- Email: [email protected]
BLOOD-PRESSURE
1403
releasing hormone revealed gonadotrophin deficiency which was complete in 2 and partial in the 1 patient who menstruated but did not ovulate. Conception has not occurred in 2 patients because of blocked fallopian tubes (demonstrated by salpingography and laparoscopy) and in 1 woman who is married to a man with oligospermia; conception has been avoided by 5 women, using mechanical methods of contraception (3 in group 1 and 2 in group 2). We do not yet know the cause of the failure of the remaining 2 patients to conceive, but the fertility of most of these patients is remarkable: most of them conceived within three cycles and the most recent pregnancy occurred in a woman of 42 who had presented with primary amenorrhcea and galactorrhoea. From these data it can be seen that if careful gynaecological and endocrine evaluation is used to select patients for appropriate therapy,’ an ovulation and conception rate considerably greater than that reported by Seppala et al. can be expected from treatment with bromocriptine of amenorrhoeic women with hvnernrolactinwmia.
Department of Obstetrics and Gynaecology, St Mary’s Hospital Medical School, London W2 1PG Middlesex Hospital,
H.
S. JACOBS
London W1
S. FRANKS
Department of Obstetrics and Gynæcology, St Mary’s Hospital Medical School,
M. G. R. HULL
Middlesex Hospiral, London W1
S. J. STEELE J. D. N. NABARRO
SERUM-COBALT
SiR,—We read with interest the letter by Dr Lins and Dr Pehrsson on cobalt intoxication in uraemic myocardiopathy (May 29, p. 1191). It illustrates how radically previously reported data differ concerning plasma (or serum) cobalt concentration in health and disease. In 1966 and 1968 Kesteloot et al.12 presented a new syndrome in chronic beer drinkers, called alcoholic perimyocardiopathy. The serum-cobalt concentration was reported as being 0.15 p.p.m. (parts per 10’)—130 p.p.b. (parts per 109) -in a patient as against 70 p.p.b. in controls who never drank beer containing cobalt. Comparison of the values in the controls of Dr Lins and Dr Pehrsson and other investigators demonstrates the confusion about "normal values" in trace-element analysis (see table). PUBLISHED SERUM-COBALT CONCENTRATIONS IN HEALTHY INDIVIDUALS
We determined the serum-cobalt concentration in 20 normal subjects by neutron-activation analysis as will be described in detail elsewhere. Our results (mean ±s.D. =0.105±0.058 p.p.b., range =0.0384-0-264) are similar to those reported by Dr Lins and Dr Pehrsson and Thiers et a1.3 It is worth empha-
sising that we found 0.228 p.p.b. in one apparently healthy individual and 0.264 p.p.b. in another. It is time to clarify the discrepancies in publications on trace elements, as has been realised for Únc8-1O and manganese. 11-14 Only then will it be possible to make substantial progress. Section of Gasteroenterology, Department of Internal Medicine, Academisch Ziekenhuis, and Laboratory for Analytical Chemistry, Institute for Nuclear Sciences, Rijksuniversiteit Gent, B-9000 Gent, Belgium
J. VERSIECK J. HOSTE F. BARBIER L. VANBALLENBERGHE
BLOOD-PRESSURE
