1242
maternal deaths in Sri Lanka, 25% in Nigeria, and 36% in Chile-countries in which legal abortion is not available.9 In these countries women know that illegal abortion often results in death but still feel compelled to resort to this action when faced by the probable consequences of continuing their pregnancy. If the safe and efficient induction of abortion with mifepristone/misoprostol is confirmed in large multicentre trials, this method could be used world wide and the death rate from illegal abortion could be vastly reduced. Unfortunately, many countries have political and religious barriers to the provision of legal abortion that condemn women with unwanted pregnancies to the hazards of illegal abortion or to becoming the parents of a child for whom they cannot provide adequately. Introduction of an effective, safe, and potentially inexpensive method for legal abortion should be welcomed. C, Renault M, Rezvani Y, Baulieu E-E, Ulmann A. Voluntary interruption of pregnancy with mifepristone (RU 486) and a prostaglandin analogue: a large-scale French experience. N Engl J Med 1990; 322: 645-48.
1. Silvestre L, Dubois
2. UK Multicentre Trial. The efficacy and tolerance of mifepristone and prostaglandin in first trimester termination of pregnancy. Br J Obstet Gynaecol 1990; 97: 480-86. 3. Rodger MW, Baird DT. Induction of therapeutic abortion in early pregnancy with mifepristone in combination with prostaglandin pessary. Lancet 1987; ii: 1415-18. 4. Mifegyne (mifepristone): a guide to its use in clinical practice. Uxbridge: Roussel Laboratories Ltd, 1991. 5. Medical termination of early pregnancy: Mifegyne (mifepristone) data file. Uxbridge: Roussel Laboratories Ltd, 1991. 6. Schonhöfer PS. Misuse of misoprostol as an abortifacient may induce malformations. Lancet 1991; 337: 1534-35. 7. Aubeny E, Baulieu E-E. Activité contragestive de l’association au RU486 d’une prostaglandin active par voie orale. C R Acad Sci III 1991; 312: 539-45. 8. Abortion statistics, England and Wales, 1989. Series AB No 16. London: HM Stationery Office, 1991. 9. World Health Organisation, Population Council, and World Watch Institute. Cited in Scientific American, August 8, 1991.
Moderate neonatal hyperbilirubinaemia: hold
tight
Severe neonatal hyperbilirubinaemia (peak > 340 umol/1) results in kernicterus1 and bilirubin encephalopathy-an acute syndrome of stupor, hypertonia, and fever or the chronic syndrome of neurological sequelae, athetosis, gaze disturbance, and hearing loss. When this condition was reported in premature infants with lower bilirubin concentrations
(peak 160-265 lunol/1),Z many paediatricians adopted vigorous policy of treating neonatal jaundice, especially in premature babies. But how vigorous a
should we be? In full-term infants with haemolytic disease, exchange transfusions carried out at a bilirubin concentration of 340 pmol/l avoided deaths due to kernicterus,3but infants without rhesus disease are less likely to get kemicteruS4and there is a morbidity and even mortality associated with exchange transfusion. Phototherapy might be considered the wiser option because such treatment likewise decreased the incidence of kernicterus6 and reduced
exchange transfusion rate in infants weighing less than 2500 g (low birthweight) from 24.4 to 4-1%/ Moreover, phototherapy has no long-term complications.7 Examination of 1399 six-year-old children who, in the neonatal period, were randomised at certain bilirubin concentrations to receive phototherapy or not, showed no significant difference between the two groups with respect to mortality, incidence of cerebral palsy, hearing loss, hypotonia, clumsiness, and either the verbal or performance component of the Wechsler intelligence scale.7 Phototherapy is most effective in small premature infants8 because of the thinness and translucency of their skin and the increased surface area to volume ratio. However, the effectiveness of phototherapy is dependent on the initial concentration. The decline in bilirubin is greater with higher initial concentrations;9 the rate slows down until, at 100 jjmol/1, phototherapy has no further effect. Thus it makes sense to administer phototherapy only when "significant" concentrations of bilirubin are reached, especially because there is some evidence that bilirubin has useful propertieseg, it may be an important component of the body’s natural defences against injury by organic free radicals.1O Bilirubin has antioxidant properties even when bound to human serum albumin, and at physiological concentrations can protect linoleic acid from peroxyl radical induced oxidation in vitro by efficient scavenging of peroxyl radicals. At low partial pressures of oxygen, bilirubin is a better inhibitor of lipid peroxidation in liposomes than is vitamin E. What are "significant" concentrations of bilirubin for preterm infants? The potential for toxicity of intermediate concentrations (170-323 umol/1) has been investigated in several follow-up studies. Early reportsll,12 suggested that preterm infants might be at risk of