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ANTIBIOTICS AND CONGENITAL MALFORMATIONS
298 One can only surmise what might have happened had his blood-pressure been lowered in the presence of such inadequate cerebral blood-flow. I should like to submit that any patient with hypertension who has had a transient neurological deficit be considered for cerebral arteriography before antihypertensive drugs are used, and that any patient with a systolic bruit in the neck or supraclavicular fossae be so studied, even if there have been no neurological symptoms, before such drugs are employed. Peter Bent Brigham Hospital, Boston, Mass.
JOHN SHILLITO, Jr.
WORKING MOTHERS SIR,-Your annotation of July 13 has relevance to a current problem-the shortage of medical manpower. I understand from consultant colleagues that, were it not for the large number of doctors from the Commonwealth, many of our smaller hospitals must close down, or at least restrict their capacity. Yet there must be in this country a large pool of potential " woman-power ", not able to secure medical work because of family
commitments. You refer to the need " for the supervision of children after school until their parents return from work ". Since medical work is notorious for the irregularity and unpredictability of its hours, I must agree wholeheartedly with this need, but may I point out that this is only a minor problem ? The greater need is for suitable arrangements during school holidays. One answer to this is to employ a person to take charge of the children; but the mother does not always wish to relinquish her responsibility to this extent, nor is it always easy to find someone who is suitable. May I suggest that the Ministry of Health, through its hospital management committees, also takes action, and makes available posts to medical mothers, tenable during the school term. Much valuable work can be done between the hours of 9 A.M. and 4 P.M. in those 39 weeks of the year, and much personal satisfaction would be gained by the ladies involved. Further, when the children are older, and return to full-time work is feasible, the re-entry into medicine will not be so difficult or so painful a process. Crawley, Sussex.
W. P. GOODYEAR.
are as
careless
as
Mr.
Chief Pharmacist.
London, S.W.1.
ANTIBIOTICS AND CONGENITAL MALFORMATIONS Carter and Dr. Wilson (June 8), SIR,-Dr.
giving figures which they think suggest a teratogenic effect produced by antibiotics given in early pregnancy, invite further studies. Towards the end of 1962 when their suspicions became known to the research committee of the council of the College of General Practitioners, an attempt was made to check their findings by a retrospective survey, employing a group of G.P.S who specialise in carefully kept and indexed records (the retrospective survey group), augmented for this study by two or three practitioners with known accurate maternity records. Dr. Carter and Dr. Wilson’s criteria were used. In an effort to identify any other teratogenic factors, the practitioners were also asked to divide their cases into those who in the first twelve weeks of pregnancy had been: (a) given antibiotics, (b) given other drugs, (c) given drugs for vomiting of pregnancy, (d) immunised, (e) treated without antibiotics for sore throats or febrile illnesses, (f) untreated with
STERILITY OF EYE MEDICAMENTS
SIR,ńIt Australian pharmacists
all possible bacterial contamination of the eye, it must surely be accepted that the possibility of contamination from the other sources encountered continuously in the atmosphere and from the methods employed by patients in applying drops, lotions, and ointments far outweighs any risk from pharmaceutical preparations made in accordance with normal procedure. To require sterility testing of all eye lotions extemporaneously prepared in the pharmacy would seem cumbersome and would probably not achieve the object intended, Mr. Crompton will have noticed that the comment in the British Pharmaceutical Codex on the possibility of fungal growth in eye lotions is given in a context which makes it clear that this is a reason for requiring eye lotions to be freshly prepared using freshly boiled and cooled purified water, &c, It is open to the prescriber to ask for a bacteriostatic or fungicidal preservative to be added if he feels this to be necessary, HERBERT S. GRAINGER Westminster Hospital,
The results
anv
drug
were as
or
immunisation.
