592

study. Inspection of the hospital notes of obstetricpatients, the source of many estimates, is particularlylikely to be unreliable since it will include only thosecases in which fetal products are specifically identifiedby macroscopic or microscopic examination. Yet it is

widely and probably correctly assumed that the majorityof spontaneous abortions occur in the earliest stagesof pregnancy, either during the luteal phase of thecycle in which fertilisation occurs, producing nointerruption in menstrual rhythm, or a week or twothereafter leading to -a short interruption which thewoman may recall as a delayed period but for whichshe is unlikely to seek medical advice. Roberts andLowe 8 lately made a courageous attempt to estimatethe true incidence of spontaneous abortion. Workingfrom a set of limiting assumptions on the number ofpotential fertilisations in women of reproductiveage, they concluded that not more than 22% of

conceptions actually reach maturity. The problemwith this highly plausible hypothesis is that of proof;but this difficulty is not insuperable. Although thereare no practical means, short of hysterectomy anddetailed morphological examination, for detectingthe preimplantation blastocyst, there are methodsfor detection shortly after implantation. Specificmeasurement of chorionic gonadotrophin (H.C.G.) inblood or urine by radioimmunoassay 9 presents theopportunity for identification of a pregnancy as littleas 7-9 days post-conception-substantially before thefirst missed period. Tests of this type are now avail-able in the U.K. and are of more than academic orsocial significance. For example, in a considerableproportion of couples presenting with infertility,careful examination of both partners reveals no ab-

normality. Is it possible that some of the women are"

early aborters " ? This is a question which can andshould be answered.

BETA-BLOCKADE WITHDRAWAL

REBOUND effects can follow abrupt withdrawal ofseveral types of medication, narcotics apart. Suddenwithdrawal of the antihypertensive drug clonidine,for example, may result in alarming hypertension.loWithdrawal of any central depressant drug may causeinsomnia, restlessness, or even hypomania, whilesudden cessation of fenfluramine may result in

depression some days later. 11 Although the mechanismsunderlying most of these reactions are unknown, theyemphasise the profound and sustained effect whichpotent drugs have upon physiological systems. In1969 Wilson et al. 12 noted that substitution of placebofor oxprenolol in a double-blind trial caused severeexacerbation of angina attacks in 6 of 18 patients.8. Roberts, C. J., Lowe, C. R. ibid. 1975, i, 498.9. Vaitukaitis, J. L., Braunstein, G. D., Ross, G. T. Am. J. Obstet.

Gynec. 1972, 113, 751.10. Hunyor, S. N., Hansson, L., Harrison, T. S., Hoobler, S. W.

Br. med. J. 1973, ii, 209.11. Oswald, I., Lewis, S. A., Dunleavy, D. L. F., Brezinova, V.,

Briggs, M. ibid. 1971, iii, 70.12. Wilson, D. F., Watson, O. F., Peel, J. S., Turner, A. S. ibid. 1969,

ii, 155.

Two years ago, two short reports 13, 14 suggested thatmyocardial infarction might occur after, and becausally related to, abrupt withdrawal of propranololtherapy; and there were later accounts of acute severemyocardial ischaemic episodes in similar circum-stances. 15. 16 A causal relation is difficult to provebecause propranolol was being used to treat anginapectoris in patients with coronary-artery disease-agroup who are, of course, at particular risk of suchacute complications. Miller et al.17 have now deter-mined the incidence of rebound effects in the courseof a controlled trial: propranolol and placebo werebeing compared in a double-blind crossover efficacystudy in 20 outpatients with stable angina pectorisand confirmed coronary-artery disease. During theperiod of propranolol treatment (160-320 mg daily)no patient had increased angina and there were nohospital admissions or deaths. The design of thetrial involved sudden cessation of propranolol, at theend of a preliminary dose-finding period and after

completion of 12 weeks’ active treatment in thecrossover part of the trial. 2 patients died, 1 patienthad an episode of ventricular tachycardia requiringdirect-current cardioversion, and 3 patients had