SiR,—The other week I was most hospitably and kindly entertained by the M.R.C. Blood Pressure Unit in Glasgow. Dr Brown, Dr Lever, and Dr Robertson gave me a preview of their work awaiting publication, amongst which were the papers you published on June 5. They were unaware-and I am sure most of your readers will be unaware-that I published a rather similar hypothesis fifteen years gO.15 Since my evidence is different from theirs and my conclusion slightly different, it may help if I summarise them. Allbutt defined hyperpiesia (which we now call essential hypertension) as a condition in which the blood-pressure rises excessively in middle age. Our investigation showed that, in the population at large, arterial pressure tends to be continuously distributed at all ages, the frequency distribution curves being Gaussian when plotted on a logarithmic scale, and that arterial pressure tends to rise with age, but it rises more and faster in some subjects than others. Our family studies, supplemented by those of Miall and Oldham, showed that: (1) arterial pressure seems to be inherited; (2) the inheritance, like that of stature, is quantitative; (3) the coefficient of resemblance in first-degree relatives is of the order of 0.3; and (4) the resemblance is of the same order in those with low, normal or raised pressures (the resemblance breaks down in those with the highest pressures). We also found that the rate of rise of pressure with age is the same in families of subjects with hypertension and those with normal pressures. Thus what is inherited seems to be a tendency for a given pressure at a given age; the rate of rise of pressure with age seems to be acquired or, in other words, due to the impact of environmental influences. How is this brought about? I had in the course of my clinical and experimental work become aware of a series of instances in which the removal or repair of the lesion causing the high pressure did not restore arterial pressure to its original value or to the value expected for that age and sex in the general population. Three of these examples were in man. In my department we found that in three patients removal of a phseochromocytoma either left the pressure unaltered or very high, though no excess catecholamine excretion could thereafter be demonstrated. Removal of a unilaterally diseased kidney strikingly reduced arterial pressure in only half the patients and even in those the pressure tended to remain relatively high. Counihan showed that repair of an aortic coarctation reduced arterial pressure but the postoperative values were higher than would be expected for that age and sex in the general population. Why does the arterial pressure tend to remain high in some subjects? An observation of mine in the rabbit suggested that the new factor was time. When in a rabbit, one kidney was
1.
Kesteloot, H., Terryn, R., Bosmans, P., Joossens, J. V. Acta cardiol. 1966, 21, 341. 2. Kesteloot, H., Roelandt, J., Willems, J., Claes, J. H., Joossens, J. V. Circulation, 1968, 37, 854. 3. Thiers, R. E., Williams, J. F., Yoe, J. H. Analyt. Chem. 1955, 27, 1725. 4. Parr, R. M., Taylor, D. M. Biochem. J. 1964, 91, 424. 5. Giovanetti, S., Maggiore, Q., Malvano, R. in Nuclear Activation Techniques in the Life Sciences; p. 511. International Atomic Energy Agency, Vienna, 1976. 6. Kasperek, K., Schicha, H., Siller, V., Feinendegen, L. E. Strahlentherapie, 1972, 143, 468. 7. Koch, H. J., Smith, E. R., Shimp, N. F., Connor, J. Cancer, 1956, 9, 499.
8. 9.
Davies, I. J. T., Musa, M., Dormandy, P. L. J. clin Path. 1968, 21, 359. Vallee, B. L., Wacker, W. E. C., Bartholomay, A. F., Robin, E. D. New
Engl. J. Med. 1956, 255, 403. Versieck, J., Barbier, F., Speecke, A., Hoste, J. Lancet, 1974, i, 682. Cotzias, G. C., Miller, S. T., Edwards, J. J. Lab. clin. Med. 1966, 67, 836. Heydorn, K., Nørgård, K. Talanta, 1973, 20, 835. Versieck, J., Barbier, F., Speecke, A., Hoste, J. Acta endocr. Copenh. 1974, 76, 783. 14. Versieck, J., Barbier, F., Speecke, A., Hoste, J. Clin. Chem. 1975, 21, 578. 15. Pickering, G. The Nature of Essential Hypertension. London, 1961. 10. 11. 12. 13.
