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WARFARIN ANTICOAGULATION AND PREGNANCY
862 How to achieve this end ? First, and most obviously (and you, Sir, are to be congratulated for endeavouring to persuade doctors to give a lead in the matter), we must press for maximum provision of contraceptive facilities, education in sex matters, and availability of abortion where contraceptive measures fail. Will that be enough ? We cannot tell. But surely it is wise to make plans contingent So if not penalties, then what ? on its being inadequate. Could we not explore the possibility of inducements to postpone childbearing ? Could there not be started, for example, for each girl of 16, an interest-bearing cumulative fund formed from a yearly contribution from the exchequer if she is in full-time education, or from part of her insurance contribution if she works, so long as she remains childless ? It could be repaid on the birth of her first child, or at age 23 or 25, or such age as should be dictated by the success of the scheme. Apart from securing its aim of stabilising population in a civilised (if paternalistic) manner, the State would promote education and acquisition of job skills for women (factors themselves likely to be conducive to smaller families), discourage unstable teenage marriages, and be instrumental in securing a useful financial provision at a most opportune time. Alternatively, might it not be possible to alter the tax structure so as to favour postponement of childbearing by newly married couples ? Certainly if the distrust of people such as the Child Poverty Action Group and Shelter are to be overcome, then some such measures will have to be devised. MICHAEL TUCK. Bishopsteignton.
ISCHÆMIC CRANIAL NEUROPATHIES SIR,-Dr. Weber (March 27, p. 645) maintains that the incidence of diabetes in patients with non-compressive oculomotor neuropathy is about 30%, in contrast with the 66% incidence of diabetes in my patients with Bell’s palsy.l Both the articles which he cites 2,3 are far from clear on several points, especially regarding the criteria for diagnosing diabetes and for performing arteriography in order to exclude compressive lesions. Rucker2 found 21 " diabetics " " vascular " cases, and perhaps one should among his 63 add the 95 cases with undetermined aetiology. The frequency of diabetes thus becomes 13%. However, it seems that these were all patients who had previously been diagnosed as diabetics, since this was a retrospective study; no blood-tests are mentioned and most patients were seen once only. In my series of 130 patients, 18 were known diabetics-giving a similar frequency of 14%. Green et awl. probably did test the glucose tolerance. " They found 25 diabetics " and 20 undetermined (" neuritis ") cases, bringing the frequency to 56% diabetics among their patients with idiopathic oculomotor paresis, compared with my figure of 66%. It thus seems that mononeuritides affecting the oculomotor and facial nerves both have very similar frequency of diabetic background. Dr. Weber rightly points to the important question of the relationship of hypertension and arteriosclerosis to mononeuritis. In my series careful histories were taken, E.C.G.S performed, and blood-pressures measured. Abnormalities were found in 35 of the 130 patients: 21 had hypertension, 24 had evidence of probable coronary-artery disease, 3 had peripheral vascular disease, and 2 had had cerebrovascular events (more than one disease was present in several patients). As could be expected, most of these patients were in the older age-groups, only 3 being younger than 45 years. Perhaps more significant is the fact that, of the 35 patients, 1. 2. 3.
Korczyn A. D. Lancet, Jan. 16, 1971, p. 108. Rucker, C. W. Am. J. Ophthal. 1958, 46, 787. Green, W. R., Hackett, E. R., Schlezinger, N. S. Archs Ophthal. 1964, 72, 154.