neurological damage even at concentrations as low as 204 jmol/1. The US collaborative perinatal multicentre cohort study enrolled 54 043 women who became pregnant between 1959 to 1965, and their infants were followed to 8 years of age. Initial analysis of the data13 showed a statistically significant negative association between total serum bilirubin and infant development: this relation was found for bilirubin concentrations as low as 204 lunol/1. However, subsequent analysis" stratifying the data for gestational age and race showed that the association was significant only for preterm low birthweight infants. Even then the effect was small-0-009-0-018 IQ points per nmol/1 serum bilirubin, or a loss of 3 IQ points with an increase in the peak bilirubin from 170 to 340 pmol/l. Another study, 12 which included preterm infants, showed that the proportion of children at 4 years of age with an IQ less than 90 increased in a dose-related fashion as the total serum bilirubin increased from 272 umol/1, but again the "real" effect was small14-about 0-018 IQ points per the
pmol/1 according to logistic regression techniques. Other groups15,16 have
suggested that any effect of
1243
moderately raised bilirubin concentrations on development is temporary, 15,16 disappearing by school age. van der Bor and colleaguesl5 undertook neurodevelopmental examination at 2 years of 831 infants born at a gestational age of less than 32 weeks and/or birthweight less than 1500 g; they found an odds ratio of 2 2 for handicap with a peak bilirubin of 251-300 umol/1 100 umol/1, but re-examination of the cohort at 5 years showed that the increased risk of handicap due to hyperbilirubinaemia was confined to those who had sustained an intracerebral haemorrhage in the neonatal period. Similarly, Rubin et a116 could not show that hyperbilirubinaemia was predictive of impaired cognitive development at 4-7 years, although it had been associated with reduced motor development at 8 months and an increased incidence of neurological abnormalities at 1 year. Many studies7,17-21 have produced comforting results on neurological impairment at school age of children who had moderately raised bilirubin concentrations. For example, Broman et al20 found no significant association of low school achievement and peak bilirubin concentrations when such children were compared with matched controls. However, some of these studies17-19 were small and the sample size may therefore have been insufficient to detect a minor but clinically significant effect. The reports 7,21 from the National Institute of Child Health and Human Development collaborative phototherapy trial are therefore very reassuring since they include follow-up of 1399 newborn infants. These infants were randomised to receive phototherapy or not (controls) at a concentration of 171 or 222 umol/1 depending on their birthweight; in both groups exchange transfusion was done if necessary according to predetermined criteria to prevent high bilirubin concentrations. When the children were seen at 6 years, despite a higher maximum neonatal bilirubin in the control group (171 umol/1) than in the phototherapy group (103 umol/1), there was no difference between the groups with respect to average intelligence scores or frequencies of cerebral palsy, mental retardation, seizure disorder, or defects of vision and hearing.Recent analysis of those data2l focused on 224 children from the control group who had a birthweight less than 2000 g. The rate of cerebral palsy was not significantly associated with maximum bilirubin concentration, and the mean bilirubin concentration for the children with cerebral palsy was not significantly different from those without. Intelligence did not correlate significantly with maximum bilirubin, mean bilirubin, or time and duration of exposure to bilirubin. Thus these data provide no support, even in immature infants, for starting phototherapy "early" at low concentrations of bilirubin. This policy would only achieve inefficient removal of a potentially helpful antioxidant. More important, the balance of recent evidence is reassuring that hyperbilirubinaemia with concentrations < 170 umol/1, even in small
high-risk infants (birthweight < 1250 g), does not lead to long-term neurological impairment. 1. Schmorl G. Zur Kenntis des Icterus Neonatorum. Verh Dtsch Ges Pathol 1903; 6: 109-21. 2. Gartner LM, Snyder RN, Chabon RS, Bernstein J. Kernicterus: high incidence in premature infants with low serum bilirubin concentrations. Pediatrics 1970; 45: 906-17. 3. Lucey JF. Bilirubin and brain damage—a real mess. Pediatrics 1982; 69: 381-82. 4. Killander A, Michaelsson M, Muller-Eberhard U. Hyperbilirubinaemia in full term new born infants. A follow-up study. Acta Paediatr Scand 1963; 52: 481-84. 5. Mores A, Fargasora I, Minarikova E. The relationship of hyperbilirubinaemia in newborns without isoimmunisation to kernicterus. Acta Paediatr Scand 1959; 48: 590-602. 6. Tan KL. Some aspects on management of neonatal jaundice in Singapore. J Sing Pediatr Soc 1978; 29: 122-32.