1404 removed and the other renal artery constricted, then excising the ischwmic kidney after two weeks reduced arterial pressure to normal in about four hours, but after two months left the arterial pressure unaltered. I also found evidence (inconclusive it is true) that in its early stages hypertension produced by renal-artery constriction was compatible with release of renin from the kidney; in the later stages it was not. I therefore concluded that, if the hypertension lasts long enough, a secondary change may occur which is itself sufficient to sustain arterial pressure. I thought that the most probable candidate for the secondary change was hypertrophy of arteries and arterioles for which Folkow and his colleagues have produced increasingly convincing evidence. The most recent form of this hypothesis was published in 1974.16 On p. 13 of that book I wrote:
measurements are
made
on
individual patients between and
during hypertensive episodes. Our own data confirm that a proportion of patients with essential hypertension do indeed have raised plasma-noradrenaline concentrations in the recumbent position. However, the increase in plasma-noradrenaline is enhanced in hypertensive patients compared with a normotensive group when levels are estimated during orthostasis at a time when the sympathetic nervous system is "turned on". Medical Unit, St Mary’s Hospital, London W2 1NY
PETER S. SEVER
"
"We are beginning to learn that certain situations in life elevate the arteriole pressure. It is quite likely that during the next 10 or 15 years these situations will be better understood and better defined than they are today. It is likely that at least some of them will be definable in terms of the behaviour of the mind. The more frequent these situations and the longer they last, the higher will be the arterial pressure and the greater the degree of medial hypertrophy. It seems not unlikely that temperament, possibly inherited, will play a part in the size and duration of these responses and thus that inheritance may also contribute to the rate of rise of pressure with age. "The hypothesis just outlined derives support from the fact, now abundantly illustrated from many clinics, that reducing the arterial pressure from very high levels may, after several years of treatment, produce a patient whose arterial pressure controls itself at lower levels." "
that my evidence supplements that of the workers. Whether the secondary fault lies in the arteries and arterioles in general, or specificatly in the kidney is a question that remains up to now unresolved. The full references will be found in the two works I have cited. It
seems to me
Glasgow
5 Horwood
Close,
Headington, Oxford OX3 7RF
GEORGE PICKERING
SIR,-Dr Brown and his colleagues (June 5, p. 1217) state that "the search for a single cause of benign essential hypertension has been fruitless". They state that "plasma renin, renin activity, and angiotensin n are usually normal and that exchangeable sodium, plasma volume, and extracellular volume are unremarkable". They do, however, admit that plasmacathecholamines are slightly raised, but dismiss this evidence for a dominant role of the sympathetic nervous system in the pathogenesis of essential hypertension by comparing plasmanoradrenaline levels in essential hypertension with those found in phseochromocytoma with comparable hypertension. This reasoning is untenable because when raised plasma levels of noradrenaline occur in essential hypertension, they may not reflect accurately "overactivity" of the sympathetic nervous system, since most of the noradrenaline released by postganglionic nerve endings, sited anatomically on the outside of blood-vessels, is subjected to a complex process of re-uptake and metabolism. Overflow of unmetabolised amine from the synaptic cleft may well pass into the extracellular spaces, be removed by the lymphatics, or diffuse into the circulation. Thus the quantum of noradrenaline released, causing constriction of resistance vessels and raising arterial pressure, is poorly reflected by changes in plasma levels. This situation differs greatly from the hypertensive events associated with phxochromocytoma where catecholamines are liberated directly into the circulation. Further comparisons with phaeochromocytoma must be made with caution since even in this condition there is a poor correlation between actual concentration of plasma-catecholamines and the level of arterial pressure when repeated 16.Pickering, G. Hypertension: Causes, Consequences burgh, 1974.
and
Management.