6 were known diabetics and only 5 had normal glucosetolerance tests. The relationship of hypertension, arteriosclerosis, and diabetes to angiopathy is far from clear. In many cases it is impossible to decide whether vascular lesions have an arteriosclerotic or diabetic basis; in fact, some would regard the question as irrelevant, maintaining that diabetes merely accelerates the arteriosclerotic processes. Pathologically, diabetic angiopathy is characterised by periodic-acid/Schiffpositive thickening of the vessel wall. However, patients without evidence of diabetes sometimes manifest similar lesions, and many diabetics show hyaline-i.e., P.A.S.negative-thickening of the arteries. The case of oculomotor-nerve palsy in a diabetic lately described by Weber et al.4 probably belongs to this group. Should this case be " " regarded as diabetic " or arteriosclerotic " ? The suggestion that diabetic angiopathy is the commonest cause for Bell’s palsy was based on the high incidence of abnormal glucose-tolerance tests in young patients,! on the one hand, and the occurrence of typical diabetic angiopathy in the conjunctivx and nail-beds seen on capil-
laroscopy.5 As Dr. Weber writes, aberrant regeneration following ischaemic oculomotor neuropathy is extremely rare, if it occurs at all. In our series of idiopathic facial paralysis, were synkinesias present in 3 patients (2-3%). This low figure may be related to the fact that treatment by electrical stimulation was avoided. It was suggested by Duchenne a century agothat faradisation of the nerve may result in contractures and aberrant regeneration. Beilinson Hospital, Tel-Aviv University Medical Israel.
School,
A. D. KORCZYN.
WARFARIN ANTICOAGULATION AND PREGNANCY SIR,-Dr. Fedrick and Professor Butler (Jan. 23, p. 192) report from the 1958 British Perinatal Mortality Survey that an infant delivered by caesarean section before 37 weeks to a mother with severe pre-eclampsia would be 85 times more likely to die with massive pulmonary haemorrhage than an infant born normally at term. They also point out that intraventricular haemorrhage and cerebral birth trauma are associated with severe pre-eclampsia and immaturity. These important facts in no way detract from Dr. Ikonen and his colleagues’ warning7 on the possible hazards of warfarin in late pregnancy. On the contrary they emphasise the high incidence of hsemorrhagic complications associated with pre-eclampsia and prematurity, hence the importance of avoiding any maternal therapy which will further impair the haemostatic competence of the infant. The levels of factor 11, vii, ix, and x in the healthy newborn are particularly low,8 and coumarin derivatives (molecular weight about 1000) which cross the placenta produce a further depletion of these vitamin-Kdependent factors. When the baby is already at risk from serious haemorrhage and anticoagulant therapy must be continued in late pregnancy, heparin, which does not cross the placental barrier, is the anticoagulant of choice. In the fetal interest, therefore, coumarin drugs should be discontinued and heparin employed for 3 to 4 weeks before the time of expected or proposed delivery. Such a regimen 4.
5. 6.
7.
8.
Weber, R. B., Daroff, R. B., Mackey, E. A. Neurology, Minneap. 1970, 20, 835. Korczyn, A. D., Kadish, U., Kochen, I. Proceedings of Sixth European Conference on the Microcirculation, 1970, p. 151. Duchenne, G. B. A. De l’Ectrisation Localisée; p. 853. Paris 1872. (New Sydenham Society edition translated by G. V. Poore; p. 249. London, 1883.) Ikonen, E., Merikallio, E., Österlund, K., Seppälä, M. Lancet, 1970, ii, 1252. Bonnar, J., McNicol, G. P., Douglas, A. S. J. Obstet. Gynœc. Br. Commonw. (in the press).
863 will allow the fetal clotting-factors levels hefore deliverv. 9,10 Nuffield Department of Obstetrics and Gynæcology, University of Oxford.
to return to
their normal
JOHN BONNAR.
A.L.G. AFTER RENAL ALLOTRANSPLANTATION SiR,—The report of Mr. Sheil and his co-workers (Feb. 20, p. 359) contains certain statistical conclusions which are not justified by the protocol and the results. We should all recognise the necessity of a large controlled study to place antilymphocyte globulin (A.L.G.) in its proper perspective. However, this study may add conIn order to compare fusion rather than information. results between a " treatment group " and a " control group " and then determine a P value, the assignment of patients to the respective groups should be unbiased and predetermined. During the early phase of this study, Mr. Sheil made assignments by the alternate-patient method, but subsequently did so by arbitrary criteria which would tend to destroy the validity of subsequent statistical analysis. The use of P analysis implies comparability between the treatment and control groups and an unbiased method of patient selection. If one finds that the two groups are not comparable by various parameters, then either greater numbers are necessary or bias has entered into the method of selection. To attempt to establish comparability between two groups by arbitrary selection of patients creates severe bias and any subsequent statistical analysis must be viewed with scepticism. Furthermore, there were 3 patients who were originally assigned to the A.L.G. group who were subsequently removed and added to the control group because of their inability to take A.L.G. While one may be justified in analysing the treatment group with and without these patients, they should not be placed within the control group. If these 3 patients all rejected their allografts, a considerable difference in the p values would be apparent. These 3 patients may not have had an adequate trial of A.L.G., but in reality must be considered as A.L.G. failures, since one is not able to administer the drug to them. The results of this study certainly bear reporting, since a substantial number of patients are involved, but Mr. Sheil, and those of us who have read his report, must view the data with the scepticism that thev deserve. Renal Unit, Memorial Hospital of Springfield, Springfield, Illinois 62701.
