1024

SIR,-Your issue of Oct. 8 contained two epidemiological studies recording a higher mortality-rate from heart and circulation disorders among oral-contraceptive users than among non-users. Higher mortality-rates were observed among older women, heavy smokers, and/or those who had taken the pill for more than 5 years. The conclusion was that women over 35 should consider alternative forms of contraception, a suggestion supported by the presidents of the Royal College of Obstetricians and Gynxcologists and the Royal College of General Practitioners and, editorially, by The Lancet and the British M:’ca/yoMr7:a/. This seems to us a subjective interpretation of the findings. The data, especially those from the R.C.G.P., are difficult to understand. It is not clear what is hidden in the standardised values based on 100 000 women-years. Data from a few women followed up for a long time result in the same standardised rate for 100 000 women-years as the data of many women followed up for a shorter period. The rates therefore cannot be traced back to the original data, and they allow only an incomplete retrieval of the basic information. Epidemiological studies, whether prospective or retrospective, do not permit statements about causality. They can only point to differences between the observed groups. By self-selection, which is how the decision to use an oral contraceptive must be regarded, the ever-users are a special group who differ from the never-users, and not just in their methods of contraception. This is mentioned in the R.C.G.P. paper. In both studies the tables show that ever-users and never-users are differentiated by the frequency of carcinomas, accidents, suicide, and cigarette consumption. The ever-users comprise users and ex-users. For these subjects the risks for all circulation disorders show the same magnitude-namely, 26 8 and 23.9, respectively, compared with 5.5S deaths among never-users, in 100 000 women-years (table III in the R.C.G.P. article). In your editorial you refer to evidence that the carry-over effect of the pill after discontinuation lasts a few weeks only, and at most 3 months. It is reasonable, therefore, to assume that the excess mortality seen in ex-users is due to a different prognosis of circulatory disorders in the ever-user group compared with controls. This different prognosis is seen also in other conditions. Even if the pill causes hypertension, this cannot be the only explanation. Ex-users still had a higher mortality-rate from circulation disorders than never-users even when those with hypertension were excluded. This finding can be explained by an a priori difference in prognosis among ever-users. We are still of the opinion that the prescription of hormonal contraceptives must be carefully considered in every case and must be adjusted to suit individual needs. Medical Information, and Department of

Biometry and Statistics,

Schering AG,

KLAUS DETERING EDZARD HARTMANN

D-1 Berlin 65, West Germany

SIR,-The possible synergistic effect of smoking and oralcontraceptive use in premenopausal women is worrying. The extensive prospective study by the Royal College of General Practitioners provides a fine opportunity to investigate the relationship of age, smoking, and pill usage. The care with which the study was set up in terms of age-matching users and non-users

is to be commended.

some aspects of the data and would suggest that the data be scrutinised further. No attempt was made to assess level or duration of smoking (table iv). If synergism is real the length of time the two agents have to interact would be expected to be related directly to the increased risk of circulatory disorders. Also, the levels of smoking would tend to increase risk in the same direction. Other studies (e.g., Jain’s’) have implied such a dose-res-

We

are

concerned, however, with

handling,

1. Jain, A. K. Am. J. Obstet. Gynec. 1976, 126, 301.

ponse relation. No detailed account of the relationship between usage and smoking within age-groups was given (table v). The focus of current concern is the over-40 woman who uses oral contraceptives and smokes heavily; but the R.C.G.P. data do not relate to this critical question specifically, despite the recommendations from Dr Kuenssberg and Sir John Dewhurst (Oct. 8, p. 757).3 On the one hand, the handling of data under-

pill

differences between the heavy-smoking oral-conand non-smoking oral-contraceptive users over 40. Left unanswered, on the other hand, is the question of selfselection. Is it possible that the women who smoke and use oral contraceptives (particularly the older group) are simply reflective of a more flamboyant life style which may well include more stress, more alcohol, more medication (including "downers" and "uppers"), or marihuana use? Were those factors looked at and adjusted for in the data analysis? There seem to be nothing’in the data which would answer once and for all the questions-is it the smoker or the smoking which creates risk difference and is it the oral contraceptive user or oral-contraceptive use which is at the bottom of it all? Somehow epidemiological and laboratory studies must be designed to distinguish among the possible aetiologies. Let us not let preconceived ideas affect objectivity in examining the possible hypotheses. The mix of factors (including genetic) may be more complex than we think. Until these questions are resolved, however, we would not disagree with the recommendations of Kuenssberg and Dewhurst. states

the

vast

traceptive users

Division of Biometry, Tobacco & Health Research Institute,

University of Kentucky, Lexington, Kentucky 40506, U.S.A.