Edin-
ALPHAFETOPROTEIN ASSAY IN ALL AMNIOCENTESIS SAMPLES
SIR,-Several workersl-3 have argued that alphafetoprotein (A.F.P.) concentrations should be assayed in every amnioticfluid sample taken, whatever the indication for amniocentesis. This depends on the specificity of the A.F.P. test-its ability to detect serious fetal abnormalities without false positives. Ultrasonography may be used to confirm a diagnosis of anencephaly, but in general cannot be used for spina bifida, where most terminations of pregnancy are entirely dependent on the A.F.P. values. Even if the specificity of the test was as high as 99% there could be a substantial number of normal pregnancies terminated. Milunsky and Alpert3 have briefly reported on 3536 amniocentesis samples in which A.F.P. was determined. Their falsepositive rate is judged to be 1%. In the face of this alarming figure it is difficult to see how A.F.P. assay can be justified except for high-risk pregnancies selected because of a previous child with a neural-tube defect or a high serum-A.F.P. value. In an unselected population more normal pregnancies than affected pregnancies would be terminated. However, a 1% false-positive rate is probably an overestimate. The European Medical Research Councils in a survey of 3565 cases reported 3 false positives (0.1 %). In our own experience of 997 cases, raised A.F.P. values (greater than 3 standard deviations above the mean) were obtained in 45 cases. 12 of these were due to fetal blood contamination. Termination of pregnancy was recommended in the remaining 33, and the outcome was 16 cases of anencephaly, 15 of spina bifida, 1 of intrauterine death, and 1 of exomphalos. Though this series is considerably smaller than that of Milunsky and Alpert the false-positive rate is to date zero. The most important aspect of maintaining the specificity of amniotic-fluid A.F.P. assay is in eliminating distortions produced by contamination of the fluid with fetal blood,5 If the normal range has been constructed by using amniotic fluids which have been spun down and frozen, there is no way of knowing how many of these may have been contaminated by fetal serum, so that an unusually wide distribution of normal values is obtained. Fresh samples in which there is substantial presence of fetal red blood-cells must be regarded as unusable and a second amniocentesis requested. When fetal blood is present it is usually because mixing has taken place in the syringe being used for amniocentesis rather than in the main body of the amniocentesis being affected by a small fetal bleed which occurred at the time of the first amniocentesis. If the above precautions are observed we maintain that the false-positive rate in amniotic-fluid A.F.P. assay should be less than 0.1%. University Department of Human Western General Hospital, Edinburgh EH42XU
Genetics,
Department of Obstetrics and Gynaecology, Western General Hospital, Edinburgh 1. Wright, E. 2. Ainbender,
D.
J. H. BROCK
J.
B. SCRIMGEOUR
V., McIntosh, A. S., Foulds, J. W. Lancet, 1975, u, 769. E., Hirschhorn, K. ibid. 1976, i, 595. 3. Milunsky, A., Alpert, E. ibid. 1976, i, 1015. 4. Lindsten, J., Zetterstrom, R., Ferguson-Smith, M. in Prenatal Diagnosis of Genetic Disorders of the Fœtus, INSERM, Pans, 1976. 5. Brock, D. J. H. Lancet, 1975, ii, 495.
releasing hormone revealed gonadotrophin deficiency which was complete in 2 and partial in the 1 patient who menstruated but did not ovulate. Conception has not occurred in 2 patients because of blocked fallopian tubes (demonstrated by salpingography and laparoscopy) and in 1 woman who is married to a man with oligospermia; conception has been avoided by 5 women, using mechanical methods of contraception (3 in group 1 and 2 in group 2). We do not yet know the cause of the failure of the remaining 2 patients to conceive, but the fertility of most of these patients is remarkable: most of them conceived within three cycles and the most recent pregnancy occurred in a woman of 42 who had presented with primary amenorrhcea and galactorrhoea. From these data it can be seen that if careful gynaecological and endocrine evaluation is used to select patients for appropriate therapy,’ an ovulation and conception rate considerably greater than that reported by Seppala et al. can be expected from treatment with bromocriptine of amenorrhoeic women with hvnernrolactinwmia.
Department of Obstetrics and Gynaecology, St Mary’s Hospital Medical School, London W2 1PG Middlesex Hospital,
H.