7. Scheidt PC,
Bryla DA, Nelson KB, Hirtz DG, Hoffman JH. Phototherapy for neonatal hyperbulirubinemia: six-year follow-up of the National Institute of Child Health and Human Development
clinical trial. Pediatrics 1990; 85: 455-63. 8. Tan KL, Boey BW. Efficacy of phototherapy in non-haemolytic hyperbilirubinaemia. Br Med J 1986; 293: 1361-63. 9. Tan KL. The pattern of bilirubin response to phototherapy for neonatal hyperbilirubinemia. Pediatr Res 1982; 16: 670-74. 10. Stocker R, Yamamoto Y, McDonagh AF. Bilirubin is an antioxidant of possible physiological importance. Science 1987; 235: 1043-46. 11. Scheidt PC, Mellitz ED, Hardy JB. Toxicity to bilirubin in neonates. Infant development during first year in relation to maximum neonatal serum bilirubin concentration. J Pediatr 1977; 91: 292-97. 12. Naeye RL. The role of congenital bacterial infections in serum bilirubin brain damage. Pediatrics 1978; 62: 497-503. 13. Boggs T, Hardy J, Frazier T. Correlation of neonatal serum total bilirubin concentration and developmental status at age eight months preliminary report from the collaborative project. J Pediatr 1967; 71: 553-60. 14. Newman TB, Maisels MJ. Does hyperbilirubinemia damage the brain of healthy full term infants? Clin Perinatol 1990; 17: 331-58. 15. van de Bor M, van Zeben-van der Aa TM, Verloove-Vanhorick SP, Brand R, Ruys JH. Hyperbilirubinemia in preterm infants and neurodevelopmental outcome at 2 years of age: results of a national collaborative survey. Pediatrics 1989; 83: 915-20. 16. Rubin RA, Balow B, Fisch RO. Neonatal serum bilirubin levels related to cognitive development at ages 4 through 7 years. J Pediatr 1979; 94: 601-04. 17. Bjure J, Liden G, Reinard T. A follow-up study of hyperbilirubinaemia in full term infants without isoimmunisation. Acta Paediatr Scand 1961; 50: 437-43. 18. Culley P, Powell J, Waterhouse J. Sequelae of neonatal jaundice. Br Med J 1970; iii: 383-86. 19. Rosta ZM, Bekel D, Popper P. Neonatal pathological jaundice: seven to nine years follow-up. Acta Paediatr Acad Sci Hung 1971; 12: 317-21. 20. Broman SH, Bien E, Shaughnessy P. Low achieving children: the first seven years. Hillsdale, NJ: Erlbaum, 1985: 284. 21. Scheidt PC, Braudbard BI, Nelson KB, et al. Intelligence at six years in relation to neonatal bilirubin level: follow-up of the National Institute of Child Health and Human Development clinical trial of phototherapy. Pediatrics 1991; 87: 797-805.
