1241
offered
further
measures
to
terminate
their
EDITORIALS
pregnancy.
Misoprostol
and legal medical abortion
Unwanted pregnancies
are encountered the world and are a consequence of the great difficulty that many couples have in planning their sexual activity and in using contraception. All existing methods have side-effects and may fail. Effective use depends on availability and on couples having a relationship in which they can communicate and agree about this aspect of their behaviour. When an unwanted conception occurs, most people now believe that it is better to provide legal abortion services than to coerce the woman into continuing a pregnancy that would have serious effects on her future and that of her over
family. The progesterone-blocking drug mifepristone (RU486), used in combination with a prostaglandin, can provide safe and effective medical abortion in the first nine weeks of pregnancy.1-3 Potentially, this approach allows legal abortion to be provided from simple day-care facilities. Abortion at such an early stage of gestation results in pain and bleeding and resembles a spontaneous miscarriage; and, as with a miscarriage, a small proportion of women have troublesome bleeding, usually when the abortion remains incomplete. In about 5% of patients undergoing mifepristone/prostaglandin abortion the uterus has to be evacuated with a suction cannula, and
occasional enough blood an
patient (less than 1 %) will lose require transfusion. Emergency
to
gynaecological services must be available but need not be a part of the abortion-providing service itself. The method fails in about 1% and routine follow-up examination is essential so that such patients can be
Medical abortion depends on drugs that tend to be very expensive. The large clinical trials cited above used 600 mg of mifepristone given on one occasion, but conversation between sessions at scientific meetings suggests that much smaller amounts may be equally effective. Cost is an important factor in the provision of a service, especially one with such obvious applicability in developing countries. The current price of mifepristone to the UK National Health Service is /;42.90 ($74) per 600 mg.4 The prostaglandins given two days after the mifepristone of natural prostaglandins. Both are analogues sulprostone by injection and gemeprost by vaginal pessary are effective, and gemeprost has been licensed for use in the UK. Gemeprost pessaries often cause vomiting and diarrhoea as well as expulsive uterine contraction but, in contrast to sulprostone,s seem to be free of serious cardiovascular side-effects. Cost is also a drawback with gemeprost-the NHS price for a 1 mg pessary is about 21. Pessaries have to be transported and stored in a refrigerator, making their use practicable only in prosperous countries with efficient services. A prostaglandin analogue that was as effective as gemeprost, active by mouth, inexpensive, and stable at room temperature would facilitate the provision of medical abortion with mifepristone. Misoprostol may meet these criteria. Misoprostol is licensed for sale in many countries for the treatment of gastric and duodenal ulceration; in the UK 400 Jlg costs the NHS about 46 pence. In Brazil, where abortion is illegal, misoprostol has been used as an over-the-counter abortifacient.6Although such unregulated use may be dangerous and misoprostol is usually ineffective for this purpose when given alone, the combination with mifepristone looks promising. In France, Aubeny and Baulieu’ tried 600 mg of mifepristone followed, 2 days later, by 400 g of misoprostol by mouth in 100 women who were undergoing legal abortion at gestations of up to 49 days. 95 had a complete abortion, 69 during the 4 hours that followed the misoprostol. 4 women had an incomplete abortion and required suction evacuation; evacuation was also required for 1 pregnancy that continued despite the treatment. The pain experienced by the women was said to be less than with sulprostone and the gastrointestinal side-effects were similar. In this issue (p 1233), Norman et al in Edinburgh report on a smaller number of women but they have confirmed these important observations and have extended the experience of this combination up to 56 days of gestation. In addition, they have shown that, although misoprostol taken alone induced a rise in intrauterine pressure in early pregnancy, abortion followed a 400 ug dose in only 2 of 40 women studied. Legal abortion has a death rate of less than 1 per 100 000 in England and Wales.8By contrast, illegal abortion is estimated to cause about 13% of all
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
offered
further
measures
to
terminate
their
EDITORIALS
pregnancy.
Misoprostol
and legal medical abortion
Unwanted pregnancies
are encountered the world and are a consequence of the great difficulty that many couples have in planning their sexual activity and in using contraception. All existing methods have side-effects and may fail. Effective use depends on availability and on couples having a relationship in which they can communicate and agree about this aspect of their behaviour. When an unwanted conception occurs, most people now believe that it is better to provide legal abortion services than to coerce the woman into continuing a pregnancy that would have serious effects on her future and that of her over
family. The progesterone-blocking drug mifepristone (RU486), used in combination with a prostaglandin, can provide safe and effective medical abortion in the first nine weeks of pregnancy.1-3 Potentially, this approach allows legal abortion to be provided from simple day-care facilities. Abortion at such an early stage of gestation results in pain and bleeding and resembles a spontaneous miscarriage; and, as with a miscarriage, a small proportion of women have troublesome bleeding, usually when the abortion remains incomplete. In about 5% of patients undergoing mifepristone/prostaglandin abortion the uterus has to be evacuated with a suction cannula, and
occasional enough blood an
patient (less than 1 %) will lose require transfusion. Emergency
to
gynaecological services must be available but need not be a part of the abortion-providing service itself. The method fails in about 1% and routine follow-up examination is essential so that such patients can be
Medical abortion depends on drugs that tend to be very expensive. The large clinical trials cited above used 600 mg of mifepristone given on one occasion, but conversation between sessions at scientific meetings suggests that much smaller amounts may be equally effective. Cost is an important factor in the provision of a service, especially one with such obvious applicability in developing countries. The current price of mifepristone to the UK National Health Service is /;42.90 ($74) per 600 mg.4 The prostaglandins given two days after the mifepristone of natural prostaglandins. Both are analogues sulprostone by injection and gemeprost by vaginal pessary are effective, and gemeprost has been licensed for use in the UK. Gemeprost pessaries often cause vomiting and diarrhoea as well as expulsive uterine contraction but, in contrast to sulprostone,s seem to be free of serious cardiovascular side-effects. Cost is also a drawback with gemeprost-the NHS price for a 1 mg pessary is about 21. Pessaries have to be transported and stored in a refrigerator, making their use practicable only in prosperous countries with efficient services. A prostaglandin analogue that was as effective as gemeprost, active by mouth, inexpensive, and stable at room temperature would facilitate the provision of medical abortion with mifepristone. Misoprostol may meet these criteria. Misoprostol is licensed for sale in many countries for the treatment of gastric and duodenal ulceration; in the UK 400 Jlg costs the NHS about 46 pence. In Brazil, where abortion is illegal, misoprostol has been used as an over-the-counter abortifacient.6Although such unregulated use may be dangerous and misoprostol is usually ineffective for this purpose when given alone, the combination with mifepristone looks promising. In France, Aubeny and Baulieu’ tried 600 mg of mifepristone followed, 2 days later, by 400 g of misoprostol by mouth in 100 women who were undergoing legal abortion at gestations of up to 49 days. 95 had a complete abortion, 69 during the 4 hours that followed the misoprostol. 4 women had an incomplete abortion and required suction evacuation; evacuation was also required for 1 pregnancy that continued despite the treatment. The pain experienced by the women was said to be less than with sulprostone and the gastrointestinal side-effects were similar. In this issue (p 1233), Norman et al in Edinburgh report on a smaller number of women but they have confirmed these important observations and have extended the experience of this combination up to 56 days of gestation. In addition, they have shown that, although misoprostol taken alone induced a rise in intrauterine pressure in early pregnancy, abortion followed a 400 ug dose in only 2 of 40 women studied. Legal abortion has a death rate of less than 1 per 100 000 in England and Wales.8By contrast, illegal abortion is estimated to cause about 13% of all
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