ALTON J. MORRIS.
* * * We showed this letter to Mr. Sheil and his colleagues, and their reply follows.-ED. L. SIR,-Patient selection by random method in a controlled trial of A.L.G. treatment, as suggested by Dr. Morris, might be ideal in theory, but would require impractically large patient numbers to eliminate the effect of other factors known to influence the outcome following cadaveric-donor renal transplantation. With small numbers of patients, as is necessary at present, even a powerfully beneficial effect of A.L.G. could be missed. Our method of selection was predetermined and used the basic statistical principle of " grouping " or " blocking ". As a result there were similar proportions of patients having factors known to alter the prognosis for recipients of cadaveric-donor renal allografts in the treated and control groups. These factors were grafts with delayed onset of 9. 10.
Hirsh, J., Kade, J. F., O’Sullivan, E. F. Br. med. J. 1970, i, 270. Bonnar, J., McNicol, G. P., Douglas, A. S. in Scientific Basis of Obstetrics and Gynaecology (edited by R. R. Macdonald); p. 243. London, 1971.
adequate function following operation, various grades of tissue compatibility, the presence before operation of circulating cytotoxic antibodies, and secondary grafts. Almost always one of two patients who received the kidneys of a single donor would receive treatment. Selection was determined only by the requirement to restore balance to the trial with regard to the factors mentioned, and other influences were thus randomised. Rather than introduce bias, as suggested by Dr. Morris, the method effectively prevents the known influences from strongly affecting the trial and renders the treated and control
comparable. regard to the " 3 patients who were originally assigned to the A.L.G. group who were subsequently removed and added to the control group ", each received a single subcutaneous test dose (0-25 ml.) of A.L.G. only, as stated. Because of local reaction, A.L.G. was withheld and the patients were placed in the control group. Dr. Morris says " These 3 patients may not have had an adequate trial of A.L.G....", which rather understates the groups
With
situation since it is inconceivable that the amount of globulin given to each (0-003 mg.) could have influenced the outcome in these patients. In any case, none of them rejected the allograft, so that, apart from inclusion in the control group, as was done, placement of these patients in any other way (inclusion in the A.L.G.-treated group, exclusion from the control group, exclusion from the trial) would favour the conclusion that A.L.G. therapy is beneficial. A. G. R. SHEIL D. MEARS G. E. KELLY J. H. ROGERS B. G. STOREY J. R. JOHNSON J. CHARLESWORTH J. MAY S. KALOWSKI J. H. STEWART. Department of Surgery,
University of Sydney, and Renal and Transplant Units of Sydney Hospital and Royal Prince Alfred Hospital, Sydney, N.S.W. 2006, Australia.
PREVALENCE OF GLYCOSURIA IN NORMAL PREGNANCY were interested to read the paper by Dr. Soler SIR,-We and Professor Malins (March 27, p. 619). We would like to add some comment since we believe that their conclusions cannot be easily translated into practical advice backed by their own or others’ data. Their own work did not disclose any diabetics as a result of testing 50 pregnant women. They suggest that an improved index of glycosuria is the glucose-excretion rate, although it is notoriously difficult for pregnant women to empty the bladder completely. Having recommended the index of glucose-excretion rate, no reference is made to this in the practical advice in the final sentence, where they state that " If the 1 % to 5 % of glucosuric women with gestational diabetes are not to be missed, pregnant women with repeated positive urine tests showing more than light clinistix or trace clinitest should be further investigated." They compare their incidence of 8% (4 out of 50) of women with positive’ Clinistix ’ in a fasting specimen with our own report of 0-8% of second morning fasting glycosuria in 1418 pregnant women. They suggest the discrepancy may be due to varying sensitivity of clinistix strips, but in fact it seems that a more likely explanation is the difference in the populations studied. Our reportwas intended to indicate the incidence of second morning fasting glycosuria in a large antenatal clinic population at any one time. Their clinical material consisted of 50 women followed through 1.
