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Contraception and HealthIN 1968, two major prospective investigations of

the influence of oral contraceptives on the health ofwomen were started in Britain. The Royal Collegeof General Practitioners (R.C.G.P.) published an in-terim report of their study involving 46 000 womenin 1974.1 VESSEY and his colleagues2 have nowsummarised their findings in a group of over17 000 women attending Family Planning Associ-ation clinics. Despite differences in the design ofthe investigations the findings are strikingly simi-lar, and in general confirm the results of previousretrospective work. VESSEY et al. compared thehospital referral-rates of groups of women usingoral contraceptives, the diaphragm, or an intra-uterine device (I.U.D.). Their analysis was limited tothree cohorts defined by contraceptive practice atentry to the study, but the mean proportion ofwoman years during which the women adhered totheir initial contraceptive practice was high, rang-ing from 70% to 84%. Any changes in contracep-tive practice would have diminished differencesbetween the experiences of the three groups. Oral-contraceptive users showed an excess of hospitalreferrals for cerebrovascular disease, cervical ero-sion, and venous thrombosis and embolism but adeficiency of referrals for benign lesions of the

breast, cancer, and menstrual disorders other thanamenorrhoea. Women who used a diaphragm werereferred more often for haemorrhoids and less oftenfor dysplasia and carcinoma-in-situ of the cervix.Women who used an i.u.D. showed increased refer-ral-rates for anaemia, varicose veins, and salp-ingitis.Of particular interest to the prospective user is

fertility when contraception is stopped. TheR.C.G.P. study reported conception rates in 2291women who stopped the pill with a view to becom-ing pregnant. 7% and 15% of parous and nulli-parous women, respectively, had failed to conceiveat the end of 2 years. Although control data for thisstudy were not available, the figures were reassur-ing in that about 10% of couples in the generalpopulation are generally believed to be infertile.

Analysis of conception-rates by month after the endof oral contraception showed a rise up to the thirdmonth, followed by a fall. Subsequent peaks in themonthly conception-rate occurred at 7 and 10

months, but these may have been fortuitous.VESSEY et al. studied delivery-rates, including bothlivebirths and stillbirths, in a group of 3404 womenwho abandoned birth control with a view to preg-nancy. In the early part of the study, delivery-rateswere clearly lower in women who had used oralcontraceptives than in those who stopped other

1. Royal College of General Practitioners. Oral Contraceptives and Health.London, 1974.

2. Vessey, M., Doll, R., Peto, R., Johnson, B., Wiggins, P. J. biosoc. Sci. 1976,8, 373.

3. Evrard, J. R., Buxton, B. H., Erickson, D. Am. J. Obstet. Gynec. 1976, 124,88.

methods of contraception. The difference betweenthe groups lessened with time and was not apparentin parous women 30 months after contraceptionwas discontinued. At this stage, however, 16% ofnulliparous previous oral-contraceptive users hadfailed to deliver; the corresponding figure for thenulliparous previous oral-contraceptive users werestill childless; the corresponding figure for the nul-liparous group who had used other contraceptivemethods was only 11%. Neither study showed anyclearcut effect of the duration of oral contraceptivemedication on subsequent fertility.

In summary, both studies suggest that fertility isimpaired in the early months after oral-contracep-tive medication. While this impairment is tempor-ary in parous women, doubt remains about sub-sequent fertility in a small proportion of

nulliparous women. This should be resolved byfurther work. The cause of the impaired fertility isnot clear. It seems unlikely that nulliparous womenwho elected to use oral contraceptives were less fer-tile than those using physical methods. Post-pillamenorrhoea (P.P.A.), defined as absence of mensesfor 6 months or more after oral contraceptive medi-cation, occurs in 2-3% of users.3 4 But the inci-dence of amenorrhoea in women using alternativecontraceptive measures is unknown. A fewwomen have also had galactorrhoea and raised ser-um-prolactin concentrations.5 Other factors associ-ated with P.P.A. include a previous history of oligo-menorrhoea and late onset of the menarche. In a

prospective study3 of 326 nulliparous women, only11 % failed to menstruate within 2 months of stop-ping the pill. By 3 months, this figure had fallen to7% and eventually all women menstruated, the lon-gest period of amenorrhoea being 18 months.VESSEY et al., however, observed delivery-rates of55% and 31% in their nulliparous women 12months after stopping physical and oral methods ofcontraception, respectively. Clearly, this differenceis unlikely to be wholly due to an increased inci-dence of amenorrhoea in the post-oral-contracep-tive group. Contraceptive steroids suppress boththe uterine endometrium and the hypothalamic/pi-tuitary/gonadal axis and it is hardly surprising thatthe sophisticated control systems responsible forovulation, fertilisation, and implantation need timeto recover.

With regard to the outcome of pregnancies aftercontraception, both the R.C.G.P. studies’ andthat ofVESSEY et al.2 are reassuring. In particular,previous oral-contraceptive medication does not

seem to affect the incidence of multiple pregnan-cies, congenital malformations, stillbirths, miscar-riages, ectopic gestation, nor the sex ratio or birth-weight of infants. Prospective studies, however,

4. Br. med. J. 1976, i, 660.5. Tyson, J. E., Andreasson, B., Huth, J., Smith, B., Zacur, H. Obstet. Gynec.

1975, 46, 1.6. Royal College of General Practitioners’ Oral Contraception Study, Br. J.

Obstet. Gynæc. 1976, 83, 608.