follows:
Crompton suggests (July 20) this is a matter for concern. So far as this hospital is concerned, all eyedrops are sterile when they leave the pharmacy and are preserved, so far as suitable agents can be found, against subsequent contamination. I do not think we are very different in this respect from the majority of hospitals where eyedrops are prepared in this country. On the question of sterilising eye ointments, to give any degree of assurance against contamination, paraffins and other oils must be heated to a temperature which would destroy the majority of the active ingredients. The best that can be done, therefore, is a compromise whereby the active material is incorporated into previously sterilised base and filled into sterilised recipients under conditions which are designed to reduce the risk of contamination as much as possible. This is the method in the British Pharmaceutical Codex. Apart from spores, very few organisms remain viable in paraffin for a long period. It is notoriously difficult to test oils for sterility, and it would be interesting to know what techniques were used at Mr. Crompton’s hospital and what organisms were found. The juxtaposition of his paragraphs suggests that the contaminant might have been Pseudomonas pyocyanea, which would be rather surprising. As the matter is of considerable pharmaceutical importance, it is unfortunate that no publication is quoted. Whilst no-one would dispute the importance of avoiding
Adding together the last two rows of the above table, were 954 pregnancies without antibiotics being prescribed. Of these, the pregnancy wastage (abortions, non-malformed stillbirths, malformations, and recorded neonatal deaths) was 137 (14-4%), whilst in 50 pregnancies with antibiotics prescribed the wastage was 13 (26-0%). This difference is just statistically significant at the 5% level. Comparing the malformation-rates in the two groups, 2-4% and 8-0% (4 cases) respectively, no significant difference was found. This was the largest accurately documented retrospective series which we were able to amass. A much larger series would be needed to put Dr. Carter and Dr. Wilson’s theory to the test. A complicating factor in evaluating the figures was the borderline nature of some of the reported malformations. An interesting incidental finding was the low abortionrate (2-4%) among the 331 patients requiring treatment
there
"
"
299
for vomiting of pregnancy compared with the abortionrate (10-2%) for the 954 patients where no such treatment was given. This difference is highly significant (p < 0-001) and confirms the observation of Medalie,l who found a significant inverse relationship between nausea and vomiting and abortion. . ----- ----g
--"
Felsted, Essex.
P. A. WALFORD.
MUTATION, AUTOIMMUNITY, AND AGEING SIR,-Dr. Comfort (July 20) fears there is an "... over mutational immunological ageing..." because in most recognised autoimmune diseases there is female preponderance; women, however, age rather more slowly than men. Dr. Comfort believes that a recent discussion2 of the setiology of rheumatoid arthritis supports his doubts, but a subsequent paper3 might appear to reinforce them very substantially. To take an extreme example (Hashimoto’s thyroiditis) from the later paper, the sex-ratio, F/M, is between 10 and 20. Although this and other evidence3 is most unpropitious, I wish to suggest that it does not necessarily negate autoimmune hypotheses of ageing. Consider firstly three possible origins of sex-differences in disturbed-tolerance autoimmunity:
impasse
examples (figs. 1 and 2) will suffice xtiological diversity.
to
illustrate the
These mortality statistics for chronic rheumatic heart-disease and arteriosclerosis share one significant property. Over most of adult life, age- and sex-specific mortality-rates are closely proportional to a constant power of age. These striking characteristics are found in certain other cardiovascular diseases (International Abridged List 1955: B22, B27, B28, B29, and A85); and also in many cancers,6 but not, for example, in nephritis and nephrosis. Various models have been proposed to account for a power-law relationship in the context of carcinogenesis 6-12; they are all stochastic, and they all require that at least two random events (somatic mutations of some kind) should be involved in the aetiology. This kind of hypothesis, requiring only a few random events, seems reasonable in connection with carcinogenesis, because we know that a single transplanted cancer cell can propagate a tumour in a suitable host animal. Multifocal tumours can also be accounted for.13 In cardiovascular disease enormous numbers of cells, in different parts of the body, are affected simultaneously and it is not immediately obvious how a few somatic mutations could bring this about. Burnet’s forbidden-clone hypothesis4 provides an answer. One or a small number of somatic mutations in a stem-cell could well give rise to a clone of forbidden lymphocytes containing (and maintaining) a very large number of cells. Clonal growth gives the magnification for translating one or a small number of discrete events into a widespread systemic pathology. This is the essence of the interpretation suggested for several disturbed-tolerance autoimmune diseases 23 and it could also provide the basis of the aetiology of various cardiovascular diseases.
