ORAL CONTRACEPTIVES AND BREAST CANCER

97

reported in women who conceive while taking ACE inhibitors but stop the drug when pregnancy is diagnosed. In our case liquor volume improved from "virtually no liquor" to "normal liquor volume" when the ACE inhibitor was replaced by labetalol. After delivery anuria was not a problem, but severe respiratory failure with hypoplastic lungs was. The fact that oligohydramnios/neonatal anuria has been reported only when the mother was taking an ACE inhibitor at the time of fetal death or delivery may be paralleled by study of Robillard et al of the harmful effects of captopril on fetal and neonatal renal function in animals.6 This complication is not inevitable but it has appeared in a proportion of reports on ACE inhibitor therapy in mid-pregnancy. This is not evidence of causality, but it would appear prudent to avoid the use of these agents in pregnancy. Department of Obstetrics and Gynaecology, University Hospital, Queen’s Medical Centre, Nottingham NG7 2UH

F. BROUGHTON PIPKIN P. N. BAKER E. M. SYMONDS

Guignard JP, Burgener F, Calame A. Persistent anuria in a neonate: a side-effect of captopnl? Int J Pediatr Nephrol 1981; 2: 133. 2. Boutroy M-J, Vert P, Hurault de Ligny B, Milton A. Captopril administration in pregnancy impairs fetal angiotensin converting enzyme activity and neonatal adaptation. Lancet 1984; ii: 935-36. 3. Plouin PE, Tchobroutsky C. Inhibition de l’enzyme de conversion de l’angiotensine au 1.

de la grossesse humaine. Presse Méd 1985; 14: 2175-78. 4. Knott PD, Thorpe SS, Lamont CAR. Congential renal dysgenesis possibly due to captopril. Lancet 1989; i: 451. 5. Schubiger G, Flury G, Nussberger J. Enalapril for pregnancy-induced hypertension: acute renal failure in a neonate. Ann Intern Med 1988; 108: 215-16. 6. Robillard JE, Nakamura K, Matherne P, et al. Renal hemodynamics and functional adjustments to postnatal life. Sem Perinatol 1988; 12: 143-50. cours

TREATMENT OF CHRONIC PROCTOSIGMOIDITIS WITH CYCLOSPORIN ENEMAS

SIR,-Our fmdings are similar to those of Dr Brynskov and colleagues (April 1, p 721) who used cyclosporin retention enemas successfully in eight patients with refractory distal ulcerative colitis. We have used topical cyclosporin in six patients with chronically active idiopathic proctosigmoiditis unresponsive to conventional therapy. 6-10 months previously three of them had had an ileostomy and subtotal colectomy, sigmoidorectal remnant being brought to the surface to form a mucous fistula, because of severe ulcerative colitis requiring emergency surgery (to be followed, if possible, by ileorectal anastomosis). Active disease of the rectosigmoid stump persisted despite topical treatment with betamethasone 2 mg and/or mesalazine (5-aminosalicylic acid) 1 -5 g in 100 ml water twice a day. The other three patients had chronic active proctosigmoiditis despite treatment for more than 6 months with oral sulphasalazine 3 g/daily and topical corticosteroids and/or mesalazine as above. In all the patients the disease was severe on endoscopic and histological criteria. All six patients continued the previous treatment for a further month except that cyclosporin was added to the enemas. In three patients cyclosporin (Sandoz oral solution) was added to the enemas at doses of 2-5 mg/kg, and the mixture vigorously shaken; in the other three patients intravenous solution was added at doses of 0-75 routine blood tests (including

mg/kg. Clinical assessment, drug blood levels), and

sigmoidoscopy with rectal biopsy were done before treatment and after 10, 20, and 30 days of treatment. One

patient with

intravenous solution

a

rectosigmoid stump (treated with the enemas) and two not previously

as

colectomised (one given the intravenous and the other the oral cyclosporin solution as enemas) progressively improved clinically at endoscopy, and histologically at the end of treatment were in complete remission. In the first patient ileorectal anastomosis could be done as planned. All three patients suspended topical treatment and are still in remission after 5, 5, and 6 months. No changes were seen in the other three patients. As in Brynskov’s patients, cyclosporin blood levels (Sandoz radioimmunoassay) were less than 60 ng/ml, with one exception (100 ng/ml). No side-effects were noted. The fact that three of six patients with proctosigmoiditis of more than 6 months’ duration unresponsive to full-dose conventional

therapy

achieved complete and persistent remission after topical cydosporin was added for a month, strongly suggests that topical

cyclosporin has a role in the management of such patients. The efficacy, absorption, and tolerability of cyclosporin enemas that we observed are similar to the experiences of Brynskov et al, even though the enema composition was different and the doses were much smaller and administered twice daily. TULLIO RANZI MARIA CRISTINA CAMPANINI PIETRO VELIO Department of Special Medical Pathology III, FILIPPO QUARTO DI PALO of University Milan, PAOLO BIANCHI 20122 Milan, Italy

