1336 hearted support for the proposition that you mention. This circular introduces a discussion paper which " sets out some of the options that appear to be open but it does not in any sense represent the department’s final views on the solution of the problems ". Department of Clinical Physics and Bio-Engineering, West of Scotland Health Boards, 11 West Graham Street, Glasgow G4 9LF.
A. H. ETCHELLS.
ULTRASOUND IN DIAGNOSIS OF SPINA BIFIDA
SIR,-Dr Campbell and his colleagues (May 10,
p.
1065)
report three cases in which ultrasonic examination was used in the antenatal diagnosis of neural-tube defect. Ultrasound was successful in one case, partially successful in the second, and unsuccessful in the third. On the basis of these three cases, the authors " conclude that ultrasonic examination has an important part to play in the prenatal assessment of cases at risk of having a spina-bifida baby". Did The Lancet print this conclusion as an example of "scientific " medicine ? Heatherwyck, High Hurst Close, Newick, Sussex.
F. GRAY.
SIR,-We read with great interest the description by Campbell and his colleagues (May 10, p. 1065) of three therapeutic abortions induced because of spina bifida suspected on the grounds of cc-fetoprotein (A.F.P.) estimation. One of the three fetuses was apparently normal, and merits further discussion. The first amniotic-fluid sample was described as heavily blood-stained; it is not improbable that this included some fetal blood, which would readily explain the high levels of A.F.P. The half-life of A.F.P. in the amniotic fluid is not known, but it is unlikely to be less than its half-life of one to six days in the adult circulation.1 The second amniotic-fluid specimen one week later contained a decreased but nevertheless high amount of A.F.P., and this could be compatible with a natural decline of Dr
A.F.P. The raised level of A.F.P. in maternal blood may also have been an artefact, since the level can sometimes rise significantly after amniocentesis, probably due to damage to the fetal vessels in the placenta during the procedure. In order to avoid this problem it is routine practice in our laboratory to characterise the haemoglobin as fetal or adult in any blood-stained specimen of liquor amnii. If a proportion of the blood is of fetal origin the levels of A.F.P. in amniotic fluid, and in any maternal sample collected subsequently, are considered to be unreliable. M. J. KITAU Department of Reproductive Physiology, P. LEIGHTON St. Bartholomew’s Hospital, Y. B. GORDON 51-53 Bartholomew Close, T. CHARD. London EC1.
colleagues report the case of at-risk patient who was found to have a raised amnioticfluid A.F.P. concentration at 17 weeks and again, though considerably lower, at 19 weeks. The pregnancy was subsequently terminated and the fetus found to be normal. In their discussion the authors point out that the amniotic fluid was heavily bloodstained, but conclude that this complication would be unlikely to cause a rise of the magnitude observed. We suggest that this conclusion is unjustified and agree with Harris et al. who claim that meaningful assay of SIR,-Dr Campbell and his
an
1. 2. 3.
T. Am. J. Obstet. Gynec. 1973,
Ishiguro, T., Nishimura, 116, Chard, T., Kitau, M. J., Ledward, R., Coltart, T., Seller, M. Br. J. Obstet. Gynœc. (in the press). Harris, R., Jennison, R. F., Barson, A. J., Laurence, J. M., Ruoslahti, E., Sepälä, M. Lancet, 1974, i, 429. 27.
bloodstained amniotic fluid may be impossible. We say this on theoretical grounds and in the light of our own experience. The fetal serum-A.F.P. level at 17-18 weeks is of the order of 2000-3000 !g. per m1.,4 therefore 3-4% contamination of liquor with fetal blood would be expected to result in A.F.P. concentrations of the order of 100 ,g. per ml. We therefore treat bloodstained liquor samples with great care, and a recent experience illustrates the point. A patient in her fourth pregnancy, with a history of having had an affected child, underwent amniocentesis at 16 weeks. A very bloodstained liquor sample was obtained in which the A.F.P. concentration * was found to be 66 ;j.g. per ml., which is well above .our 95th percentile for 16 weeks (43 ;j.g. per ml.). The red cells in the sample were examined for fetal cells by the Kleihauer acid-elution technique and it was found that 80% of the cells were of fetal origin. A repeat amniocentesis was recommended. This was done at 19 weeks and a sample containing only a few red cells, none of which could be shown to be fetal, was obtained. The A.F.P. concentration in this sample was 17-0 J.Lg. per ml., which is well below our 90th percentile for 19 weeks (26-6 g. per ml.). On the basis of the normal second result and the contamination of the first sample it was suggested that no action be taken. As the patient has not yet been delivered (estimated date Aug. 18), we cannot be certain that she does not have an affected fetus, but we think that it is most likely that the abnormal first result was due to contamination with fetal blood. In contrast to this case we have also examined three other bloodstained liquors recently; in none of these were fetal cells detected and in each case the A.F.P. concentration was normal. We would therefore urge that bloodstained amniotic-fluid samples should be treated with great caution and that, as recommended by Allan et al.,s fetal cells are looked for in every case. Samples found to be contaminated with fetal blood should be discarded as unsuitable for analysis.