943

require collection of large amounts of data to detectdifferences in the occurrence of rare events in twoor more groups. Retrospective case/control analy-ses, although more open to bias, can provide ananswer to a specific question with fewer subjects.Several studies of this type have suggested that ad-ministration of sex steroids during early pregnancymay exert a teratogenic effect. 8 While neither ofthe British prospective studies has accumulated

enough cases of each of the major types of congeni-tal malformation to confirm or deny these reports,it does seem that the delayed return of fertility fol-lowing oral-contraceptive use may offer some

advantage to the fetus. In the case of unplannedpregnancies, VESSEY et al. observed high rates ofmiscarriage (56%) and ectopic gestation (9%) inwomen using an 1-U.D.The failure-rate of a contraceptive depends both

on the efficiency of the method and on the reliabi-lity of the subject, but the contribution of each fac-tor is difficult to determine except in the case of theLU.D. The diaphragm or the sheath, in well-moti-vated couples, may have lower failure-rates thanthose usually reported from large-scale studies. Ex-perience during the past 20 years has consistentlyshown that combined oral contraceptives offer themost effective method of reversible contraception.Unfortunately they produce in the user a wide var-iety of biochemical changes which are not neces-sary for contraception. The long-term conse-

quences of these changes on the health of the userare unknown and indeed may only become appar-ent later in life, perhaps many years after exposure.For this reason alone, it is to be hoped that thewell-organised studies of the R.C.G.P. and ofVESSEY and his colleagues will continue.

IMMUNOLOGICAL TOLERANCE TO TREATPENICILLIN ALLERGY?

PENIcILLIN, though among the least toxic of drugs,causes allergy in up to 10% of patients. The benzyl peni-cilloyl (s.P.o.) hapten is the antigenic determinant re-sponsible for most cases of immediate hypersensitivity’IgE-mediated allergy) to the drug.9 Two groups in theUnited States have lately reported that animals can bemade specifically tolerant to the B.P.o. determinant, sothat they become unable to produce significant amountsof anti-B.p.o. antibodies of either IgE or IgG class.These experiments follow from earlier observations thathaptenic determinants, when coupled to certain non-immunogenic carrier molecules, not only fail to elicit

antibody but tend instead to produce specific immunolo-gical tolerance."The two research groups, both working with mice,

7 Janerich, D T., Piper, J. M., Glebatis, D. M. New Engl. J. Med. 1974, 291,697

8 Nora, J J , Nora, A. H. Lancet, 1973, i, 941.9 Parker, C. W., Shapiro, J., Kern, M., Eisen, H N. J exp. Med. 1962, 115,

82110 Katz, D H , Davie, J M , Paul, W. E , Benacerraf, B. ibid. 1971, 134, 201.

chose different non-immunogenic carrier molecules.Katz and his colleagues" coupled the B.P.o. hapten toa synthetic random polymer of D-glutamic acid andD-lysine, whereas Borel and his co-workersl2 used mouseimmunoglobulin itself as a non-immunogenic carrier.Both groups recorded specific and long-lasting toleranceto the B.P.o. determinant in previously unsensitised miceafter injection of hapten/carrier conjugates. Further-more, when these conjugates were injected into animalsalready sensitised to the B.P.o. determinant, no freshanti-B.P.o. antibodies were elicited and the previouslyactive antibody-producing mechanism seemed to beswitched off. This tolerance was specifically directed tothe B.P.o. hapten, leaving other antibody responses in-tact. Tolerance induction in this system is not fully un-derstood. It is perhaps relevant that the carrier mole-cules tend to be poorly recognised by the host, so thatthe hapten is allowed to persist in contact with the sur-faces of B lymphocytes responsible for anti-s.P.o. anti-body production. This prolonged contact may interferewith B-cell activation and subsequent antibody elabo-oration. 13The eventual aim of this work is to produce tolerance

to the B.P.o. determinant in penicillin-sensitive humanbeings. Progress will necessarily be slow, because of thedanger that, in sensitised allergic patients, administra-tion of hapten/carrier conjugates may precipitate acuteanaphylactic reactions. In mice, mast-cell degranulationand anaphylaxis seem most likely when B.p.o. hapten/carrier conjugates are given intravenously; subcu-taneous injection seems safe, although it would be fool-ish to assume that the same will apply to man. Neverthe-less, the research carries promise of important thera-peutic advances, not only in penicillin allergy but also inother situations where antibodies are harmful. The diffi-

culty will be in defining antigens with the chemical pre-cision necessary to make clean hapten/carrier conjuga-tes-the B.p.o. determinant of penicillin is at presentone of a very few clinically relevant allergens withknown chemical structure. These demonstrations of spe-cific B-cell tolerance to that important hapten ought per-haps to prompt more effort towards the purification andidentification of naturally occurring allergens.

ACRYLIC CEMENT FOR PATHOLOGICALFRACTURES

IN patients with pathological fractures of long bonesdue to metastatic carcinomatous deposits the main

objectives of treatment are to relieve pain and to restoremobility as quickly as possible, thus keeping up morale.40% of these patients survive for six months and 30% fora year or more.14 The management of these fractures is

essentially surgical (often supplemented by radio-

therapy), and if at all feasible an attempt is made tosecure the fracture by some internal fixation device suchas an intramedullary nail, pin and plate, or femoral-head prosthesis. Indeed, with careful outpatient super-

11 Chiorazzi, N., Eshhar, Z., Katz, D. H. Proc. natn. Acad. Sci. 1976, 73,2091.

12. Borel, Y., Kilham, L., Hyslop, N., Borel, H. Nature, 1976, 261, 50.13 Ault, K A., Unanue, E. R., Katz, D H., Benacerraf, B. Proc. natn. Acad.

Sci. 1974, 71, 311114. Marcove, R. C., Yang, D. J. Cancer, 1967, 20, 2154.