Sutherland, H. W., Stowers, J. M., McKenzie, C. Lancet, 1970, i, 1069.
ISCHÆMIC CRANIAL NEUROPATHIES SIR,-Dr. Weber (March 27, p. 645) maintains that the incidence of diabetes in patients with non-compressive oculomotor neuropathy is about 30%, in contrast with the 66% incidence of diabetes in my patients with Bell’s palsy.l Both the articles which he cites 2,3 are far from clear on several points, especially regarding the criteria for diagnosing diabetes and for performing arteriography in order to exclude compressive lesions. Rucker2 found 21 " diabetics " " vascular " cases, and perhaps one should among his 63 add the 95 cases with undetermined aetiology. The frequency of diabetes thus becomes 13%. However, it seems that these were all patients who had previously been diagnosed as diabetics, since this was a retrospective study; no blood-tests are mentioned and most patients were seen once only. In my series of 130 patients, 18 were known diabetics-giving a similar frequency of 14%. Green et awl. probably did test the glucose tolerance. " They found 25 diabetics " and 20 undetermined (" neuritis ") cases, bringing the frequency to 56% diabetics among their patients with idiopathic oculomotor paresis, compared with my figure of 66%. It thus seems that mononeuritides affecting the oculomotor and facial nerves both have very similar frequency of diabetic background. Dr. Weber rightly points to the important question of the relationship of hypertension and arteriosclerosis to mononeuritis. In my series careful histories were taken, E.C.G.S performed, and blood-pressures measured. Abnormalities were found in 35 of the 130 patients: 21 had hypertension, 24 had evidence of probable coronary-artery disease, 3 had peripheral vascular disease, and 2 had had cerebrovascular events (more than one disease was present in several patients). As could be expected, most of these patients were in the older age-groups, only 3 being younger than 45 years. Perhaps more significant is the fact that, of the 35 patients, 1. 2. 3.
Korczyn A. D. Lancet, Jan. 16, 1971, p. 108. Rucker, C. W. Am. J. Ophthal. 1958, 46, 787. Green, W. R., Hackett, E. R., Schlezinger, N. S. Archs Ophthal. 1964, 72, 154.
6 were known diabetics and only 5 had normal glucosetolerance tests. The relationship of hypertension, arteriosclerosis, and diabetes to angiopathy is far from clear. In many cases it is impossible to decide whether vascular lesions have an arteriosclerotic or diabetic basis; in fact, some would regard the question as irrelevant, maintaining that diabetes merely accelerates the arteriosclerotic processes. Pathologically, diabetic angiopathy is characterised by periodic-acid/Schiffpositive thickening of the vessel wall. However, patients without evidence of diabetes sometimes manifest similar lesions, and many diabetics show hyaline-i.e., P.A.S.negative-thickening of the arteries. The case of oculomotor-nerve palsy in a diabetic lately described by Weber et al.4 probably belongs to this group. Should this case be " " regarded as diabetic " or arteriosclerotic " ? The suggestion that diabetic angiopathy is the commonest cause for Bell’s palsy was based on the high incidence of abnormal glucose-tolerance tests in young patients,! on the one hand, and the occurrence of typical diabetic angiopathy in the conjunctivx and nail-beds seen on capil-
laroscopy.5 As Dr. Weber writes, aberrant regeneration following ischaemic oculomotor neuropathy is extremely rare, if it occurs at all. In our series of idiopathic facial paralysis, were synkinesias present in 3 patients (2-3%). This low figure may be related to the fact that treatment by electrical stimulation was avoided. It was suggested by Duchenne a century agothat faradisation of the nerve may result in contractures and aberrant regeneration. Beilinson Hospital, Tel-Aviv University Medical Israel.