TB and deer farming: return of the king’s evil? In this issue (p 1253), Fanning and Edwards describe an outbreak of infection with Mycobacterium bovis affecting people in contact with farmed elk in Alberta, Canada. To avoid any confusion in our European readers we should point out that the North American elk is Cervus elaphus of the family Cervidae, otherwise known as red deer or wapiti, not moose (Alces alces).The epizootic was first recognised in November, 1990, in a herd of 150 animals but was subsequently found to be widespread in elk throughout the province, involving 32 of 110
maternal deaths in Sri Lanka, 25% in Nigeria, and 36% in Chile-countries in which legal abortion is not available.9 In these countries women know that illegal abortion often results in death but still feel compelled to resort to this action when faced by the probable consequences of continuing their pregnancy. If the safe and efficient induction of abortion with mifepristone/misoprostol is confirmed in large multicentre trials, this method could be used world wide and the death rate from illegal abortion could be vastly reduced. Unfortunately, many countries have political and religious barriers to the provision of legal abortion that condemn women with unwanted pregnancies to the hazards of illegal abortion or to becoming the parents of a child for whom they cannot provide adequately. Introduction of an effective, safe, and potentially inexpensive method for legal abortion should be welcomed. C, Renault M, Rezvani Y, Baulieu E-E, Ulmann A. Voluntary interruption of pregnancy with mifepristone (RU 486) and a prostaglandin analogue: a large-scale French experience. N Engl J Med 1990; 322: 645-48.
1. Silvestre L, Dubois
2. UK Multicentre Trial. The efficacy and tolerance of mifepristone and prostaglandin in first trimester termination of pregnancy. Br J Obstet Gynaecol 1990; 97: 480-86. 3. Rodger MW, Baird DT. Induction of therapeutic abortion in early pregnancy with mifepristone in combination with prostaglandin pessary. Lancet 1987; ii: 1415-18. 4. Mifegyne (mifepristone): a guide to its use in clinical practice. Uxbridge: Roussel Laboratories Ltd, 1991. 5. Medical termination of early pregnancy: Mifegyne (mifepristone) data file. Uxbridge: Roussel Laboratories Ltd, 1991. 6. Schonhöfer PS. Misuse of misoprostol as an abortifacient may induce malformations. Lancet 1991; 337: 1534-35. 7. Aubeny E, Baulieu E-E. Activité contragestive de l’association au RU486 d’une prostaglandin active par voie orale. C R Acad Sci III 1991; 312: 539-45. 8. Abortion statistics, England and Wales, 1989. Series AB No 16. London: HM Stationery Office, 1991. 9. World Health Organisation, Population Council, and World Watch Institute. Cited in Scientific American, August 8, 1991.
Moderate neonatal hyperbilirubinaemia: hold
tight
Severe neonatal hyperbilirubinaemia (peak > 340 umol/1) results in kernicterus1 and bilirubin encephalopathy-an acute syndrome of stupor, hypertonia, and fever or the chronic syndrome of neurological sequelae, athetosis, gaze disturbance, and hearing loss. When this condition was reported in premature infants with lower bilirubin concentrations
(peak 160-265 lunol/1),Z many paediatricians adopted vigorous policy of treating neonatal jaundice, especially in premature babies. But how vigorous a
should we be? In full-term infants with haemolytic disease, exchange transfusions carried out at a bilirubin concentration of 340 pmol/l avoided deaths due to kernicterus,3but infants without rhesus disease are less likely to get kemicteruS4and there is a morbidity and even mortality associated with exchange transfusion. Phototherapy might be considered the wiser option because such treatment likewise decreased the incidence of kernicterus6 and reduced
exchange transfusion rate in infants weighing less than 2500 g (low birthweight) from 24.4 to 4-1%/ Moreover, phototherapy has no long-term complications.7 Examination of 1399 six-year-old children who, in the neonatal period, were randomised at certain bilirubin concentrations to receive phototherapy or not, showed no significant difference between the two groups with respect to mortality, incidence of cerebral palsy, hearing loss, hypotonia, clumsiness, and either the verbal or performance component of the Wechsler intelligence scale.7 Phototherapy is most effective in small premature infants8 because of the thinness and translucency of their skin and the increased surface area to volume ratio. However, the effectiveness of phototherapy is dependent on the initial concentration. The decline in bilirubin is greater with higher initial concentrations;9 the rate slows down until, at 100 jjmol/1, phototherapy has no further effect. Thus it makes sense to administer phototherapy only when "significant" concentrations of bilirubin are reached, especially because there is some evidence that bilirubin has useful propertieseg, it may be an important component of the body’s natural defences against injury by organic free radicals.1O Bilirubin has antioxidant properties even when bound to human serum albumin, and at physiological concentrations can protect linoleic acid from peroxyl radical induced oxidation in vitro by efficient scavenging of peroxyl radicals. At low partial pressures of oxygen, bilirubin is a better inhibitor of lipid peroxidation in liposomes