- Email: [email protected]
The Risk of Amniocentesis
1287
data from both. The centres were in England, Wales, and Scotland; eight were teaching hospitals and the ninth was a district hospital closely associated with a teaching unit. Whilst the amniocentesis subjects were often referred to these centres, the controls were selected largely from women who had booked at these hospitals. The patients in such a group often vary considerably from background populations and so the controls might include many with not easily measurable but positively beneficial factors. To some extent this is seen in the examination of data relating to amniocentesis subjects who were left out of the analysis (some 19%) because no control mothers could be found to match them. When the control groups and the subjects are examined for basic demographic characteristics, the controls had more patients in the 25-34-year age-range and fewer at the extremes, parity differed (19% of the subjects were primiparous compared with 25% of the controls), and the social-class distribution shows a difference in favour of the subjects (37.8% in classes I and II compared with 31.9% of controls). There are several other areas where differences are hard to explain if the matching process was a valid one; for example, hypertension and pre-eclampsia occurred in a larger proportion of controls than of subjects (16 - 6% compared with 14-1%), despite the age-distribution bias-but perhaps this may reflect the greater number of primiparous patients in the control group. Elective caesarean section was more commonly done in the subject group while occipitoposterior, face, and brow presentations were more frequent in the controls. All these disparities are freely discussed in the report, but they may still give the impression that like was not being compared with like. Planners and practitioners want to know whether amniocentesis should be made more widely available, to reduce the numbers of children born with a congenital abnormality. The Clinical Genetics Society recommends a regional service capable of monitoring one pregnancy in every twelve (see p. 1321). The two principal indications for amniocentesis at present are advanced maternal age, with its increased risk of chromosome changes, and a raised serum alpha-fetoprotein (A.F.P.), which may indicate a neural-tube defect. Early this year the Department of Health and Social Security expressed itself in favour, in principle, of a national serum-A.F.P. scheme for detection of neural-tube defect, but this pronouncement met with strong criticism, notably from the Royal College of Obstetricians and Gynaecologists. As well as the ethical problems of over-kill of healthy fetuses-problems which have not been faced by society or the medical profession-there is the scarcity of people skilled at amniocentesis and at handling the ultrasound equipment which is mandatory in this proare
THE LANCET
The Risk of Amniocentesis THE long-awaited report of the Medical Research Council Working Party on Amniocentesis is published,l and the extra data may help both society and the medical profession make up their minds about the place of amniocentesis in prenatal
In essence, the working-party compared the cases of 2428 women who had an amniocentesis in the first half of pregnancy with those of the same number of matched controls. In a selected group of those who had amniocentesis; the rate of fetal loss was 2-6% compared with 1-1% in controls, and there seemed to be an increase of the same order in certain abnormalities of live-born infants, such as respiratory difficulties at birth and major orthopxdic postural deformities. As well as the immediate risks, the subjects of the trial showed an increased incidence of other complications later in pregnancy which may have been due to the amniocentesisabruptio placentx, premature rupture of the membranes, and postpartum haemorrhage. The circumstances in which amniocentesis had a good chance
diagnosis.
of detecting a fetal abnormality were a previous child with a single autosomal gene defect (25%), a raised maternal serum alpha-fetoprotein (20%), a previous child with a neural-tube defect (3% after 1, and 14% after 2 or more), and maternal age of over 40 years (Down’s syndrome in 5% of the mothers aged 40-41, 8% in those aged 42-43, and 11 % in those aged 44-47). Was the inquiry a valid one and can the results stand up to rigorous assessment? And does it help us to decide about the future practice of amniocentesis in prenatal diagnosis? The study is a multicentre one and, halfway through, the criteria for entry of controls had to be widened because of difficulty and long delays in obtaining such women and possible bias introduced in selection of some earlier controls. In consequence the survey is divided into a main study (1402 control women) and a supplementary inquiry with 1206 controls, some conclusions relate to one study whilst others 1. An Assessment of the Hazards of Amniocentesis: Report of the M.R.C. Working Party on Amniocentesis. British Journal of Obstetrics and Gynœcology, 1978, 85, suppl. 2. £2.