Department of Clinical Chemistry, Southmead Hospital, D. Westbury-on-Trym, Bristol BS10 5NB.
J. GOLDIE ANTOINETTE M. MONK.
**These letters have been shown to Dr Campbell and colleagues, whose reply follows.-ED. L.
his
must thank Dr Gray for allowing us to clarify of the arguments in our paper. Firstly, we must point out a small error in his letter; the ultrasonic examination was in fact unsuccessful in diagnosing the first case of spina bifida and successful in the second. An appraisal of this nature is probably a little simplistic and we believe that the statement should be rephrased: " in the first case ultrasonic examination was unsuccessful in detecting a small lesion mainly involving the sacrum which was probably operable while in the second ultrasound was successful in diagnosing a large dorsal lumbar lesion which was clearly inoperable ". This fact taken together with case 3 raised the question " in a case where amniotic-fluid A.F.P. is raised and ultrasound does not detect a lesion, is there a lesion present and, if so, is it operable ?" I agree that this question cannot be answered on the results of three cases and is unlikely to be adequately answered by any single group of workers. The reason for publishing these cases was to encourage others in the field of ultrasonic diagnosis to join with us in defining the place of ultrasound in the early detection of spina bifida. We do not retract the statement that ultrasonic examination has an important part to play in the prenatal assessment of cases at risk of spina bifida. In addition to a potential role in the direct diagnosis of this condition, its value also lies in:
SIR,-We
some
(i) Accurate assessment of fetal menstrual age to determine the *
measured by
radioimmunassay using purified A.F.P. from standard, Dakopatts antibody, bank serum as diluent, and employing a second antibody separation. 4. Gitlin, D., Boesman, M. J. clin. Invest. 1966, 45, 1826. 5. Allan, L. D., Ferguson-Smith, M. A., Donald, I., Sweet, E. M., Gibson, A. A. M. Lancet, 1973, ii, 522. A.F.P.
Dr E. Ruoslahti for tracer and
1337 correct timing of of A.F.P. values.
amniocentesis and prevent misinterpretation
(ii) Confirmation of fetal life (amniocentesis is contraindicated when there is fetal death because of the increased risk of infection) and the detection of other abnormalities such as hydatidiform mole in which amniocentesis is ill advised. (iii) Early diagnosis of multiple pregnancy; ultrasound will usually permit amniocentesis to be performed on each sac. This is of importance as witnessed by a patient of ours at present under study who has raised A.F.P. values in one sac and normal values in the other. (iv) The safe performance of amniocentesis which when carried out immediately following ultrasonic examination or through a biopsy transducer will reduce the hazard of direct injury to the fetus, reduce the incidence of fetomaternal transfusion and almost eliminate the occurrence of significant fetal blood contamination of the amniotic fluid. We agree with Mrs Kitau and her colleagues and with Dr Goldie and Dr Monk that fetal blood contamination can result in a significant rise in amniotic-fluid A.F.P. levels, and that a loss of approximately 10 ml. of fetal blood into the amniotic fluid would have produced a level of 110 t-tg. per ml. at 17 1/2 weeks menstrual age. It is unlikely that this was the reason for the raised A.F.P. levels in case 3 for two reasons. Firstly, the amniotic fluid was submitted to microscopy before analysis and only anuclear red cells were seen which we believed excluded a fetal loss as large as 10 ml. Secondly, an acute loss of 10 ml. at 17 weeks represents between 35% and 50% of the fetal blood volume, which is unlikely to be compatible with fetal survival. Furthermore, it should be pointed out that a sharp fall in amniotic-fluid A.F.P. levels can often occur in the presence of severe neural-tube abnormality, as exemplified by case 2. We would agree with Dr Goldie and Dr Monk that the Kleihauer acid-elution test should be performed on all samples of bloodstained amniotic fluid and that the results should be considered unreliable if a significant number of fetal cells is found to be present. The importance of having an alternative method of making the diagnosis of spina bifida in these cases is self evident.