1. Sex-ratio of carriers at birth.-In rheumatoid arthritis this appears to be unity, or very close to unity.2 Where some autoimmune diseases3 are concerned, the ratio F/M is, however, much greater than 1. ’If inherited rare dominant alleles 3 on the X-chromosome can constitute predisposing factors,3 6. Armitage, P., Doll, R. Brit. J. Cancer, 1954, 8, 1. 7. Muller, H. J. Sci. Progr. 1951, 7, 130. then the theoretical ratio of carriers at birth-proportion of 8. Fisher, J. C., Holloman, J. H. Cancer, 1951, 4, 916. n is a of be where males-should 9. Nordling, C. O. Nord. Med. 1952, 47, 817. 2n, females/proportion 10. Stocks, P. Brit. J. Cancer, 1953, 7, 407. positive integer. In Hashimoto’s thyroiditis, n may be as high 11. Armitage, P., Doll, R. ibid. 1957, 11, 161. as 4. (For a common dominant allele on the X-chromosome12. Fisher, J. C. Nature, Lond. 1958, 181, 651. Burch, P. R. J. ibid. 1962, 195, 241. say Xl-and with equal selection_pressures against homozygous 13. 14. World Health Organisation. Annual Epidemiological and Vital Statistics, females X,/X, and X2/X2, the sex-ratio of carriers at birth will 1956. Geneva. 1959. not be 2 but 3/2.) I have so far found no example of (presumed) autoimmunity where the sex-ratio (F/M) of carriers is significantly less than unity, and it seems that the cause of the slower ageing in women should be sought elsewhere. 2. Somatic mutation.-In analysing the xtiology of rheumatoid arthritis, it was argued that the rate of arthritogenic somatic gene-mutation is about twice as high in women as in mer.. Although in some other autoimmune diseases the rate of somatic mutation in males and females can be equal3 (when only autosomal genes are implicated), no example has so far been found where it can be said to be significantly lower in women than in men. 3. Defence against "forbidden clones ". 4-In inflammatory polyarthritis of Manchester clinical grades 3 and 4, the age-specific prevalence below the 5 age of 50 is probably lower in women than in men 2 although above 50 the situation is undoubtedly reversed. It was argued that more forbidden clones are usually required to produce a given clinical grade of polyarthritis in women than in men--a consequence, it was suggested, of the possession by females of a more effective natural defence mechanism against forbidden clones. Should this interpretation be valid-and it is supported by much indirect evidence 2-it gets round Dr. Comfort’s impasse. Fig. 1-Log-log graph of age- and It is interesting to consider briefly one of the sex - specific mortality - rates, most
serious and
important manifestations of
ageing-cardiovascular disease. Two contrasted 1. 2. 3. 4.
5.
Medalie, J. H. Lancet, 1957, ii, 117. Burch, P. R. J. ibid. 1963, i, 1253. Burch, P. R. J., Rowell, N. R. ibid. 1963. In the
chronic rheumatic heart-diseases (B 25), England and Wales, 1956.1a 0: Females, X: Males. Points plotted at centre of 5-year agegroup.
press.
Burnet, F. M. The Clonal Selection Theory of Acquired Immunity. London, 1959. Lawrence, J. S. Ann. rheum. Dis. 1961, 20, 11.
Fig. 2-Log-log graph of age- and sex-specific mortality-rates, arteriosclerotic and degenerative heart-disease (B 26), England and Wales, 1956.’* 0: Females,X : Males. Points plotted at centre of 5-year age-group.
JOHN SHILLITO, Jr.
WORKING MOTHERS SIR,-Your annotation of July 13 has relevance to a current problem-the shortage of medical manpower. I understand from consultant colleagues that, were it not for the large number of doctors from the Commonwealth, many of our smaller hospitals must close down, or at least restrict their capacity. Yet there must be in this country a large pool of potential " woman-power ", not able to secure medical work because of family
commitments. You refer to the need " for the supervision of children after school until their parents return from work ". Since medical work is notorious for the irregularity and unpredictability of its hours, I must agree wholeheartedly with this need, but may I point out that this is only a minor problem ? The greater need is for suitable arrangements during school holidays. One answer to this is to employ a person to take charge of the children; but the mother does not always wish to relinquish her responsibility to this extent, nor is it always easy to find someone who is suitable. May I suggest that the Ministry of Health, through its hospital management committees, also takes action, and makes available posts to medical mothers, tenable during the school term. Much valuable work can be done between the hours of 9 A.M. and 4 P.M. in those 39 weeks of the year, and much personal satisfaction would be gained by the ladies involved. Further, when the children are older, and return to full-time work is feasible, the re-entry into medicine will not be so difficult or so painful a process. Crawley, Sussex.
W. P. GOODYEAR.
are as
careless
as
Mr.
Chief Pharmacist.
London, S.W.1.
ANTIBIOTICS AND CONGENITAL MALFORMATIONS Carter and Dr. Wilson (June 8), SIR,-Dr.
