644
Cervical Neoplasia and the Pill SINCE the epithelium of the cervix uteri’is a get tissue for steroid
sex
tar-
hormones, oral contracep-
tives are unlikely to be completely without effects upon the development of cervical carcinoma. It is therefore important to discover whether they operate for good or ill, and the magnitude of any demonstrable effect. The fact that massive use of the
.
The difference is significant, but based upon small numbers. No mention is made of any case progressing to invasion. The inference that the pill increases the chance of progression towards cancer is not, however, inescapable. The severity of dysplasia is defined by the extent of loss of surface maturation. Carcinoma-insitu, by definition, has none at all. Progestagens, as used in oral contraceptives, strikingly diminish epithelial maturation in the normal cervix, and this is shown in smears by a reduced karyopyknotic index. There is no reason why a similar effect should not occur in the supposedly precancerous states. Lesions with surface maturation are not necessarily any less precancerous than those without; indeed, invasive carcinoma is often well differentiated. Accordingly, the so-called conversion from dysplasia to carcinoma-in-situ need not mean much in terms of danger to life. Another explanation of the findings is based on the fact that the epithelial lesion, if extensive, usually shows considerable variation from place to place in the same cervix, with more squamous maturation distally, and less maturation further up in the endocervical canal. Since oral contraceptives tend to cause eversion of the endocervix, a small biopsy is more likely to hit an area of carcinoma-in-situ if the patient is on the pill. That progression from dysplasia towards invasive carcinoma is enhanced by contraceptive steroids is therefore only one of several explanations of the Los Angeles data, though still a perfectly plausible one. SINGER and JORDAN9 have tried to exonerate the pill, maintaining firstly, that there is no association between oral contraceptives and cervical atypias, and secondly, if there is, "the pill itself should not be blamed". The verdict may be appropriate according to the Law of England, but the rules of science require the accused to remain in the dock. Even if oral contraceptives do eventually turn out to cause a slightly enhanced risk of cervical carcinogenesis, there is still no need to panic. A cervical smear every 3 or 5 years will readily detect dysplasia or carcinoma-in-situ, which can then be eliminated without loss of cervical function. Carcinoma of the cervix is just as preventable in those who use the pill as in those who do not.
pill.
pill has been accompanied almost everywhere by falling death-rates for cervical cancer should not lead to complacency,’ since most of the women dying of cancer belong to much older age-groups than those consuming the pill. In 1969 a report from New York’ suggested that pill users had an increased prevalence of epithelial abnormalities classified as dysplasia and carcinoma-in-situ, compared with those using the diaphragm. Evaluation was complicated by the possibility of a protective effect of the diaphragm, as well as by the fact that the choice of contraceptives varies in groups of women according to factors that influence the likelihood of cervical carcinoma.2 Some other retrospective studies of matched groups showed no significant association,3,4 nor did a further prospective study from New York. There are numerous other inconclusive papers on this subject.6 Because women coming for contraceptive advice often know what they want, random allocation is no longer possible, but this was done in the original studies from Puerto Rico. Since the pill women and the controls - had frequent cervical smears, carcinoma of the cervix was presumably not allowed to develop, but limited data have been published7 on the changes in grading of smear reports over observation periods said to extend up to 8 years, and no deleterious effect of the pill was noted. ELIZABETH STERN and her colleagues in Los Angeles8 have now published the results of a large prospective study of women attending family-planning clinics between 1967 and 1971, to see whether existing cervical dysplasia tended to run a different course in women using oral contraceptive steroids. 300 cases of dysplasia were found, and followed up by means of repeated smears and annual small biopsies. The average age was 23. Dysplasia frequently regressed during the first six months of observation, and regression was slightly more frequent in pill users; but in those with persistent lesions an increase in severity, and progression to carcinoma-in-situ, was commoner in users of the 1. Melamed, M.
R., Koss, L. G., Flehinger, B. J., Kelisky, R. P., Dubrow, H. J. 1969, iii, 195. 2. Dubrow, H., Melamed, M. R., Flehinger, B. J., Kelisky, R. P., Koss, L. G. Obstet. Gynec. Survey, 1969, 24, 1012. 3. Worth, A. J., Boyes, D. A. J. Obstet. Gynec. Br. Commonw. 1972, 79, 673. 4. Thomas, D. B. Obstet. Gynec. 1972, 40, 508. 5. Melamed, M. R., Flehinger, B. J. Gynec. Oncol. 1973, 1, 290. Br. med.