confirmed by other workers, but we believe that there is no strong, consistent, and confirmed evidence that any other form of risk-factor intervention will influence the prognosis of patients who survive a coronary attack. Indeed, apart from the routine treatment of complications such as cardiac failure or arrhythmias, there is no evidence that exercise programmes, or measures such as drugs or surgical treatment, will improve prognosis. If we are to deal rationally with such patients we should have a clear picture of the scientific basis of our treatment measures. We would support Dr Opie’s plea for physical fitness and a full secondary prevention approach because they are plausible, if not proven, methods of reducing morbidity and mortality from coronary disease and stroke. Secondary prevention measures may also reduce morbidity and mortality from other non-coronary causes, and such measures are psychologically beneficial because they will appeal to the patient’s sense of logic and they will encourage him to return to a normal and active life. St. Vincent’s Hospital, Elm Park, Dublin 4, and
University College, Dublin.
RISTEARD MULCAHY NOEL HICKEY.
ADRIAMYCIN AND LONGITUDINAL PIGMENTED BANDING OF FINGERNAILS SiR,—We wish to’ report that three patients receiving cytotoxic therapy at this hospital have developed longitudinal pigmented banding of their fingernails. All three patients are women with locally recurrent or metastatic breast cancer. Their ages are 34, 51, and 56 years. Although they have had a variety of treatments, the only drugs common to all three are adriamycin and cyclophosphamide. One patient had
STUART CAMPBELL
J. PRYSE-DAVIES Queen Charlotte’s Maternity Hospital, Goldhawk Road, London W6 0XG.
T. M. COLTART MARY SELLER J. D. SINGER.
RISK FACTORS AFTER CORONARY THROMBOSIS
SIR,-Dr Opie (May 17, p. 1142) is uncertain about the efficacy of risk-factor intervention in the management of patients with established coronary heart-disease. He states that the simplest and best-proven measure is to stop smoking, and he cites one paper1 which supports the value of stopping smoking after a heart-attack. Lest his letter should leave doubts about the significance of cigarette smoking in
patients
with established coronary heart-disease, it should be stated that there are at least two other papers which show a significant reduction in mortality amongst patients who stop smoking after a coronary attacks In fact both the Gothenberg and Dublin experiences 2,3 show that mortality in those who stop smoking is about half that of those who fail to reduce smoking. To the best of our knowledge there is no report of a similar study which denies these results. It remains to be seen whether these reports will be 1. Wilhelmsson, C., Vedin, J. A., sen, L. Lancet, 1975, i, 415.
Elmfeldt, D., Tibblin, G., Wilhem-
Matzdorff, E., Lippert, A., Schmidt, A., Schmidt, K. Dt. med. Wschr. 1973, 98, 2183. 3. Mulcahy, R., Hickey, N., Graham, I., McKenzie, G. Br. Heart J. 1975, 37, 158.
2.
Pigmented right thumbnail and normal left thumbnail of patient on adriamycin therapy been treated with cyclophosphamide at an earlier stage in her disease and had noted no abnormality of the nails at that time. It is therefore presumed that adriamycin is the cause. Banding was noted 3, 4, and 6 months after starting adriamycin, and it extended from the matrix to the tip, the pigment being grey, brown, and black, respectively. Bands appeared on one or two nails only. The pigment seems to be in the nail plate and is presumably melanin. The anatomical distribution suggests that the band is due to the activity of a single melanocyte in the matrix.
Pigmented bands have been reported with a number of drugs1 but not previously with a cytotoxic agent. There was no history of trauma. Pigmented banding has been noted after adrenalectomy, but no patient in the series had this operation, although it is interesting to speculate on a possible selective hormone-suppressive action of adria1. 2.