giving figures which they think suggest a teratogenic effect produced by antibiotics given in early pregnancy, invite further studies. Towards the end of 1962 when their suspicions became known to the research committee of the council of the College of General Practitioners, an attempt was made to check their findings by a retrospective survey, employing a group of G.P.S who specialise in carefully kept and indexed records (the retrospective survey group), augmented for this study by two or three practitioners with known accurate maternity records. Dr. Carter and Dr. Wilson’s criteria were used. In an effort to identify any other teratogenic factors, the practitioners were also asked to divide their cases into those who in the first twelve weeks of pregnancy had been: (a) given antibiotics, (b) given other drugs, (c) given drugs for vomiting of pregnancy, (d) immunised, (e) treated without antibiotics for sore throats or febrile illnesses, (f) untreated with
STERILITY OF EYE MEDICAMENTS
SIR,ńIt Australian pharmacists
all possible bacterial contamination of the eye, it must surely be accepted that the possibility of contamination from the other sources encountered continuously in the atmosphere and from the methods employed by patients in applying drops, lotions, and ointments far outweighs any risk from pharmaceutical preparations made in accordance with normal procedure. To require sterility testing of all eye lotions extemporaneously prepared in the pharmacy would seem cumbersome and would probably not achieve the object intended, Mr. Crompton will have noticed that the comment in the British Pharmaceutical Codex on the possibility of fungal growth in eye lotions is given in a context which makes it clear that this is a reason for requiring eye lotions to be freshly prepared using freshly boiled and cooled purified water, &c, It is open to the prescriber to ask for a bacteriostatic or fungicidal preservative to be added if he feels this to be necessary, HERBERT S. GRAINGER Westminster Hospital,
The results
anv
drug
were as
or
immunisation.
follows:
Crompton suggests (July 20) this is a matter for concern. So far as this hospital is concerned, all eyedrops are sterile when they leave the pharmacy and are preserved, so far as suitable agents can be found, against subsequent contamination. I do not think we are very different in this respect from the majority of hospitals where eyedrops are prepared in this country. On the question of sterilising eye ointments, to give any degree of assurance against contamination, paraffins and other oils must be heated to a temperature which would destroy the majority of the active ingredients. The best that can be done, therefore, is a compromise whereby the active material is incorporated into previously sterilised base and filled into sterilised recipients under conditions which are designed to reduce the risk of contamination as much as possible. This is the method in the British Pharmaceutical Codex. Apart from spores, very few organisms remain viable in paraffin for a long period. It is notoriously difficult to test oils for sterility, and it would be interesting to know what techniques were used at Mr. Crompton’s hospital and what organisms were found. The juxtaposition of his paragraphs suggests that the contaminant might have been Pseudomonas pyocyanea, which would be rather surprising. As the matter is of considerable pharmaceutical importance, it is unfortunate that no publication is quoted. Whilst no-one would dispute the importance of avoiding
Adding together the last two rows of the above table, were 954 pregnancies without antibiotics being prescribed. Of these, the pregnancy wastage (abortions, non-malformed stillbirths, malformations, and recorded neonatal deaths) was 137 (14-4%), whilst in 50 pregnancies with antibiotics prescribed the wastage was 13 (26-0%). This difference is just statistically significant at the 5% level. Comparing the malformation-rates in the two groups, 2-4% and 8-0% (4 cases) respectively, no significant difference was found. This was the largest accurately documented retrospective series which we were able to amass. A much larger series would be needed to put Dr. Carter and Dr. Wilson’s theory to the test. A complicating factor in evaluating the figures was the borderline nature of some of the reported malformations. An interesting incidental finding was the low abortionrate (2-4%) among the 331 patients requiring treatment
there
"
"
299
for vomiting of pregnancy compared with the abortionrate (10-2%) for the 954 patients where no such treatment was given. This difference is highly significant (p < 0-001) and confirms the observation of Medalie,l who found a significant inverse relationship between nausea and vomiting and abortion. . ----- ----g
--"
Felsted, Essex.
P. A. WALFORD.
MUTATION, AUTOIMMUNITY, AND AGEING SIR,-Dr. Comfort (July 20) fears there is an "... over mutational immunological ageing..." because in most recognised autoimmune diseases there is female preponderance; women, however, age rather more slowly than men. Dr. Comfort believes that a recent discussion2 of the setiology of rheumatoid arthritis supports his doubts, but a subsequent paper3 might appear to reinforce them very substantially. To take an extreme example (Hashimoto’s thyroiditis) from the later paper, the sex-ratio, F/M, is between 10 and 20. Although this and other evidence3 is most unpropitious, I wish to suggest that it does not necessarily negate autoimmune hypotheses of ageing. Consider firstly three possible origins of sex-differences in disturbed-tolerance autoimmunity:
impasse
examples (figs. 1 and 2) will suffice xtiological diversity.