ORAL CONTRACEPTIVES AND BREAST CANCER

SIR,-From the UK Case-Control Study Group’s data (May 6, p 973) it would seem that a combined oral contraceptive (OC) with 50 Ilg ethinyl oestradiol (or equivalent) will increase the incidence of breast cancer in young women in proportion to the length of exposure. This could be a consequence of accelerated promotion of

already initiated cancers and therefore would not affect the overall long-term incidence. From various national cancer registration data there is no evidence of an overall increase in breast cancer incidence in relation to OC use, despite many millions of women having been

exposed to OCs since

1964.

interested in the possible protective effect of OCs against breast cancer. There is evidence to indicate that oestrogen is a promoter of initiated breast cancers’-3 and that this mechanism may be opposed by progestins, the basis of the "opposed oestrogen" hypothesis.4,5 The study group’s results seem to support this hypothesis. They find a high frequency of breast carcinoma for women on high oestrogen OCs, a modest or no increase for combined low oestrogen OCs (eg, relative risk of 1-04 for 30 289 women-months on 30 Itg ethinyl oestradiol combined with levonorgestrel), and significant protection for those on progesterone-only pills, which is described as "unexpected". This raises the interesting idea that it would be possible to design an OC to prevent breast cancer and hence provide valid data on OCs and breast cancer in randomised trials. In the meantime it would seem likely that OCs with a low dose of ethinyl oestradiol combined with levonorgestrel (’Eugynon 30’, ’Ovran 30’, ’Microgynon 30’, ’Ovranette’) carry little or no risk of promotion of breast cancer and women on these OCs should continue to take them. I

am more

Division of Medicine, Royal Marsden Hospital, Sutton, Surrey SM2 5PT

TREVOR J. POWLES

1. Millar AB, Bulbrook RD. The epidemiology and etiology of breast cancers. N Engl J Med 1980; 303: 1246-48. 2. Jordan VC. Comparative anti-oestrogen action in experimental breast cancers. Adv Exp Med Biol 1981; 138: 165-78. 3. Cusick J, Wang DY, Bulbrook RD. The prevention of breast cancers. Lancet 1986; i: 83-86. 4. Mauvais-Jarvis P, Sitruk-Ware R, Kuttenn F. Luteal phase defect and breast cancer genesis. Breast Cancer Res Treat 1982; 2: 139-50. 5. Mauvais-Jarvis P, Kutterin F, Gompel A. Anti-oestrogen action of progesterone in breast tissue. Breast Cancer Res Treat 1986; 8: 179-87.

This letter has been shown to Mrs Chilvers and colleagues, reply, on behalf of the Study Group to it and to previous correspondence, follows.-ED. L. SIR,-In the group of letters (June 3, pp 1257-58) in reply to our report, Dr Stadel and his colleagues regret that our study was limited to breast cancer diagnosed before age 36. We chose that limit to explore the hypothesis that an increased risk of breast cancer is associated with oral contraceptive (OC) use either at young ages or before first full-term pregnancy. Only women under 36 would have had the opportunity to use OCs when very young. Earlier studies had shown that use of OCs during the middle reproductive years alone does not increase the risk of breast cancer. The important issue is whether the increased risk that we observe persists as the cohort ages. Our current study of women aged 36-45 should help to answer this question. Stadel et al argue that future studies should include women aged up to age 64 years. Their table in suggests otherwise. Only 13% of control women aged 45-54 had used OCs for 8 or more years and in the UK the number might be smaller due to the slightly later introduction of OCs here. Women older than 55 whose

98 would contribute little to such a study. The possibility of an effect of early use can only be examined by studying the cohort now aged about 40 as it grows older. If the effect seen in our study was one of promotion, we would still expect to find some evidence of a rise in incidence of breast cancer among young women, with a corresponding deficit as the cohort ages and ultimately no change in lifetime risk. We expressed our reservations about the interpretation of registration data, as touched on by Dr Le Fanu. The data presented by Dr Caygill and Dr Hill unfortunately do not help us to resolve the apparent inconsistency between the English and Welsh data and that from two registries chosen for the completeness of their registration. Dr Powles suggests that OCs containing 30 ag ethinyl oestradiol and levonorgestrel (used for over 30 000 woman-months in our study) should be recommended. The relative risk for these oral contraceptives is about 1 ’04 per year of use-ie, no different from all other OCs containing less than 50 ug oestrogen (our table v), but significantly less than that associated with OCs containing 50 ug oestrogen or more. We took pains to point out that the protective effect of progestogen-only pills, although statistically significant, is based on small numbers; only 14 cases and 22 controls had used these OCs for more than 2 years. More data are required from other studies to confirm or refute this finding. Dr Clayton states correctly that the relative risk associated with a positive family history of breast cancer (relative risk 2-38) is higher than that associated with 97 or more months of oral contraceptive use (relative risk 1-74). All our relative risks were, however, adjusted for family history of breast cancer. Imperial Cancer Research Fund’s Epidemiology Unit, Oxford; Section of Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG; and Department of Community Medicine and General Practice, University of Oxford

CLAIR CHILVERS K. MCPHERSON J. PETO M. C. PIKE M. P. VESSEY

SEROLOGICAL TESTING

Assays: mumps, complement fixation; measles, fluorescent antibody; and rubella, single radial haemolysis. S soluble antigen and V viral antigen. =

=

sequencing, and a report has been submitted to the Committee on Safety of Medicines and to the manufacturers of the vaccine. Serum samples were examined during hospital stay and three months later (table). The response to the measles and rubella component of the vaccine was as expected, but antibody response to mumps was transient.