.
based
on
1288
cedure. On p. 1293 Dr JOCELYN CHAMBERLAIN offers a thoughtful assessment of the human benefits and costs. She calculates that the human cost of preventing some 555 spina-bifida births a year in England and Wales (most of whom would die in early life) would be 120 dead or damaged normal infants. KENNEDy2 judged that the cost-benefit ratio in human terms would be even less advantageous, in that 95 healthy fetuses and 110 handicapped but not hopeless children would be aborted to prevent 329 seriously affected babies with spina bifida, many of whom again would not survive. In another article this week (p. 1296), Mr BENNETT and his colleagues cite data suggesting a 6% to 8% fetal-loss rate after amniocentesis when the indication is a raised serum-A.F.p. This figure includes a larger group of accidental abortions which follow amniocentesis, and a smaller group of normal babies aborted because of a false-positive amnioticfluid test. The first group may become smaller as practitioners become more experienced, though the M.R.C. trial was at nine centres with skilled operators. A wider use of amniocentesis would raise the fetal-loss rate, at least in the earlier days. The worrying false-positive rates may be reduced a little but, as Mr BENNETT and his co-workers point out, so long as there is some overlap in the distribution of the normal and abnormal population, wherever the cut-off point of normality is placed there is bound to be a small misallocation. No medical diagnostic test has a zero false-positive rate. In the M.R.C. trial the false-negative rate of tests of the amniotic fluid was 0.4% and the false positive-rate was
0 - 2%.
How may the M.R.C. trial help to resolve these problems? If its validity is accepted, it has confirmed an immediate fetal loss of up to 1.5% in the hands of skilful, well-equipped specialists and it suggests that these risks are independent of the indications for the procedure-a point of recent debate.34 Further, amniocentesis seems to increase
the likelihood of
respiratory-distress syndrome, abruptio placentx, and major orthopaedic problems. The dilemma lies in deciding what value should be placed on the gains of terminating affected fetuses and the losses of killing normal fetuses. These cannot simply be weighed against
each other in numerical terms. The value of ter. minating affected fetuses must depend on the likely degree of handicap and its effect on parents; their families, and society; some fetuses will be so severely affected that they will be stillborn or die soon after birth, in which case amniocentesis and termination cannot be said to have averted handicap. At the other end of the scale, some will be only mildly affected and have a prospect of almost norKennedy, I. The Defect. BBC Radio 3, Oct. 25, 1978. 3. Bennett, M. Lancet, 1978, ii, 987. 4. Wald, N., Barker, S., Cuckle, H., Brock, D., Stirrat, G. ibid, p. 2.
1093.
mal lives. Between these two extremes lies a full range of physical and mental disabilities. As far as damage to normal pregnancies is concerned, the M.R.C. study provides reasonably firm evidence that this results directly from amniocentesis; but what negative value is to be placed on these unwanted effects? Can most of these fetal losses be accepted because the fetuses are easily replaceable,
and can the damage to normal infants be tolerated if its severity is less than that of the condition prevented by the amniocentesis? There is at present a considerable demand for amniocentesis, but is this an informed demand? It is possible that, faced with the human-cost/ human-benefit figures revealed by the M.R.C. report, prospective parents would be less enthusiastic. What they would actually decide can be determined only by in-service evaluation.