D. G. HAACK H. E. MCKEAN

SIR, The paper from the R.C.G.P. gives age-specific death-rates. It would be interesting to see how the observations of Professor Vessey and his colleagues compare with these rates, but they do not give years of exposure by age-groups so this cannot be done. I should like to see this extra information made available for comparative purposes. Division of Computing and Statistics, Clinical Research Centre, Harrow, Middlesex HA1 3UJ

I. D. HILL

THOMSEN FRIEDENREICH ANTIGEN IN HÆMOLYTIC-URÆMIC SYNDROME

SIR,-The haemolytic-urwmic syndrome’ is usually seen in infants and it is often fatal. Its cause is obscure. McCoy et aI.I found IgM deposits in the glomeruli, using a fluorescence technique, but they did not say how these immune complexes might be formed. We have investigated two cases and found some evidence for pathogenic factors. Two 1-year-old children died from pneumococcal pneumonia with sepsis. Both showed the typical course of hsemolytic-ursmic syndrome with hxmolytic anaemia and acute kidney failure. Necropsy revealed necrosis of the renal cortex and thrombosis of the glomerular arterioles and capillaries. Using an immunofluorescent technique we found Thomsen-Friedenreich (T.F.) antigen on erythrocytes and in the glomeruli. Fluorescein-labelled peanut agglutinin (Arachis hypogaea) has a high affinity for the T.F. antigen4 and is a useful marker for this normally neuraminic-acid-coated cryptantigen. We conclude that this antigen was exposed by pneumococcal neuraminidase. T.F. antigen has been demonstrated in formalin fixed and 1. Gasser, C., Gautier, E., Steck, A., Siebenmann, R. E., Oechslin, R. Schweiz, med. Wschr. 1955, 85, 905. 2. Mc Coy, R. C., Abramowsky, C. R., Krueger, R. J. Pediat. 1974, 85, 170. 3. Klein, P. J., Newman, R. A., Müller, P., Uhlenbruck, G. G., Lennartz, K. J., Fischer, R. Unpublished. 4. Uhlenbruck, G. G., Pardoe, G. I., Bird, G. W. G. Z. Immunforsch. 1969,

138, 423.

1025 HÆMOLYNC-URÆMIC SYNDROME IN DYSENTERY

SIR,-Dr Dickinson (Aug. 27, p. 463) describes hsemolytic

bacillary dysentery and concludes that the haemolysis probably due to disseminated intravascular coagulation (D.I.C.). Our experience with a similar patient pointed to haemolytic-uraemic syndrome rather than D.I.C. as an explanation of the haemolysis. A 17-year-old boy was admitted to hospital with bloody diarrhoea. He had only slight general abdominal tenderness. Proctoscopy revealed only mild punctuate erythema and lymphoid hyperplasia affecting the proximal rectum. Haemoglobin was 16.9 g/dl, haematocrit 46%, and white blood-cells anaemia in was

12 500/{jd

with

normal differential. Blood smears revealed and normal red-cell morphology. Urinalysis was normal and four stool cultures failed to grow pathogenic bacteria. Blood-urea-nitrogen (B.u.N.) was 12.4 mg/dl. Prothrombin and partial thromboplastin times were normal. Barium enema revealed a spastic large bowel with a mucosal pattern consistent with ulcerative colitis or intramural hminorrhage. The bloody diarrhoea subsided gradually and the patient was discharged 5 days after admission. 3 days after discharge he complained of severe headache and vomiting. 3 days later he was readmitted because of severe pallor. There was no history of haematemesis, dark or bloodstained stools, dark or reddish urine, or jaundice. Physical examination revealed only pallor and a small infarct in the was 7.3 g/dl, hxmatocrit right optic fundus. The 21%, reticulocyte-count 5-8%, and platelet-count 140000/1. The blood smear showed many fragmented red blood-cells and some spherocytes. The platelets were large and some were bizzare in shape. The bilirubin was 1.2 mg/dl, B.U.N. 26.4 mg/dl, creatinine 1.4 mg/dl, and haptoglobin less than 20 mg/dl (normal 100-300). Prothrombin and partial thromboplastin times were normal. Semiquantitative assay for fibrin-degradation products (F.D.P.) in serum revealed 10-20 fLg/ml (normal less than 10). Stool guaiac was negative. A moderate amount of blood was detected in the urine by ’Labstix’ and a few red blood-cells per high-power field were seen in the urine sediment. Over the next 5 days the B.U.N. fell to 15.6 mg/dl, the haemoglobin rose to 8.1g/dl with a reticulocyte-count of 17.6%, the platelets increased to 450000/[J, and no more blood was detected in the urine. The headaches and vomiting subsided and the patient was discharged after 5 days. His haemoglobin 6 days and 3 weeks after discharge was 10-9and 14.1g/dl, respectively. Red-cell morphology in the blood smear was normal 3 weeks after the patient’s discharge. Haemolytic-urEemic syndrome (H.u.s.) may develop after shigellosis’2 and the syndrome may, on presentation, mimic ulcerative colitis.3.4 Gastroenteritis is also a common antecedent illness in H.U.S..5 D.I.C. may be confused with H.U.S., though haemolysis is usually not as significant a problem as bleeding in D.I.C..6 Our patient had no bleeding problem and normal coagulation studies, as in earlier cases of H.u.s. with bloody diarrhoea.3.4 No bleeding problems are reported in Dickinson’s patients. Coagulation abnormalities are not common in H.u.s., but are found in almost all patients with D.I.C..6 The slight increase in F.D.P. and the raised B.U.N. in our patient and Dickinson’s case 2 also suggest the clinical picture of H.U.S. rather than D.I.C. We hope that further clinical observations, including coagulation studies, will allow distinction between these two pathoa