6. I.A.R.C. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man: no. 6, Sex Hormones; p. 223. Lyon, 1974. 7. Fuertes-de la Haba, A., Pelegrina, L., Bangdiwala, I. S., Hernándes-Cibes, J. J. J. reprod. Med. 1973, 10, 3. 8. Stern, E., Forsythe, A. B., Youkeles, L., Coffelt, C. F., Science, 1977, 196, 1460.
SOME CONSEQUENCES OF BEING BORN TOO SOON OR BORN TOO SMALL deserves its reputation as the best infant in some pregnancies fetal nutrition falters but incubator, and the syndrome of placental insufficiency ensues. The result is a stillbirthor a light-for-dates infant (who faces such immediate dangers as perinatal asphyxia, meconium aspiration, and hypoglycsemia). Now that fetal health and growth can be monitored by biochemical and ultrasonic methods, placental insufficiency may THE
uterus
9. Singer, A.,
Jordan, J. A. Lancet, 1977, ii, 359.
645 be diagnosed in the third trimester giving the obstetrician an opportunity to intervene. But at what cost? The pre-term baby risks hyaline-membrane disease, infection, and perhaps disruption of mother/baby relationships. If a pregnancy is to be ended early then the benefits must unequivocally outweigh the disadvantages both in the neonatal period and more distantly. Which is better: to be born too soon (prematurely) or to be born too small (light for dates)? Drawing on data from the Newcastle upon Tyne Survey of Child Development, the late Gerald Neligan and his colleagues attempted to provide a long-term answer.’ They report on 387 children who were born to Newcastle mothers during 1960-62: 59 were of short gestation (less than 36 weeks), 141 light for dates (weight less than the 10th centile for gestational age), and 187 controls (term babies of appropriate weight). The two abnormal groups represent 10% of births then; mean birth-weights of the groups were 2415 g (short gestation) and 2537 g (light for dates). At ages 5, 6, and 7 years these children were assessed by conventional neurological, anthropometric, and psychometric methods and by reports on their behaviour from mothers, teachers, and psychiatrists. Care was taken to allow for distorting factors such as clinical abnormalities of pregnancy and labour, biological factors (sex and birth rank), and postnatal environmental influences such as social class. The conclusions are clear: the growth and performance of the short-gestation and the light-for-dates children were worse than those of the term children. Moreover, if the light-for-dates group is divided into rather light for dates (weight 5th to 10th centiles) and very light for dates (less than 5th centile) the degree of impairment of school-age performance was proportional to the severity of intrauterine growth retardation, since the scores of rather-light-for-dates children were intermediate between the very-light-for-dates and control children. The most crucial finding was that the overall attainment of the very-light-for-dates group was significantly worse than that of the short-gestation group-in other words, it is clearly better to be born too soon than too small. What is the import of these results today, when some of the study children will already have left school? The risks from being born prematurely are being reduced. Prenatal therapeutics may help (steroids to prevent hyaline membrane disease; phenobarbitone for jaundice) and neonatal intensive care has improved the survival of very-low-birth-weight infants without appreciably increasing handicap .2,3 Much remains to be done; even the choice of food for very small babies is still controversial.4,5 The major adverse influences on the light-fordates infant cease after birth and the benefits from improvement in neonatal care for this group will be marginal. Efforts must be directed towards early screening of all pregnancies for the risk baby6 and to the 1 Born too Soon or Born too Small (Clinics in Developmental Medicine no. 61). by G. A. NELIGAN, I. KOLVIN, D. SCOTT, and R. F. GARSIDE. 1976. 2 3
London: Heinemann. Philadelphia: Lippincott. Pp. 101. £4.50. Marriage, K. J, Davies, P. A. Archs Dis. Child., 1977, 52, 176. Stewart, A. L., Turcan, D. M., Rawlings, G. R., Reynolds, E. O.