S. JACOBS
London W1
S. FRANKS
Department of Obstetrics and Gynæcology, St Mary’s Hospital Medical School,
M. G. R. HULL
Middlesex Hospiral, London W1
S. J. STEELE J. D. N. NABARRO
SERUM-COBALT
SiR,—We read with interest the letter by Dr Lins and Dr Pehrsson on cobalt intoxication in uraemic myocardiopathy (May 29, p. 1191). It illustrates how radically previously reported data differ concerning plasma (or serum) cobalt concentration in health and disease. In 1966 and 1968 Kesteloot et al.12 presented a new syndrome in chronic beer drinkers, called alcoholic perimyocardiopathy. The serum-cobalt concentration was reported as being 0.15 p.p.m. (parts per 10’)—130 p.p.b. (parts per 109) -in a patient as against 70 p.p.b. in controls who never drank beer containing cobalt. Comparison of the values in the controls of Dr Lins and Dr Pehrsson and other investigators demonstrates the confusion about "normal values" in trace-element analysis (see table). PUBLISHED SERUM-COBALT CONCENTRATIONS IN HEALTHY INDIVIDUALS
We determined the serum-cobalt concentration in 20 normal subjects by neutron-activation analysis as will be described in detail elsewhere. Our results (mean ±s.D. =0.105±0.058 p.p.b., range =0.0384-0-264) are similar to those reported by Dr Lins and Dr Pehrsson and Thiers et a1.3 It is worth empha-
sising that we found 0.228 p.p.b. in one apparently healthy individual and 0.264 p.p.b. in another. It is time to clarify the discrepancies in publications on trace elements, as has been realised for Únc8-1O and manganese. 11-14 Only then will it be possible to make substantial progress. Section of Gasteroenterology, Department of Internal Medicine, Academisch Ziekenhuis, and Laboratory for Analytical Chemistry, Institute for Nuclear Sciences, Rijksuniversiteit Gent, B-9000 Gent, Belgium
J. VERSIECK J. HOSTE F. BARBIER L. VANBALLENBERGHE
BLOOD-PRESSURE
SiR,—The other week I was most hospitably and kindly entertained by the M.R.C. Blood Pressure Unit in Glasgow. Dr Brown, Dr Lever, and Dr Robertson gave me a preview of their work awaiting publication, amongst which were the papers you published on June 5. They were unaware-and I am sure most of your readers will be unaware-that I published a rather similar hypothesis fifteen years gO.15 Since my evidence is different from theirs and my conclusion slightly different, it may help if I summarise them. Allbutt defined hyperpiesia (which we now call essential hypertension) as a condition in which the blood-pressure rises excessively in middle age. Our investigation showed that, in the population at large, arterial pressure tends to be continuously distributed at all ages, the frequency distribution curves being Gaussian when plotted on a logarithmic scale, and that arterial pressure tends to rise with age, but it rises more and faster in some subjects than others. Our family studies, supplemented by those of Miall and Oldham, showed that: (1) arterial pressure seems to be inherited; (2) the inheritance, like that of stature, is quantitative; (3) the coefficient of resemblance in first-degree relatives is of the order of 0.3; and (4) the resemblance is of the same order in those with low, normal or raised pressures (the resemblance breaks down in those with the highest pressures). We also found that the rate of rise of pressure with age is the same in families of subjects with hypertension and those with normal pressures. Thus what is inherited seems to be a tendency for a given pressure at a given age; the rate of rise of pressure with age seems to be acquired or, in other words, due to the impact of environmental influences. How is this brought about? I had in the course of my clinical and experimental work become aware of a series of instances in which the removal or repair of the lesion causing the high pressure did not restore arterial pressure to its original value or to the value expected for that age and sex in the general population. Three of these examples were in man. In my department we found that in three patients removal of a phseochromocytoma either left the pressure unaltered or very high, though no excess catecholamine excretion could thereafter be demonstrated. Removal of a unilaterally diseased kidney strikingly reduced arterial pressure in only half the patients and even in those the pressure tended to remain relatively high. Counihan showed that repair of an aortic coarctation reduced arterial pressure but the postoperative values were higher than would be expected for that age and sex in the general population. Why does the arterial pressure tend to remain high in some subjects? An observation of mine in the rabbit suggested that the new factor was time. When in a rabbit, one kidney was
1.
Kesteloot, H., Terryn, R., Bosmans, P., Joossens, J. V. Acta cardiol. 1966, 21, 341. 2. Kesteloot, H., Roelandt, J., Willems, J., Claes, J. H., Joossens, J. V. Circulation, 1968, 37, 854. 3. Thiers, R. E., Williams, J. F., Yoe, J. H. Analyt. Chem. 1955, 27, 1725. 4. Parr, R. M., Taylor, D. M. Biochem. J. 1964, 91, 424. 5. Giovanetti, S., Maggiore, Q., Malvano, R. in Nuclear Activation Techniques in the Life Sciences; p. 511. International Atomic Energy Agency, Vienna, 1976. 6. Kasperek, K., Schicha, H., Siller, V., Feinendegen, L. E. Strahlentherapie, 1972, 143, 468. 7. Koch, H. J., Smith, E. R., Shimp, N. F., Connor, J. Cancer, 1956, 9, 499.