adequate platelets

Fig. I-Tissue section of kidney treated with fluoresceinlabelled peanut agglutinin. Selective linear fluorescence in the glomeruli of formalin fixed and paraffin embedded necropsy material from patient with h2emolytic urzmic syndrome.

haemoglobin

Fig. 2-Mechanism of haemotytic urtemic syndrome in infections with bacteria and viruses that produce neuraminidase. T.F. Thomsen-Friedenreich antigen. H.U.S. Hsemotytic urxmic syndrome. =

=

paraffin embedded kidney sections,3.5 and weak IgM deposits in the glomeruli, in both our patients was indicative of the reaction of this antigen with anti-T.F. antibodies. These antibodies are found in all human sera, regardless of blood type. Neuraminidase, produced by viruses and bacteria, may thus be of direct significance in the aetiology of at least some cases of hasmolytic-ursemic syndrome. Our work with peanut agglutinin as a marker for T.F. antigen and immunofluorescence testing confirms an earlier concept6which was based on clinical observations and animal experiments, and we have demonstrated, for the first time, T.F. antigen on human kidney tissue. When haemolytic uraemic system develops in a patient with pneumococcal infection three main cell systems (erythrocytes,8 platelets,9 and kidney) may be responsible for the blood coagulation disorder, especially thrombocytopenia, haemolysis, and acute renal failure, regularly demonstrable in this syndrome (fig. 2). In cases in which such a mechanism cannot be found at least the same tissues (i.e., erythrocyte membrane and the kidney glomeruli) must be damaged. P. J. KLEIN M. BULLA R. A. NEWMAN P. MÜLLER Pathologisches Institut, ImmunbiologischeAbteilung G. UHLENBRUCK der Inneren Klinik, H. E. SCHAEFER und Kinderklinik, G. KRUGER Universität Köln, 5 Köln41,WestGermany R. FISHER 5. Newman, R. A., Klein, P. J., Müller, P., Uhlenbruck, G. G., Lennartz, K. J., Fischer, R. Unpublished. 6. Fischer, K., Poschmann, A., Oster, H. Mschr.Kinderheilk. 1971, 119, 2. 7. Poschmann, A., Fischer, K.Med.Klin. 1974, 69, 1821. 8. Poulsen, M. P. E. Polyagglutinabilitet og T-Omdannelse. Copenhagen, 1961. 9 Glöckner, W. M., Kaulen, H. D., Uhlenbruck, G. G. Thrombos. Res. (in the press).

1. Chesney, R. W., Kaplan, B. S. J.Pediat, 1974, 84, 312. 2. Rahaman, M. M., Jamiul Alam, A. K. M., Islam, M.

R., Greenough, Lindenbaum, J. Johns Hopkins med. J. 1975, 136, 65. 3. Berman, W., Jr. J. Pediat. 1972, 81, 275. 4. Craner, G., Burdick, G. Am. J. dig. Dis. 1976, 21, 74. 5. Lieberman, E. J. Pediat. 1972, 80, 1. 6. Wintrobe, M. M. Clinical Hematology; p.1211. Philadelphia, 1974. 7. Wintrobe, M. M. ibid. p. 940.

W.

B.,