than is vitamin E. What are "significant" concentrations of bilirubin for preterm infants? The potential for toxicity of intermediate concentrations (170-323 umol/1) has been investigated in several follow-up studies. Early reportsll,12 suggested that preterm infants might be at risk of neurological damage even at concentrations as low as 204 jmol/1. The US collaborative perinatal multicentre cohort study enrolled 54 043 women who became pregnant between 1959 to 1965, and their infants were followed to 8 years of age. Initial analysis of the data13 showed a statistically significant negative association between total serum bilirubin and infant development: this relation was found for bilirubin concentrations as low as 204 lunol/1. However, subsequent analysis" stratifying the data for gestational age and race showed that the association was significant only for preterm low birthweight infants. Even then the effect was small-0-009-0-018 IQ points per nmol/1 serum bilirubin, or a loss of 3 IQ points with an increase in the peak bilirubin from 170 to 340 pmol/l. Another study, 12 which included preterm infants, showed that the proportion of children at 4 years of age with an IQ less than 90 increased in a dose-related fashion as the total serum bilirubin increased from 272 umol/1, but again the "real" effect was small14-about 0-018 IQ points per the
pmol/1 according to logistic regression techniques. Other groups15,16 have
suggested that any effect of
1243
moderately raised bilirubin concentrations on development is temporary, 15,16 disappearing by school age. van der Bor and colleaguesl5 undertook neurodevelopmental examination at 2 years of 831 infants born at a gestational age of less than 32 weeks and/or birthweight less than 1500 g; they found an odds ratio of 2 2 for handicap with a peak bilirubin of 251-300 umol/1 100 umol/1, but re-examination of the cohort at 5 years showed that the increased risk of handicap due to hyperbilirubinaemia was confined to those who had sustained an intracerebral haemorrhage in the neonatal period. Similarly, Rubin et a116 could not show that hyperbilirubinaemia was predictive of impaired cognitive development at 4-7 years, although it had been associated with reduced motor development at 8 months and an increased incidence of neurological abnormalities at 1 year. Many studies7,17-21 have produced comforting results on neurological impairment at school age of children who had moderately raised bilirubin concentrations. For example, Broman et al20 found no significant association of low school achievement and peak bilirubin concentrations when such children were compared with matched controls. However, some of these studies17-19 were small and the sample size may therefore have been insufficient to detect a minor but clinically significant effect. The reports 7,21 from the National Institute of Child Health and Human Development collaborative phototherapy trial are therefore very reassuring since they include follow-up of 1399 newborn infants. These infants were randomised to receive phototherapy or not (controls) at a concentration of 171 or 222 umol/1 depending on their birthweight; in both groups exchange transfusion was done if necessary according to predetermined criteria to prevent high bilirubin concentrations. When the children were seen at 6 years, despite a higher maximum neonatal bilirubin in the control group (171 umol/1) than in the phototherapy group (103 umol/1), there was no difference between the groups with respect to average intelligence scores or frequencies of cerebral palsy, mental retardation, seizure disorder, or defects of vision and hearing.Recent analysis of those data2l focused on 224 children from the control group who had a birthweight less than 2000 g. The rate of cerebral palsy was not significantly associated with maximum bilirubin concentration, and the mean bilirubin concentration for the children with cerebral palsy was not significantly different from those without. Intelligence did not correlate significantly with maximum bilirubin, mean bilirubin, or time and duration of exposure to bilirubin. Thus these data provide no support, even in immature infants, for starting phototherapy "early" at low concentrations of bilirubin. This policy would only achieve inefficient removal of a potentially helpful antioxidant. More important, the balance of recent evidence is reassuring that hyperbilirubinaemia with concentrations < 170 umol/1, even in small
high-risk infants (birthweight < 1250 g), does not lead to long-term neurological impairment. 1. Schmorl G. Zur Kenntis des Icterus Neonatorum. Verh Dtsch Ges Pathol 1903; 6: 109-21. 2. Gartner LM, Snyder RN, Chabon RS, Bernstein J. Kernicterus: high incidence in premature infants with low serum bilirubin concentrations. Pediatrics 1970; 45: 906-17. 3. Lucey JF. Bilirubin and brain damage—a real mess. Pediatrics 1982; 69: 381-82. 4. Killander A, Michaelsson M, Muller-Eberhard U. Hyperbilirubinaemia in full term new born infants. A follow-up study. Acta Paediatr Scand 1963; 52: 481-84. 5. Mores A, Fargasora I, Minarikova E. The relationship of hyperbilirubinaemia in newborns without isoimmunisation to kernicterus. Acta Paediatr Scand 1959; 48: 590-602. 6. Tan KL. Some aspects on management of neonatal jaundice in Singapore. J Sing Pediatr Soc 1978; 29: 122-32.