School,
A. D. KORCZYN.
WARFARIN ANTICOAGULATION AND PREGNANCY SIR,-Dr. Fedrick and Professor Butler (Jan. 23, p. 192) report from the 1958 British Perinatal Mortality Survey that an infant delivered by caesarean section before 37 weeks to a mother with severe pre-eclampsia would be 85 times more likely to die with massive pulmonary haemorrhage than an infant born normally at term. They also point out that intraventricular haemorrhage and cerebral birth trauma are associated with severe pre-eclampsia and immaturity. These important facts in no way detract from Dr. Ikonen and his colleagues’ warning7 on the possible hazards of warfarin in late pregnancy. On the contrary they emphasise the high incidence of hsemorrhagic complications associated with pre-eclampsia and prematurity, hence the importance of avoiding any maternal therapy which will further impair the haemostatic competence of the infant. The levels of factor 11, vii, ix, and x in the healthy newborn are particularly low,8 and coumarin derivatives (molecular weight about 1000) which cross the placenta produce a further depletion of these vitamin-Kdependent factors. When the baby is already at risk from serious haemorrhage and anticoagulant therapy must be continued in late pregnancy, heparin, which does not cross the placental barrier, is the anticoagulant of choice. In the fetal interest, therefore, coumarin drugs should be discontinued and heparin employed for 3 to 4 weeks before the time of expected or proposed delivery. Such a regimen 4.
5. 6.
7.
8.
Weber, R. B., Daroff, R. B., Mackey, E. A. Neurology, Minneap. 1970, 20, 835. Korczyn, A. D., Kadish, U., Kochen, I. Proceedings of Sixth European Conference on the Microcirculation, 1970, p. 151. Duchenne, G. B. A. De l’Ectrisation Localisée; p. 853. Paris 1872. (New Sydenham Society edition translated by G. V. Poore; p. 249. London, 1883.) Ikonen, E., Merikallio, E., Österlund, K., Seppälä, M. Lancet, 1970, ii, 1252. Bonnar, J., McNicol, G. P., Douglas, A. S. J. Obstet. Gynœc. Br. Commonw. (in the press).
863 will allow the fetal clotting-factors levels hefore deliverv. 9,10 Nuffield Department of Obstetrics and Gynæcology, University of Oxford.
to return to
their normal
JOHN BONNAR.
A.L.G. AFTER RENAL ALLOTRANSPLANTATION SiR,—The report of Mr. Sheil and his co-workers (Feb. 20, p. 359) contains certain statistical conclusions which are not justified by the protocol and the results. We should all recognise the necessity of a large controlled study to place antilymphocyte globulin (A.L.G.) in its proper perspective. However, this study may add conIn order to compare fusion rather than information. results between a " treatment group " and a " control group " and then determine a P value, the assignment of patients to the respective groups should be unbiased and predetermined. During the early phase of this study, Mr. Sheil made assignments by the alternate-patient method, but subsequently did so by arbitrary criteria which would tend to destroy the validity of subsequent statistical analysis. The use of P analysis implies comparability between the treatment and control groups and an unbiased method of patient selection. If one finds that the two groups are not comparable by various parameters, then either greater numbers are necessary or bias has entered into the method of selection. To attempt to establish comparability between two groups by arbitrary selection of patients creates severe bias and any subsequent statistical analysis must be viewed with scepticism. Furthermore, there were 3 patients who were originally assigned to the A.L.G. group who were subsequently removed and added to the control group because of their inability to take A.L.G. While one may be justified in analysing the treatment group with and without these patients, they should not be placed within the control group. If these 3 patients all rejected their allografts, a considerable difference in the p values would be apparent. These 3 patients may not have had an adequate trial of A.L.G., but in reality must be considered as A.L.G. failures, since one is not able to administer the drug to them. The results of this study certainly bear reporting, since a substantial number of patients are involved, but Mr. Sheil, and those of us who have read his report, must view the data with the scepticism that thev deserve. Renal Unit, Memorial Hospital of Springfield, Springfield, Illinois 62701.