Digoxin—More Problems than Solutions been used in clinical practice for two hundred years. Currently, in the United Kingdom about 300 000 people are on digitalis or one of its successors, despite the fact that these drugs have a narrow therapeutic ratio (small margin between toxic and therapeutic dose) and lifethreatening toxic effects; in hospital patients treated with cardiac glycosides the reported incidence of toxicity is from 4% to as high as 35%.2 Almost ten years ago, a reliable method for quantitative assay of non-radioactive digoxin in body fluids3 offered fresh hope that digoxin could be prescribed more scientifically and that its use in clinical medicine would become more rational. How far has this hope been fulfilled? Experimental work on the clinical pharmacokinetics of digoxin4has given rise to various equations, nomograms, and scoring systems to help the physician decide on the most suitable dosage regimen for the individual patient. 5-12 As a means DIGITALIS has
now
given steady-state plasma digoxin-conof these has proved very satisfactory: 13 for example, a computer program for digoxin dosage, designed to achieve a serum concentration of 1 ng/ml, could assure only that the of achieving
centrations,
none
1. Lancet, 1976, ii, 405. 2. Smith, T. W. Am. J. Med. 1975, 58, 470. 3. Smith, T. W., Butler, V. P., Haber, E. New Engl. J. Med. 1969, 281, 1212. 4. Iisalo, E. Clin. Pharmacokin. 1977, 2, 1. 5. Dettli, L., Ohnaus, E. E., Spring, P. Br. J. Pharmac. 1972, 44, 373P. 6. Sheiner, L. B., Rosenberg, B., Melmon, K. L. Comput. biomed. Res. 1972, 7.
5, 441. Bättig, P., Brune, K., Schmitt, H., Walz,
D. Europ. J. clin. Pharmac. 1974, 7, 233. 8. Jelliffe, R. W., Brooker, G. Am. J. Med. 1974, 57, 63. 9. Tozer, T. N.J. Pharmacokinet. Biopharm. 1974, 2, 13. 10. Dobbs, S. M., Mawer, G. E., Rodgers, E. M., Woodcock, B. G., Lucas, S. B. Br. J. clin. Pharmac. 1976, 3, 231. 11. Sumner, D. J., Russell, A. J., Whiting, B. ibid. p. 221. 12. Nicholson, P. W., Dobbs, S. M., McGill, A. P. J., Rodgers, E. M. Br. Heart J. 1978, 40, 177. 13. Aronson, J. K. Br. J. clin. Pharmac. 1978, 5, 55.
data from both. The centres were in England, Wales, and Scotland; eight were teaching hospitals and the ninth was a district hospital closely associated with a teaching unit. Whilst the amniocentesis subjects were often referred to these centres, the controls were selected largely from women who had booked at these hospitals. The patients in such a group often vary considerably from background populations and so the controls might include many with not easily measurable but positively beneficial factors. To some extent this is seen in the examination of data relating to amniocentesis subjects who were left out of the analysis (some 19%) because no control mothers could be found to match them. When the control groups and the subjects are examined for basic demographic characteristics, the controls had more patients in the 25-34-year age-range and fewer at the extremes, parity differed (19% of the subjects were primiparous compared with 25% of the controls), and the social-class distribution shows a difference in favour of the subjects (37.8% in classes I and II compared with 31.9% of controls). There are several other areas where differences are hard to explain if the matching process was a valid one; for example, hypertension and pre-eclampsia occurred in a larger proportion of controls than of subjects (16 - 6% compared with 14-1%), despite the age-distribution bias-but perhaps this may reflect the greater number of primiparous patients in the control group. Elective caesarean section was more commonly done in the subject group while occipitoposterior, face, and brow presentations were more frequent in the controls. All these disparities are freely discussed in the report, but they may still give the impression that like was not being compared with like. Planners and practitioners want to know whether amniocentesis should be made more widely available, to reduce the numbers of children born with a congenital abnormality. The Clinical Genetics Society recommends a regional service capable of monitoring one pregnancy in every twelve (see p. 1321). The two principal indications for amniocentesis at present are advanced maternal age, with its increased risk of chromosome changes, and a raised serum alpha-fetoprotein (A.F.P.), which may indicate a neural-tube defect. Early this year the Department of Health and Social Security expressed itself in favour, in principle, of a national serum-A.F.P. scheme for detection of neural-tube defect, but this pronouncement met with strong criticism, notably from the Royal College of Obstetricians and Gynaecologists. As well as the ethical problems of over-kill of healthy fetuses-problems which have not been faced by society or the medical profession-there is the scarcity of people skilled at amniocentesis and at handling the ultrasound equipment which is mandatory in this proare
THE LANCET
The Risk of Amniocentesis THE long-awaited report of the Medical Research Council Working Party on Amniocentesis is published,l and the extra data may help both society and the medical profession make up their minds about the place of amniocentesis in prenatal
In essence, the working-party compared the cases of 2428 women who had an amniocentesis in the first half of pregnancy with those of the same number of matched controls. In a selected group of those who had amniocentesis; the rate of fetal loss was 2-6% compared with 1-1% in controls, and there seemed to be an increase of the same order in certain abnormalities of live-born infants, such as respiratory difficulties at birth and major orthopxdic postural deformities. As well as the immediate risks, the subjects of the trial showed an increased incidence of other complications later in pregnancy which may have been due to the amniocentesisabruptio placentx, premature rupture of the membranes, and postpartum haemorrhage. The circumstances in which amniocentesis had a good chance
diagnosis.