R. ibid.
p. 97. Wald, N, Cuckle, H., Stirrat, G. M., Bennett, M. J., Turnbull, A. C. Lancet, 1977, ii, 268. 5. Fomon, S. J., Ziegler, E. E., Vazquez, H. D. Am. J. Dis. Child. 1977, 131,
4
463. 6
Davies, D. P. Archs Dis. Child. 1977, 52, 296.
prompt diagnosis of placental insufficiency by observing growth and placental function. When this happens, labour may be induced before serious growth failure occurs, or, more enticingly, intrauterine nutrition may be enhanced and the baby allowed to thrive in its natural incubator. These remedies are expensive, especially for a service whose funds are threatened. The Lancet has consistently warned7,8 against complacency about the results of British perinatal practice and we welcome the formation of the British Psediatric Perinatal Group to foster research and education and as a pressure group. The Department of Health9 has promised support for services concerned with prevention: how much more evidence must be offered before prevention of handicap is rated as important as maternal and perinatal mortality, and maternity and neonatal services are developed to an acceptable and uniform standard?
COUNCIL OF WAR ON ALIMENTARY CANCER THE task of the Medical Research Council in deciding which projects to support with its shrinking finances is far from easy. Even in palmier times the Council had to try to do more than make arbitrary judgments between competing claims. Today it sees a great need to define worthwhile objectives-not only worthwhile in the desirability of their goal but also justified in the likelihood of yielding fruitful results. The Council also has a responsibility to guide medical researchers in Britain towards promising areas and to point them towards unexplored territory which deserves investigation. Cancer research is not short of enthusiasts in any of its aspects, and throughout Britain cancer epidemiology, immunology, clinical management, and diagnosis has been explored for a long time. Yet, while the results in some
areas-lymph-node lymphoma, leuksemia, epider-
mal neoplasms, head-and-neck cancer-have shown useful benefit from research, gastrointestinal cancer still presents a doleful picture. About 1 person in 5 in the United Kingdom dies of cancer, and alimentary neoplasms account for 28% of all these deaths. Even the five-year survival(not a particularly stringent test of therapy) is only 6% for gastric carcinoma and 27% for colorectal cancer. One of the few bright spots is a declining incidence of gastric carcinoma in the United Kingdom, though the reason for this is a mystery. It was this gloomy state, with no sign of improvement, which encouraged the Council to hold a review meeting in April, 1977, at which workers, well informed about different aspects of alimentary malignancy, might pool their information, discuss it, and thereby enable the Council to point the way forward and direct its resources aright. A readable summary of that meeting has been published’ and deserves careful consideration. It was written by a small group of participants with feet firmly on the ground. While picking out promising directions of research, it equally emphasises the problems likely to arise in their exploitation. Thus, though point7. Lancet, 1976, i, 729. 8. ibid. 1976, ii, 941. 9. Priorities for Health and Personal Social Services in England. Department of Health and Social Security, 1976. 1. Review of Gastric and Colo-rectal Cancers: report of a conference held on 2 and 3 April, 1977, in Edinburgh. Copies available free from the Medical Research Council, 20 Park Crescent, London W1N 4AL.
Cervical Neoplasia and the Pill SINCE the epithelium of the cervix uteri’is a get tissue for steroid
sex
tar-
hormones, oral contracep-
tives are unlikely to be completely without effects upon the development of cervical carcinoma. It is therefore important to discover whether they operate for good or ill, and the magnitude of any demonstrable effect. The fact that massive use of the
.
The difference is significant, but based upon small numbers. No mention is made of any case progressing to invasion. The inference that the pill increases the chance of progression towards cancer is not, however, inescapable. The severity of dysplasia is defined by the extent of loss of surface maturation. Carcinoma-insitu, by definition, has none at all. Progestagens, as used in oral contraceptives, strikingly diminish epithelial maturation in the normal cervix, and this is shown in smears by a reduced karyopyknotic index. There is no reason why a similar effect should not occur in the supposedly precancerous states. Lesions with surface maturation are not necessarily any less precancerous than those without; indeed, invasive carcinoma is often well differentiated. Accordingly, the so-called conversion from dysplasia to carcinoma-in-situ need not mean much in terms of danger to life. Another explanation of the findings is based on the fact that the epithelial lesion, if extensive, usually shows considerable variation from place to place in the same cervix, with more squamous maturation distally, and less maturation further up in the endocervical canal. Since oral contraceptives tend to cause eversion of the endocervix, a small biopsy is more likely to hit an area of carcinoma-in-situ if the patient is on the pill. That progression from dysplasia towards invasive carcinoma is enhanced by contraceptive steroids is therefore only one of several explanations of the Los Angeles data, though still a perfectly plausible one. SINGER and JORDAN9 have tried to exonerate the pill, maintaining firstly, that there is no association between oral contraceptives and cervical atypias, and secondly, if there is, "the pill itself should not be blamed". The verdict may be appropriate according to the Law of England, but the rules of science require the accused to remain in the dock. Even if oral contraceptives do eventually turn out to cause a slightly enhanced risk of cervical carcinogenesis, there is still no need to panic. A cervical smear every 3 or 5 years will readily detect dysplasia or carcinoma-in-situ, which can then be eliminated without loss of cervical function. Carcinoma of the cervix is just as preventable in those who use the pill as in those who do not.