episodes of severe angina at rest within fourteen daysof propranolol withdrawal. This group of patientshad shown a significant response to propranololtreatment compared with placebo, in terms of fre-quency of anginal attacks, nitroglycerin use, andexercise tolerance. 4 further patients had an increaseof more than 50% in number of anginal attacks withinthis same 14-day period after propranolol withdrawal,and this small group, too, had shown a significantclinical response to propranolol. The remaining10 patients had little change in their angina afterpropranolol withdrawal, and it is noteworthy that

they had not shown any significant clinical responseto the drug. This carefully controlled study revealed,therefore, that patients with myocardial diseasetreated with moderate doses of propranolol are at

considerable risk of important ischaemic complicationsif the drug is withdrawn suddenly.The pharmacological mechanisms responsible for

this withdrawal syndrome are uncertain, but pro-pranolol improves exercise tolerance, and continuationat the previous activity level after withdrawal of thedrug may well be one factor. In keeping with this isthe observation of Miller and his colleagues that seriousadverse sequelx did not arise after abrupt withdrawalof high doses of propranolol in a large number ofcoronary patients who were in hospital for cardiaccatheterisation rather than ambulant outpatients.Furthermore, propranolol withdrawal must be followedby an increase in sympathetic drive upon the heart,leading to augmented cardiac contractibility and rate,so increasing myocardial oxygen requirements. Other

possible, but more controversial, mechanisms mightinvolve changes in platelet aggregation,18 in the renin/angiotensin system,19 and in the oxyhaemoglobin-13. Slome, R. Lancet, 1973, i, 156.14. Diaz, R. G., Somberg, J. C., Freeman, E., Levitt, B. ibid. p. 1068.15. Alderman, E. L., et al. Ann. intern. Med. 1974, 81, 625.16. Allen, R., Glenovese, B. ibid. 1975, 82, 431.17. Miller, R. R., Olson, H. G., Amsterdam, E. A., Mason, D. T.

New Engl. J. Med. 1975, 293, 416.18. Fishman, W. H., et al. Circulation, 1974, 50, 887.19. Bühler, F. R., et al. Am. J. Cardiol. 1973, 32, 511.

593

dissociation curve .20,21 Whatever the pharmacologicalbasis of this withdrawal phenomenon, the implicationsare clear. Propranolol should not be withdrawn

abruptly from patients with angina pectoris, particularlythose whose symptoms have been improved by it.

Probably this also applies to the other beta-adreno-ceptor-blocking drugs.

B.C.G. AT SCHOOL

THE risk of children being infected by tuberclebacilli in the United Kingdom is decreasing rapidly,halving every 5 years. The present policy of B.C.G.vaccination needs to be reviewed. A survey carriedout by the British Thoracic and Tuberculosis Associa-tion provides the necessary data.22 During 1973, 259persons aged 15-19 years were both notified as havingtuberculosis and had been eligible for the schoolB.C.G. vaccination scheme during the years 1966-71.During this period the total eligible population hadbeen 3-3 million. Of these, 2-6 million (79%) hadbeen tuberculin tested. 9% had been recorded tuber-culin-positive. (The proportion actually infected bytubercle bacilli was probably smaller since the criterionof positivity did not distinguish between tuberculousand other mycobacterial sensitisation.) Of the

tuberculin-negative children, 2-3 million (88%) hadbeen vaccinated. Thus, there was still considerablepublic support for B.C.G. vaccination during theseyears. The notification-rate per 100 000 was 12-9

among the tuberculin-negative unvaccinated and 2-7among the vaccinated. Thus, about 10 notificationsseem to have been prevented by vaccination. Furtheranalyses suggested that, allowing for the decliningrisk of infection, each 100 000 vaccinations during1966-71 would prevent 133 notifications during thenext 15 years. Put another way, to prevent 1 noti-fication required 750 13-year-old children to bevaccinated. And with the rapidly declining infectionrisk the number of vaccinations required will increase.Thus, in 1973, 1500 were required to prevent 1 noti-

fication ; in 1978, 3000 will be needed and in 1983,6000.