ALTON J. MORRIS.
* * * We showed this letter to Mr. Sheil and his colleagues, and their reply follows.-ED. L. SIR,-Patient selection by random method in a controlled trial of A.L.G. treatment, as suggested by Dr. Morris, might be ideal in theory, but would require impractically large patient numbers to eliminate the effect of other factors known to influence the outcome following cadaveric-donor renal transplantation. With small numbers of patients, as is necessary at present, even a powerfully beneficial effect of A.L.G. could be missed. Our method of selection was predetermined and used the basic statistical principle of " grouping " or " blocking ". As a result there were similar proportions of patients having factors known to alter the prognosis for recipients of cadaveric-donor renal allografts in the treated and control groups. These factors were grafts with delayed onset of 9. 10.
Hirsh, J., Kade, J. F., O’Sullivan, E. F. Br. med. J. 1970, i, 270. Bonnar, J., McNicol, G. P., Douglas, A. S. in Scientific Basis of Obstetrics and Gynaecology (edited by R. R. Macdonald); p. 243. London, 1971.
adequate function following operation, various grades of tissue compatibility, the presence before operation of circulating cytotoxic antibodies, and secondary grafts. Almost always one of two patients who received the kidneys of a single donor would receive treatment. Selection was determined only by the requirement to restore balance to the trial with regard to the factors mentioned, and other influences were thus randomised. Rather than introduce bias, as suggested by Dr. Morris, the method effectively prevents the known influences from strongly affecting the trial and renders the treated and control
comparable. regard to the " 3 patients who were originally assigned to the A.L.G. group who were subsequently removed and added to the control group ", each received a single subcutaneous test dose (0-25 ml.) of A.L.G. only, as stated. Because of local reaction, A.L.G. was withheld and the patients were placed in the control group. Dr. Morris says " These 3 patients may not have had an adequate trial of A.L.G....", which rather understates the groups
With
situation since it is inconceivable that the amount of globulin given to each (0-003 mg.) could have influenced the outcome in these patients. In any case, none of them rejected the allograft, so that, apart from inclusion in the control group, as was done, placement of these patients in any other way (inclusion in the A.L.G.-treated group, exclusion from the control group, exclusion from the trial) would favour the conclusion that A.L.G. therapy is beneficial. A. G. R. SHEIL D. MEARS G. E. KELLY J. H. ROGERS B. G. STOREY J. R. JOHNSON J. CHARLESWORTH J. MAY S. KALOWSKI J. H. STEWART. Department of Surgery,
University of Sydney, and Renal and Transplant Units of Sydney Hospital and Royal Prince Alfred Hospital, Sydney, N.S.W. 2006, Australia.
PREVALENCE OF GLYCOSURIA IN NORMAL PREGNANCY were interested to read the paper by Dr. Soler SIR,-We and Professor Malins (March 27, p. 619). We would like to add some comment since we believe that their conclusions cannot be easily translated into practical advice backed by their own or others’ data. Their own work did not disclose any diabetics as a result of testing 50 pregnant women. They suggest that an improved index of glycosuria is the glucose-excretion rate, although it is notoriously difficult for pregnant women to empty the bladder completely. Having recommended the index of glucose-excretion rate, no reference is made to this in the practical advice in the final sentence, where they state that " If the 1 % to 5 % of glucosuric women with gestational diabetes are not to be missed, pregnant women with repeated positive urine tests showing more than light clinistix or trace clinitest should be further investigated." They compare their incidence of 8% (4 out of 50) of women with positive’ Clinistix ’ in a fasting specimen with our own report of 0-8% of second morning fasting glycosuria in 1418 pregnant women. They suggest the discrepancy may be due to varying sensitivity of clinistix strips, but in fact it seems that a more likely explanation is the difference in the populations studied. Our reportwas intended to indicate the incidence of second morning fasting glycosuria in a large antenatal clinic population at any one time. Their clinical material consisted of 50 women followed through 1.
Sutherland, H. W., Stowers, J. M., McKenzie, C. Lancet, 1970, i, 1069.