8. 9.
Davies, I. J. T., Musa, M., Dormandy, P. L. J. clin Path. 1968, 21, 359. Vallee, B. L., Wacker, W. E. C., Bartholomay, A. F., Robin, E. D. New
Engl. J. Med. 1956, 255, 403. Versieck, J., Barbier, F., Speecke, A., Hoste, J. Lancet, 1974, i, 682. Cotzias, G. C., Miller, S. T., Edwards, J. J. Lab. clin. Med. 1966, 67, 836. Heydorn, K., Nørgård, K. Talanta, 1973, 20, 835. Versieck, J., Barbier, F., Speecke, A., Hoste, J. Acta endocr. Copenh. 1974, 76, 783. 14. Versieck, J., Barbier, F., Speecke, A., Hoste, J. Clin. Chem. 1975, 21, 578. 15. Pickering, G. The Nature of Essential Hypertension. London, 1961. 10. 11. 12. 13.
1404 removed and the other renal artery constricted, then excising the ischwmic kidney after two weeks reduced arterial pressure to normal in about four hours, but after two months left the arterial pressure unaltered. I also found evidence (inconclusive it is true) that in its early stages hypertension produced by renal-artery constriction was compatible with release of renin from the kidney; in the later stages it was not. I therefore concluded that, if the hypertension lasts long enough, a secondary change may occur which is itself sufficient to sustain arterial pressure. I thought that the most probable candidate for the secondary change was hypertrophy of arteries and arterioles for which Folkow and his colleagues have produced increasingly convincing evidence. The most recent form of this hypothesis was published in 1974.16 On p. 13 of that book I wrote:
measurements are
made
on
individual patients between and
during hypertensive episodes. Our own data confirm that a proportion of patients with essential hypertension do indeed have raised plasma-noradrenaline concentrations in the recumbent position. However, the increase in plasma-noradrenaline is enhanced in hypertensive patients compared with a normotensive group when levels are estimated during orthostasis at a time when the sympathetic nervous system is "turned on". Medical Unit, St Mary’s Hospital, London W2 1NY
PETER S. SEVER
"
"We are beginning to learn that certain situations in life elevate the arteriole pressure. It is quite likely that during the next 10 or 15 years these situations will be better understood and better defined than they are today. It is likely that at least some of them will be definable in terms of the behaviour of the mind. The more frequent these situations and the longer they last, the higher will be the arterial pressure and the greater the degree of medial hypertrophy. It seems not unlikely that temperament, possibly inherited, will play a part in the size and duration of these responses and thus that inheritance may also contribute to the rate of rise of pressure with age. "The hypothesis just outlined derives support from the fact, now abundantly illustrated from many clinics, that reducing the arterial pressure from very high levels may, after several years of treatment, produce a patient whose arterial pressure controls itself at lower levels." "
that my evidence supplements that of the workers. Whether the secondary fault lies in the arteries and arterioles in general, or specificatly in the kidney is a question that remains up to now unresolved. The full references will be found in the two works I have cited. It
seems to me
Glasgow
5 Horwood
Close,
Headington, Oxford OX3 7RF
GEORGE PICKERING
SIR,-Dr Brown and his colleagues (June 5, p. 1217) state that "the search for a single cause of benign essential hypertension has been fruitless". They state that "plasma renin, renin activity, and angiotensin n are usually normal and that exchangeable sodium, plasma volume, and extracellular volume are unremarkable". They do, however, admit that plasmacathecholamines are slightly raised, but dismiss this evidence for a dominant role of the sympathetic nervous system in the pathogenesis of essential hypertension by comparing plasmanoradrenaline levels in essential hypertension with those found in phseochromocytoma with comparable hypertension. This reasoning is untenable because when raised plasma levels of noradrenaline occur in essential hypertension, they may not reflect accurately "overactivity" of the sympathetic nervous system, since most of the noradrenaline released by postganglionic nerve endings, sited anatomically on the outside of blood-vessels, is subjected to a complex process of re-uptake and metabolism. Overflow of unmetabolised amine from the synaptic cleft may well pass into the extracellular spaces, be removed by the lymphatics, or diffuse into the circulation. Thus the quantum of noradrenaline released, causing constriction of resistance vessels and raising arterial pressure, is poorly reflected by changes in plasma levels. This situation differs greatly from the hypertensive events associated with phxochromocytoma where catecholamines are liberated directly into the circulation. Further comparisons with phaeochromocytoma must be made with caution since even in this condition there is a poor correlation between actual concentration of plasma-catecholamines and the level of arterial pressure when repeated 16.Pickering, G. Hypertension: Causes, Consequences burgh, 1974.