of detecting a fetal abnormality were a previous child with a single autosomal gene defect (25%), a raised maternal serum alpha-fetoprotein (20%), a previous child with a neural-tube defect (3% after 1, and 14% after 2 or more), and maternal age of over 40 years (Down’s syndrome in 5% of the mothers aged 40-41, 8% in those aged 42-43, and 11 % in those aged 44-47). Was the inquiry a valid one and can the results stand up to rigorous assessment? And does it help us to decide about the future practice of amniocentesis in prenatal diagnosis? The study is a multicentre one and, halfway through, the criteria for entry of controls had to be widened because of difficulty and long delays in obtaining such women and possible bias introduced in selection of some earlier controls. In consequence the survey is divided into a main study (1402 control women) and a supplementary inquiry with 1206 controls, some conclusions relate to one study whilst others 1. An Assessment of the Hazards of Amniocentesis: Report of the M.R.C. Working Party on Amniocentesis. British Journal of Obstetrics and Gynœcology, 1978, 85, suppl. 2. £2.
.
based
on
1288
cedure. On p. 1293 Dr JOCELYN CHAMBERLAIN offers a thoughtful assessment of the human benefits and costs. She calculates that the human cost of preventing some 555 spina-bifida births a year in England and Wales (most of whom would die in early life) would be 120 dead or damaged normal infants. KENNEDy2 judged that the cost-benefit ratio in human terms would be even less advantageous, in that 95 healthy fetuses and 110 handicapped but not hopeless children would be aborted to prevent 329 seriously affected babies with spina bifida, many of whom again would not survive. In another article this week (p. 1296), Mr BENNETT and his colleagues cite data suggesting a 6% to 8% fetal-loss rate after amniocentesis when the indication is a raised serum-A.F.p. This figure includes a larger group of accidental abortions which follow amniocentesis, and a smaller group of normal babies aborted because of a false-positive amnioticfluid test. The first group may become smaller as practitioners become more experienced, though the M.R.C. trial was at nine centres with skilled operators. A wider use of amniocentesis would raise the fetal-loss rate, at least in the earlier days. The worrying false-positive rates may be reduced a little but, as Mr BENNETT and his co-workers point out, so long as there is some overlap in the distribution of the normal and abnormal population, wherever the cut-off point of normality is placed there is bound to be a small misallocation. No medical diagnostic test has a zero false-positive rate. In the M.R.C. trial the false-negative rate of tests of the amniotic fluid was 0.4% and the false positive-rate was
0 - 2%.