to
illustrate the
These mortality statistics for chronic rheumatic heart-disease and arteriosclerosis share one significant property. Over most of adult life, age- and sex-specific mortality-rates are closely proportional to a constant power of age. These striking characteristics are found in certain other cardiovascular diseases (International Abridged List 1955: B22, B27, B28, B29, and A85); and also in many cancers,6 but not, for example, in nephritis and nephrosis. Various models have been proposed to account for a power-law relationship in the context of carcinogenesis 6-12; they are all stochastic, and they all require that at least two random events (somatic mutations of some kind) should be involved in the aetiology. This kind of hypothesis, requiring only a few random events, seems reasonable in connection with carcinogenesis, because we know that a single transplanted cancer cell can propagate a tumour in a suitable host animal. Multifocal tumours can also be accounted for.13 In cardiovascular disease enormous numbers of cells, in different parts of the body, are affected simultaneously and it is not immediately obvious how a few somatic mutations could bring this about. Burnet’s forbidden-clone hypothesis4 provides an answer. One or a small number of somatic mutations in a stem-cell could well give rise to a clone of forbidden lymphocytes containing (and maintaining) a very large number of cells. Clonal growth gives the magnification for translating one or a small number of discrete events into a widespread systemic pathology. This is the essence of the interpretation suggested for several disturbed-tolerance autoimmune diseases 23 and it could also provide the basis of the aetiology of various cardiovascular diseases.
1. Sex-ratio of carriers at birth.-In rheumatoid arthritis this appears to be unity, or very close to unity.2 Where some autoimmune diseases3 are concerned, the ratio F/M is, however, much greater than 1. ’If inherited rare dominant alleles 3 on the X-chromosome can constitute predisposing factors,3 6. Armitage, P., Doll, R. Brit. J. Cancer, 1954, 8, 1. 7. Muller, H. J. Sci. Progr. 1951, 7, 130. then the theoretical ratio of carriers at birth-proportion of 8. Fisher, J. C., Holloman, J. H. Cancer, 1951, 4, 916. n is a of be where males-should 9. Nordling, C. O. Nord. Med. 1952, 47, 817. 2n, females/proportion 10. Stocks, P. Brit. J. Cancer, 1953, 7, 407. positive integer. In Hashimoto’s thyroiditis, n may be as high 11. Armitage, P., Doll, R. ibid. 1957, 11, 161. as 4. (For a common dominant allele on the X-chromosome12. Fisher, J. C. Nature, Lond. 1958, 181, 651. Burch, P. R. J. ibid. 1962, 195, 241. say Xl-and with equal selection_pressures against homozygous 13. 14. World Health Organisation. Annual Epidemiological and Vital Statistics, females X,/X, and X2/X2, the sex-ratio of carriers at birth will 1956. Geneva. 1959. not be 2 but 3/2.) I have so far found no example of (presumed) autoimmunity where the sex-ratio (F/M) of carriers is significantly less than unity, and it seems that the cause of the slower ageing in women should be sought elsewhere. 2. Somatic mutation.-In analysing the xtiology of rheumatoid arthritis, it was argued that the rate of arthritogenic somatic gene-mutation is about twice as high in women as in mer.. Although in some other autoimmune diseases the rate of somatic mutation in males and females can be equal3 (when only autosomal genes are implicated), no example has so far been found where it can be said to be significantly lower in women than in men. 3. Defence against "forbidden clones ". 4-In inflammatory polyarthritis of Manchester clinical grades 3 and 4, the age-specific prevalence below the 5 age of 50 is probably lower in women than in men 2 although above 50 the situation is undoubtedly reversed. It was argued that more forbidden clones are usually required to produce a given clinical grade of polyarthritis in women than in men--a consequence, it was suggested, of the possession by females of a more effective natural defence mechanism against forbidden clones. Should this interpretation be valid-and it is supported by much indirect evidence 2-it gets round Dr. Comfort’s impasse. Fig. 1-Log-log graph of age- and It is interesting to consider briefly one of the sex - specific mortality - rates, most
serious and
important manifestations of
ageing-cardiovascular disease. Two contrasted 1. 2. 3. 4.
5.
Medalie, J. H. Lancet, 1957, ii, 117. Burch, P. R. J. ibid. 1963, i, 1253. Burch, P. R. J., Rowell, N. R. ibid. 1963. In the
chronic rheumatic heart-diseases (B 25), England and Wales, 1956.1a 0: Females, X: Males. Points plotted at centre of 5-year agegroup.
press.
Burnet, F. M. The Clonal Selection Theory of Acquired Immunity. London, 1959. Lawrence, J. S. Ann. rheum. Dis. 1961, 20, 11.
Fig. 2-Log-log graph of age- and sex-specific mortality-rates, arteriosclerotic and degenerative heart-disease (B 26), England and Wales, 1956.’* 0: Females,X : Males. Points plotted at centre of 5-year age-group.