7. Scheidt PC,
Bryla DA, Nelson KB, Hirtz DG, Hoffman JH. Phototherapy for neonatal hyperbulirubinemia: six-year follow-up of the National Institute of Child Health and Human Development
clinical trial. Pediatrics 1990; 85: 455-63. 8. Tan KL, Boey BW. Efficacy of phototherapy in non-haemolytic hyperbilirubinaemia. Br Med J 1986; 293: 1361-63. 9. Tan KL. The pattern of bilirubin response to phototherapy for neonatal hyperbilirubinemia. Pediatr Res 1982; 16: 670-74. 10. Stocker R, Yamamoto Y, McDonagh AF. Bilirubin is an antioxidant of possible physiological importance. Science 1987; 235: 1043-46. 11. Scheidt PC, Mellitz ED, Hardy JB. Toxicity to bilirubin in neonates. Infant development during first year in relation to maximum neonatal serum bilirubin concentration. J Pediatr 1977; 91: 292-97. 12. Naeye RL. The role of congenital bacterial infections in serum bilirubin brain damage. Pediatrics 1978; 62: 497-503. 13. Boggs T, Hardy J, Frazier T. Correlation of neonatal serum total bilirubin concentration and developmental status at age eight months preliminary report from the collaborative project. J Pediatr 1967; 71: 553-60. 14. Newman TB, Maisels MJ. Does hyperbilirubinemia damage the brain of healthy full term infants? Clin Perinatol 1990; 17: 331-58. 15. van de Bor M, van Zeben-van der Aa TM, Verloove-Vanhorick SP, Brand R, Ruys JH. Hyperbilirubinemia in preterm infants and neurodevelopmental outcome at 2 years of age: results of a national collaborative survey. Pediatrics 1989; 83: 915-20. 16. Rubin RA, Balow B, Fisch RO. Neonatal serum bilirubin levels related to cognitive development at ages 4 through 7 years. J Pediatr 1979; 94: 601-04. 17. Bjure J, Liden G, Reinard T. A follow-up study of hyperbilirubinaemia in full term infants without isoimmunisation. Acta Paediatr Scand 1961; 50: 437-43. 18. Culley P, Powell J, Waterhouse J. Sequelae of neonatal jaundice. Br Med J 1970; iii: 383-86. 19. Rosta ZM, Bekel D, Popper P. Neonatal pathological jaundice: seven to nine years follow-up. Acta Paediatr Acad Sci Hung 1971; 12: 317-21. 20. Broman SH, Bien E, Shaughnessy P. Low achieving children: the first seven years. Hillsdale, NJ: Erlbaum, 1985: 284. 21. Scheidt PC, Braudbard BI, Nelson KB, et al. Intelligence at six years in relation to neonatal bilirubin level: follow-up of the National Institute of Child Health and Human Development clinical trial of phototherapy. Pediatrics 1991; 87: 797-805.
TB and deer farming: return of the king’s evil? In this issue (p 1253), Fanning and Edwards describe an outbreak of infection with Mycobacterium bovis affecting people in contact with farmed elk in Alberta, Canada. To avoid any confusion in our European readers we should point out that the North American elk is Cervus elaphus of the family Cervidae, otherwise known as red deer or wapiti, not moose (Alces alces).The epizootic was first recognised in November, 1990, in a herd of 150 animals but was subsequently found to be widespread in elk throughout the province, involving 32 of 110