Caron, G. A. Lancet, 1962, i, 508. Bondy, P. K., Harwick, H. J. New Engl. J. Med. 1969, 281, 1056.
A. H. ETCHELLS.
ULTRASOUND IN DIAGNOSIS OF SPINA BIFIDA
SIR,-Dr Campbell and his colleagues (May 10,
p.
1065)
report three cases in which ultrasonic examination was used in the antenatal diagnosis of neural-tube defect. Ultrasound was successful in one case, partially successful in the second, and unsuccessful in the third. On the basis of these three cases, the authors " conclude that ultrasonic examination has an important part to play in the prenatal assessment of cases at risk of having a spina-bifida baby". Did The Lancet print this conclusion as an example of "scientific " medicine ? Heatherwyck, High Hurst Close, Newick, Sussex.
F. GRAY.
SIR,-We read with great interest the description by Campbell and his colleagues (May 10, p. 1065) of three therapeutic abortions induced because of spina bifida suspected on the grounds of cc-fetoprotein (A.F.P.) estimation. One of the three fetuses was apparently normal, and merits further discussion. The first amniotic-fluid sample was described as heavily blood-stained; it is not improbable that this included some fetal blood, which would readily explain the high levels of A.F.P. The half-life of A.F.P. in the amniotic fluid is not known, but it is unlikely to be less than its half-life of one to six days in the adult circulation.1 The second amniotic-fluid specimen one week later contained a decreased but nevertheless high amount of A.F.P., and this could be compatible with a natural decline of Dr
A.F.P. The raised level of A.F.P. in maternal blood may also have been an artefact, since the level can sometimes rise significantly after amniocentesis, probably due to damage to the fetal vessels in the placenta during the procedure. In order to avoid this problem it is routine practice in our laboratory to characterise the haemoglobin as fetal or adult in any blood-stained specimen of liquor amnii. If a proportion of the blood is of fetal origin the levels of A.F.P. in amniotic fluid, and in any maternal sample collected subsequently, are considered to be unreliable. M. J. KITAU Department of Reproductive Physiology, P. LEIGHTON St. Bartholomew’s Hospital, Y. B. GORDON 51-53 Bartholomew Close, T. CHARD. London EC1.
colleagues report the case of at-risk patient who was found to have a raised amnioticfluid A.F.P. concentration at 17 weeks and again, though considerably lower, at 19 weeks. The pregnancy was subsequently terminated and the fetus found to be normal. In their discussion the authors point out that the amniotic fluid was heavily bloodstained, but conclude that this complication would be unlikely to cause a rise of the magnitude observed. We suggest that this conclusion is unjustified and agree with Harris et al. who claim that meaningful assay of SIR,-Dr Campbell and his
an
1. 2. 3.
T. Am. J. Obstet. Gynec. 1973,
Ishiguro, T., Nishimura, 116, Chard, T., Kitau, M. J., Ledward, R., Coltart, T., Seller, M. Br. J. Obstet. Gynœc. (in the press). Harris, R., Jennison, R. F., Barson, A. J., Laurence, J. M., Ruoslahti, E., Sepälä, M. Lancet, 1974, i, 429. 27.
bloodstained amniotic fluid may be impossible. We say this on theoretical grounds and in the light of our own experience. The fetal serum-A.F.P. level at 17-18 weeks is of the order of 2000-3000 !g. per m1.,4 therefore 3-4% contamination of liquor with fetal blood would be expected to result in A.F.P. concentrations of the order of 100 ,g. per ml. We therefore treat bloodstained liquor samples with great care, and a recent experience illustrates the point. A patient in her fourth pregnancy, with a history of having had an affected child, underwent amniocentesis at 16 weeks. A very bloodstained liquor sample was obtained in which the A.F.P. concentration * was found to be 66 ;j.g. per ml., which is well above .our 95th percentile for 16 weeks (43 ;j.g. per ml.). The red cells in the sample were examined for fetal cells by the Kleihauer acid-elution technique and it was found that 80% of the cells were of fetal origin. A repeat amniocentesis was recommended. This was done at 19 weeks and a sample containing only a few red cells, none of which could be shown to be fetal, was obtained. The A.F.P. concentration in this sample was 17-0 J.Lg. per ml., which is well below our 90th percentile for 19 weeks (26-6 g. per ml.). On the basis of the normal second result and the contamination of the first sample it was suggested that no action be taken. As the patient has not yet been delivered (estimated date Aug. 18), we cannot be certain that she does not have an affected fetus, but we think that it is most likely that the abnormal first result was due to contamination with fetal blood. In contrast to this case we have also examined three other bloodstained liquors recently; in none of these were fetal cells detected and in each case the A.F.P. concentration was normal. We would therefore urge that bloodstained amniotic-fluid samples should be treated with great caution and that, as recommended by Allan et al.,s fetal cells are looked for in every case. Samples found to be contaminated with fetal blood should be discarded as unsuitable for analysis.