How may the M.R.C. trial help to resolve these problems? If its validity is accepted, it has confirmed an immediate fetal loss of up to 1.5% in the hands of skilful, well-equipped specialists and it suggests that these risks are independent of the indications for the procedure-a point of recent debate.34 Further, amniocentesis seems to increase
the likelihood of
respiratory-distress syndrome, abruptio placentx, and major orthopaedic problems. The dilemma lies in deciding what value should be placed on the gains of terminating affected fetuses and the losses of killing normal fetuses. These cannot simply be weighed against
each other in numerical terms. The value of ter. minating affected fetuses must depend on the likely degree of handicap and its effect on parents; their families, and society; some fetuses will be so severely affected that they will be stillborn or die soon after birth, in which case amniocentesis and termination cannot be said to have averted handicap. At the other end of the scale, some will be only mildly affected and have a prospect of almost norKennedy, I. The Defect. BBC Radio 3, Oct. 25, 1978. 3. Bennett, M. Lancet, 1978, ii, 987. 4. Wald, N., Barker, S., Cuckle, H., Brock, D., Stirrat, G. ibid, p. 2.
1093.
mal lives. Between these two extremes lies a full range of physical and mental disabilities. As far as damage to normal pregnancies is concerned, the M.R.C. study provides reasonably firm evidence that this results directly from amniocentesis; but what negative value is to be placed on these unwanted effects? Can most of these fetal losses be accepted because the fetuses are easily replaceable,
and can the damage to normal infants be tolerated if its severity is less than that of the condition prevented by the amniocentesis? There is at present a considerable demand for amniocentesis, but is this an informed demand? It is possible that, faced with the human-cost/ human-benefit figures revealed by the M.R.C. report, prospective parents would be less enthusiastic. What they would actually decide can be determined only by in-service evaluation.
Digoxin—More Problems than Solutions been used in clinical practice for two hundred years. Currently, in the United Kingdom about 300 000 people are on digitalis or one of its successors, despite the fact that these drugs have a narrow therapeutic ratio (small margin between toxic and therapeutic dose) and lifethreatening toxic effects; in hospital patients treated with cardiac glycosides the reported incidence of toxicity is from 4% to as high as 35%.2 Almost ten years ago, a reliable method for quantitative assay of non-radioactive digoxin in body fluids3 offered fresh hope that digoxin could be prescribed more scientifically and that its use in clinical medicine would become more rational. How far has this hope been fulfilled? Experimental work on the clinical pharmacokinetics of digoxin4has given rise to various equations, nomograms, and scoring systems to help the physician decide on the most suitable dosage regimen for the individual patient. 5-12 As a means DIGITALIS has
now
given steady-state plasma digoxin-conof these has proved very satisfactory: 13 for example, a computer program for digoxin dosage, designed to achieve a serum concentration of 1 ng/ml, could assure only that the of achieving
centrations,
none
1. Lancet, 1976, ii, 405. 2. Smith, T. W. Am. J. Med. 1975, 58, 470. 3. Smith, T. W., Butler, V. P., Haber, E. New Engl. J. Med. 1969, 281, 1212. 4. Iisalo, E. Clin. Pharmacokin. 1977, 2, 1. 5. Dettli, L., Ohnaus, E. E., Spring, P. Br. J. Pharmac. 1972, 44, 373P. 6. Sheiner, L. B., Rosenberg, B., Melmon, K. L. Comput. biomed. Res. 1972, 7.
5, 441. Bättig, P., Brune, K., Schmitt, H., Walz,
D. Europ. J. clin. Pharmac. 1974, 7, 233. 8. Jelliffe, R. W., Brooker, G. Am. J. Med. 1974, 57, 63. 9. Tozer, T. N.J. Pharmacokinet. Biopharm. 1974, 2, 13. 10. Dobbs, S. M., Mawer, G. E., Rodgers, E. M., Woodcock, B. G., Lucas, S. B. Br. J. clin. Pharmac. 1976, 3, 231. 11. Sumner, D. J., Russell, A. J., Whiting, B. ibid. p. 221. 12. Nicholson, P. W., Dobbs, S. M., McGill, A. P. J., Rodgers, E. M. Br. Heart J. 1978, 40, 177. 13. Aronson, J. K. Br. J. clin. Pharmac. 1978, 5, 55.