The report makes no recommendation about whenvaccination of school-children should be stopped.The decision is difficult. The benefits of any massprophylactic procedure can be considered under threeheadings 23-epidemiological, economic, and socio-

logical. As long as there is any risk of infection thereis certainly an epidemiological advantage from massB.C.G. vaccination. The cost of a vaccination

programme is not difficult to estimate; but it is

difficult, if not impossible, to estimate accurately thecost to the community of detecting and treating thetuberculosis that would have been prevented, togetherwith the loss of production due to absence from workand the social-security payments involved. The

sociological factors are not measurable at all-that is

20 Oski, F. A., et al. Science, 1972, 175, 1372.21. Brain, M. C., et al. Br. J. clin. Pharmac. 1974, 1, 67.22. British Thoracic and Tuberculosis Association, Tubercle, 1975, 56,

129.23. Waaler, H., Rouillon, A. Bull. Un. int. Tuberc. 1974, 49, 166.

to say, people’s anxiety about getting tuberculosis andtheir concern about the discomfort and inconvenienceto their children of vaccination. It is doubtful whetherthe decision can, in fact, be made on an entirelyrational basis.

In the U.K. tuberculosis is no longer feared. It is

widely known to be curable with little inconvenienceto the patient and it carries little, if any, social stigma.As it is encountered less and less, the desire for

protection will disappear. Perhaps the best indicatorof when to stop mass B.c.G. vaccination is the responseof parents to the offer to vaccinate their children,rather than the epidemiological and economic con-siderations. Meanwhile, people should be told aboutthe rapidly declining risk and the diminishing benefitto be expected from vaccination. Mass B.c.G. vaccina-tion has played its part in controlling tuberculosis inthe U.K. It can now be allowed to quietly disappear.

THE BILLOWING MITRAL VALVE

EARLY reports 1,2 of mid-systolic sounds correctlysuggested that these were of mitral origin. This

theory lapsed for a long spell in which they were, regarded as extra-cardiac, perhaps pericardial. ThenReid 3 revived it, attributing the mid-systolic clickto abrupt tensioning of the chordx, and the late-

systolic murmur to regurgitation through the valve.The click and the murmur may vary with the

patient’s position, the click moving towards the firstheart-sound when the patient is sitting or standing,and away from it when the patient squats or lies down;the murmur correspondingly becomes longer or

shorter. In addition to these clinical features theremay be electrocardiographic abnormalities, even inthe absence of coronary-artery atheroma. Charac-

teristically the changes are in the ST segment and Twaves, usually in leads II, III, aVF, and V 6.4 Someworkers 5see this as a syndrome particularly affectingyoung women. A small number of patients havediffuse T-wave abnormalities.* Left-ventricular cine-

angiography displays billowing of the mitral valve,usually the posterior leaflet, and the associated re-

gurgitation. .6.7Of the numerous causes for these abnormal findings,

paramount are: connective-tissue disorders such asMarfan syndrome, Turner syndrome, and myxomatousdegeneration of the chordae, rheumatic disorders

(whether as an isolated late sequel or associated withchronic rheumatic mitral-valve disease); congenitaldisorders as in atrial septal (secundum) defect or

ostium-primum defect, persistent ductus arteriosus,or the Eisenmenger syndrome; familial cardiomyo-

1. Cuffer, Barbillion. Arch. gén. Méd. 1887, 1, 129.2. Potain, P. C. E, Sem. méd., Paris, 1900, 20, 175.3. Reid, J. V. O. S. Afr. med. J. 1961, 35, 353.4. Pocock, W. A., Barlow, J. B. Am. J. Med. 1971, 51, 731.5. Rizzon, P., Biasco, G., Brindicci, G., Mauro, F. Br. Heart J.

1973, 35, 245.6. Barlow, J. B., Pocock, W. A., Marchand, P., Denny, M. Am. Heart J.

1963, 66, 443.7. Stannard, M., Sloman, J. G., Hare, W. S. C., Goble, A. J. Br. med.J.

1967, iii, 71.