Department of Clinical Chemistry, Southmead Hospital, D. Westbury-on-Trym, Bristol BS10 5NB.
J. GOLDIE ANTOINETTE M. MONK.
**These letters have been shown to Dr Campbell and colleagues, whose reply follows.-ED. L.
his
must thank Dr Gray for allowing us to clarify of the arguments in our paper. Firstly, we must point out a small error in his letter; the ultrasonic examination was in fact unsuccessful in diagnosing the first case of spina bifida and successful in the second. An appraisal of this nature is probably a little simplistic and we believe that the statement should be rephrased: " in the first case ultrasonic examination was unsuccessful in detecting a small lesion mainly involving the sacrum which was probably operable while in the second ultrasound was successful in diagnosing a large dorsal lumbar lesion which was clearly inoperable ". This fact taken together with case 3 raised the question " in a case where amniotic-fluid A.F.P. is raised and ultrasound does not detect a lesion, is there a lesion present and, if so, is it operable ?" I agree that this question cannot be answered on the results of three cases and is unlikely to be adequately answered by any single group of workers. The reason for publishing these cases was to encourage others in the field of ultrasonic diagnosis to join with us in defining the place of ultrasound in the early detection of spina bifida. We do not retract the statement that ultrasonic examination has an important part to play in the prenatal assessment of cases at risk of spina bifida. In addition to a potential role in the direct diagnosis of this condition, its value also lies in:
SIR,-We
some
(i) Accurate assessment of fetal menstrual age to determine the *
measured by
radioimmunassay using purified A.F.P. from standard, Dakopatts antibody, bank serum as diluent, and employing a second antibody separation. 4. Gitlin, D., Boesman, M. J. clin. Invest. 1966, 45, 1826. 5. Allan, L. D., Ferguson-Smith, M. A., Donald, I., Sweet, E. M., Gibson, A. A. M. Lancet, 1973, ii, 522. A.F.P.
Dr E. Ruoslahti for tracer and
1337 correct timing of of A.F.P. values.
amniocentesis and prevent misinterpretation
(ii) Confirmation of fetal life (amniocentesis is contraindicated when there is fetal death because of the increased risk of infection) and the detection of other abnormalities such as hydatidiform mole in which amniocentesis is ill advised. (iii) Early diagnosis of multiple pregnancy; ultrasound will usually permit amniocentesis to be performed on each sac. This is of importance as witnessed by a patient of ours at present under study who has raised A.F.P. values in one sac and normal values in the other. (iv) The safe performance of amniocentesis which when carried out immediately following ultrasonic examination or through a biopsy transducer will reduce the hazard of direct injury to the fetus, reduce the incidence of fetomaternal transfusion and almost eliminate the occurrence of significant fetal blood contamination of the amniotic fluid. We agree with Mrs Kitau and her colleagues and with Dr Goldie and Dr Monk that fetal blood contamination can result in a significant rise in amniotic-fluid A.F.P. levels, and that a loss of approximately 10 ml. of fetal blood into the amniotic fluid would have produced a level of 110 t-tg. per ml. at 17 1/2 weeks menstrual age. It is unlikely that this was the reason for the raised A.F.P. levels in case 3 for two reasons. Firstly, the amniotic fluid was submitted to microscopy before analysis and only anuclear red cells were seen which we believed excluded a fetal loss as large as 10 ml. Secondly, an acute loss of 10 ml. at 17 weeks represents between 35% and 50% of the fetal blood volume, which is unlikely to be compatible with fetal survival. Furthermore, it should be pointed out that a sharp fall in amniotic-fluid A.F.P. levels can often occur in the presence of severe neural-tube abnormality, as exemplified by case 2. We would agree with Dr Goldie and Dr Monk that the Kleihauer acid-elution test should be performed on all samples of bloodstained amniotic fluid and that the results should be considered unreliable if a significant number of fetal cells is found to be present. The importance of having an alternative method of making the diagnosis of spina bifida in these cases is self evident.