Mumps meningoencephalitis has been reported in three patients given MMR immunisation in Canada. Although MMR vaccine has been rarely associated with mumps meningoencephalitis (incidence 0-4 per million doses), a transient reaction to the measles component and occasional side-effects from the mumps component have been reported.2 General practitioners, paediatricians, and immunisation healthcare workers should be aware of the rare occurrence of mumps meningitis. We thank Dr I. F. this patient.

Davey for further details and follow-up samples from

Regional Infectious Diseases Unit and Regional Virus Laboratory, City Hospital, Edinburgh EH10 5SB

JAMES A. GRAY SHEILA M. BURNS

1. Azzopardi P. Mumps meningitis, possibly vaccine related. Ontario Canada Dis Weekly

Rep 1988; 14: 209-10. 2. Anon. Recommendations of the Immunization Practices MMWR 1989; 38: 388-400.

MUMPS MENINGITIS FOLLOWING MEASLES, MUMPS, AND RUBELLA IMMUNISATION

SIR,-We report mumps meningitis in a girl aged 3 years and 2 months following measles, mumps, and rubella (MMR) immunisation. The child was admitted with a day’s history of

lethargy, vomiting,

headache, dry cough, and fever. Her mother and 5-year-old sibling were well and there was no known contact with mumps, although the mother said there had been a possible case of mumps at the child’s nursery many weeks previously. The patient had received full diphtheria, tetanus, and whooping cough immunisation with oral poliomyelitis immunisation and, 21 days before her present illness began, she had received MMR immunisation (’Pluserix’). Her temperature was 38°C and she was drowsy, irritable, and had mild meningeal irritation. There were no other focal abnormalities and no detectable enlargement of the salivary or lymph glands. Lumbar puncture revealed clear cerebrospinal fluid (CSF) with white blood cells 267/111 (90% lymphocytes, 10% polymorphonuclear leucocytes) and red blood cells 6/jl. No bacteria were seen on gram staining of the centrifuged deposit. There was no growth on culture. CSF glucose was 3-4 mmol/1 (blood glucose 5-7 mmol/1) and CSF protein 54 mg/dl. With paracetamol treatment alone she recovered and was discharged after eight days.

eight days. CSF taken on the day of admission and nose and throat swabs obtained on the fifth day after admission were inoculated into baboon kidney and human fibroblasts (MRC5). Nose and throat swabs were also inoculated into HEP2 cells. Six days after

inoculation, haemadsorption of guineapig red cells to the baboon kidney cells was observed in the tubes that had been inoculated with CSF. Fluorescent antibody studies with rabbit polyclonal antiserum confirmed the virus to be mumps. No virus was recovered from the swabs but this may have been due to the timing of the sample. The virus has been sent to the National Institute for Biological Standards and Control, Hertfordshire, for nucleotide

Advisory Committee.

SCREENING FOR BACTERIURIA IN ELDERLY PEOPLE

SIR,-In reply to Professor MacLaren’s letter (June 17, p 1393) study (May 20, p 1117), I would make the following points.

on our

Unlike MacLaren’s letter the title of our report did not include the word "asymptomatic". As stated in the paper over one-third of the elderly people we studied had urinary symptoms, and the screening protocol we suggested was as effective for those with as it was for those without urinary symptoms. Elderly patients often present with non-specific symptoms and signs, and many clinicians will want to know if bacteriuria is present, even in the absence of urinary symptoms. Our screening protocol can give an immediate indication of whether or not the patient has bacteriuria. The treatment of asymptomatic bacteriuria in the elderly is an entirely different area of research and not one we attempted to address in the above study. Therefore we were not recommending screening for asymptomatic bacteriuria in the elderly but suggesting screening tests (to "screen out" negative samples) on urine samples that are obtained from elderly people on clinical indications. The benefits of this type of screening would be more rapid diagnosis of urinary infection, and a reduction in the workload of the bacteriology

laboratory. Department of Geriatric Medicine, Queen’s University of Belfast, Belfast BT9 7BL

P. G. FLANAGAN

SIR,-Whilst we agree with Professor MacLaren that the screening of elderly patients for asymptomatic bacteriuria is unjustified the true value of reagent strip testing for urinary tract infection (UTI) has not been stressed. Most elderly people with bacteriuria do not have pyrexia, leucocytosis, or symptoms ofUTI.1