural hearing defect was significantly more common in the children with moderate or marked jaundice (bilirubin > 12 mg/dl) than in those with lesser degrees of jaundice. Prenatal PB is a practical, effective, and safe method for decreasing the incidence of neonatal hyperbilirubinemia.

A gene for hypospadias in a child with presumed tetrasomy 18p.

The proband and his elder brother had intrauterine growth retardation, hypospadias, cryptorchism, a high palate, distally placed axial triradii, and a functional and maturational CNS defect that improved with age and included the inability to suck, severe swallowing difficulties, and frequent vomiting. Their hypospadias is due to an autosomal dominant gene. The proband also had a small extra metacentric chromosome presumed to be an isochromosome 18p.

Oligohydramnios syndrome and XYY karyotype.

A case of oligohydramnios syndrome was found to have an XYY karyotype and an inherited 9qh inversion. It is suggested that normal and extra Y chromosomes are a predisposing factor in the aetiology of severe congenital renal anomalies.