confirmed by other workers, but we believe that there is no strong, consistent, and confirmed evidence that any other form of risk-factor intervention will influence the prognosis of patients who survive a coronary attack. Indeed, apart from the routine treatment of complications such as cardiac failure or arrhythmias, there is no evidence that exercise programmes, or measures such as drugs or surgical treatment, will improve prognosis. If we are to deal rationally with such patients we should have a clear picture of the scientific basis of our treatment measures. We would support Dr Opie’s plea for physical fitness and a full secondary prevention approach because they are plausible, if not proven, methods of reducing morbidity and mortality from coronary disease and stroke. Secondary prevention measures may also reduce morbidity and mortality from other non-coronary causes, and such measures are psychologically beneficial because they will appeal to the patient’s sense of logic and they will encourage him to return to a normal and active life. St. Vincent’s Hospital, Elm Park, Dublin 4, and
University College, Dublin.
RISTEARD MULCAHY NOEL HICKEY.
ADRIAMYCIN AND LONGITUDINAL PIGMENTED BANDING OF FINGERNAILS SiR,—We wish to’ report that three patients receiving cytotoxic therapy at this hospital have developed longitudinal pigmented banding of their fingernails. All three patients are women with locally recurrent or metastatic breast cancer. Their ages are 34, 51, and 56 years. Although they have had a variety of treatments, the only drugs common to all three are adriamycin and cyclophosphamide. One patient had
STUART CAMPBELL
J. PRYSE-DAVIES Queen Charlotte’s Maternity Hospital, Goldhawk Road, London W6 0XG.
T. M. COLTART MARY SELLER J. D. SINGER.
RISK FACTORS AFTER CORONARY THROMBOSIS
SIR,-Dr Opie (May 17, p. 1142) is uncertain about the efficacy of risk-factor intervention in the management of patients with established coronary heart-disease. He states that the simplest and best-proven measure is to stop smoking, and he cites one paper1 which supports the value of stopping smoking after a heart-attack. Lest his letter should leave doubts about the significance of cigarette smoking in
patients
with established coronary heart-disease, it should be stated that there are at least two other papers which show a significant reduction in mortality amongst patients who stop smoking after a coronary attacks In fact both the Gothenberg and Dublin experiences 2,3 show that mortality in those who stop smoking is about half that of those who fail to reduce smoking. To the best of our knowledge there is no report of a similar study which denies these results. It remains to be seen whether these reports will be 1. Wilhelmsson, C., Vedin, J. A., sen, L. Lancet, 1975, i, 415.
Elmfeldt, D., Tibblin, G., Wilhem-
Matzdorff, E., Lippert, A., Schmidt, A., Schmidt, K. Dt. med. Wschr. 1973, 98, 2183. 3. Mulcahy, R., Hickey, N., Graham, I., McKenzie, G. Br. Heart J. 1975, 37, 158.
2.
Pigmented right thumbnail and normal left thumbnail of patient on adriamycin therapy been treated with cyclophosphamide at an earlier stage in her disease and had noted no abnormality of the nails at that time. It is therefore presumed that adriamycin is the cause. Banding was noted 3, 4, and 6 months after starting adriamycin, and it extended from the matrix to the tip, the pigment being grey, brown, and black, respectively. Bands appeared on one or two nails only. The pigment seems to be in the nail plate and is presumably melanin. The anatomical distribution suggests that the band is due to the activity of a single melanocyte in the matrix.
Pigmented bands have been reported with a number of drugs1 but not previously with a cytotoxic agent. There was no history of trauma. Pigmented banding has been noted after adrenalectomy, but no patient in the series had this operation, although it is interesting to speculate on a possible selective hormone-suppressive action of adria1. 2.
Caron, G. A. Lancet, 1962, i, 508. Bondy, P. K., Harwick, H. J. New Engl. J. Med. 1969, 281, 1056.