and
Management.
Edin-
ALPHAFETOPROTEIN ASSAY IN ALL AMNIOCENTESIS SAMPLES
SIR,-Several workersl-3 have argued that alphafetoprotein (A.F.P.) concentrations should be assayed in every amnioticfluid sample taken, whatever the indication for amniocentesis. This depends on the specificity of the A.F.P. test-its ability to detect serious fetal abnormalities without false positives. Ultrasonography may be used to confirm a diagnosis of anencephaly, but in general cannot be used for spina bifida, where most terminations of pregnancy are entirely dependent on the A.F.P. values. Even if the specificity of the test was as high as 99% there could be a substantial number of normal pregnancies terminated. Milunsky and Alpert3 have briefly reported on 3536 amniocentesis samples in which A.F.P. was determined. Their falsepositive rate is judged to be 1%. In the face of this alarming figure it is difficult to see how A.F.P. assay can be justified except for high-risk pregnancies selected because of a previous child with a neural-tube defect or a high serum-A.F.P. value. In an unselected population more normal pregnancies than affected pregnancies would be terminated. However, a 1% false-positive rate is probably an overestimate. The European Medical Research Councils in a survey of 3565 cases reported 3 false positives (0.1 %). In our own experience of 997 cases, raised A.F.P. values (greater than 3 standard deviations above the mean) were obtained in 45 cases. 12 of these were due to fetal blood contamination. Termination of pregnancy was recommended in the remaining 33, and the outcome was 16 cases of anencephaly, 15 of spina bifida, 1 of intrauterine death, and 1 of exomphalos. Though this series is considerably smaller than that of Milunsky and Alpert the false-positive rate is to date zero. The most important aspect of maintaining the specificity of amniotic-fluid A.F.P. assay is in eliminating distortions produced by contamination of the fluid with fetal blood,5 If the normal range has been constructed by using amniotic fluids which have been spun down and frozen, there is no way of knowing how many of these may have been contaminated by fetal serum, so that an unusually wide distribution of normal values is obtained. Fresh samples in which there is substantial presence of fetal red blood-cells must be regarded as unusable and a second amniocentesis requested. When fetal blood is present it is usually because mixing has taken place in the syringe being used for amniocentesis rather than in the main body of the amniocentesis being affected by a small fetal bleed which occurred at the time of the first amniocentesis. If the above precautions are observed we maintain that the false-positive rate in amniotic-fluid A.F.P. assay should be less than 0.1%. University Department of Human Western General Hospital, Edinburgh EH42XU
Genetics,
Department of Obstetrics and Gynaecology, Western General Hospital, Edinburgh 1. Wright, E. 2. Ainbender,
D.
J. H. BROCK
J.
B. SCRIMGEOUR
V., McIntosh, A. S., Foulds, J. W. Lancet, 1975, u, 769. E., Hirschhorn, K. ibid. 1976, i, 595. 3. Milunsky, A., Alpert, E. ibid. 1976, i, 1015. 4. Lindsten, J., Zetterstrom, R., Ferguson-Smith, M. in Prenatal Diagnosis of Genetic Disorders of the Fœtus, INSERM, Pans, 1976. 5. Brock, D. J. H. Lancet, 1975, ii, 495.