pill.
pill has been accompanied almost everywhere by falling death-rates for cervical cancer should not lead to complacency,’ since most of the women dying of cancer belong to much older age-groups than those consuming the pill. In 1969 a report from New York’ suggested that pill users had an increased prevalence of epithelial abnormalities classified as dysplasia and carcinoma-in-situ, compared with those using the diaphragm. Evaluation was complicated by the possibility of a protective effect of the diaphragm, as well as by the fact that the choice of contraceptives varies in groups of women according to factors that influence the likelihood of cervical carcinoma.2 Some other retrospective studies of matched groups showed no significant association,3,4 nor did a further prospective study from New York. There are numerous other inconclusive papers on this subject.6 Because women coming for contraceptive advice often know what they want, random allocation is no longer possible, but this was done in the original studies from Puerto Rico. Since the pill women and the controls - had frequent cervical smears, carcinoma of the cervix was presumably not allowed to develop, but limited data have been published7 on the changes in grading of smear reports over observation periods said to extend up to 8 years, and no deleterious effect of the pill was noted. ELIZABETH STERN and her colleagues in Los Angeles8 have now published the results of a large prospective study of women attending family-planning clinics between 1967 and 1971, to see whether existing cervical dysplasia tended to run a different course in women using oral contraceptive steroids. 300 cases of dysplasia were found, and followed up by means of repeated smears and annual small biopsies. The average age was 23. Dysplasia frequently regressed during the first six months of observation, and regression was slightly more frequent in pill users; but in those with persistent lesions an increase in severity, and progression to carcinoma-in-situ, was commoner in users of the 1. Melamed, M.
R., Koss, L. G., Flehinger, B. J., Kelisky, R. P., Dubrow, H. J. 1969, iii, 195. 2. Dubrow, H., Melamed, M. R., Flehinger, B. J., Kelisky, R. P., Koss, L. G. Obstet. Gynec. Survey, 1969, 24, 1012. 3. Worth, A. J., Boyes, D. A. J. Obstet. Gynec. Br. Commonw. 1972, 79, 673. 4. Thomas, D. B. Obstet. Gynec. 1972, 40, 508. 5. Melamed, M. R., Flehinger, B. J. Gynec. Oncol. 1973, 1, 290. Br. med.
6. I.A.R.C. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man: no. 6, Sex Hormones; p. 223. Lyon, 1974. 7. Fuertes-de la Haba, A., Pelegrina, L., Bangdiwala, I. S., Hernándes-Cibes, J. J. J. reprod. Med. 1973, 10, 3. 8. Stern, E., Forsythe, A. B., Youkeles, L., Coffelt, C. F., Science, 1977, 196, 1460.
SOME CONSEQUENCES OF BEING BORN TOO SOON OR BORN TOO SMALL deserves its reputation as the best infant in some pregnancies fetal nutrition falters but incubator, and the syndrome of placental insufficiency ensues. The result is a stillbirthor a light-for-dates infant (who faces such immediate dangers as perinatal asphyxia, meconium aspiration, and hypoglycsemia). Now that fetal health and growth can be monitored by biochemical and ultrasonic methods, placental insufficiency may THE
uterus
9. Singer, A.,
Jordan, J. A. Lancet, 1977, ii, 359.
645 be diagnosed in the third trimester giving the obstetrician an opportunity to intervene. But at what cost? The pre-term baby risks hyaline-membrane disease, infection, and perhaps disruption of mother/baby relationships. If a pregnancy is to be ended early then the benefits must unequivocally outweigh the disadvantages both in the neonatal period and more distantly. Which is better: to be born too soon (prematurely) or to be born too small (light for dates)? Drawing on data from the Newcastle upon Tyne Survey of Child Development, the late Gerald Neligan and his colleagues attempted to provide a long-term answer.’ They report on 387 children who were born to Newcastle mothers during 1960-62: 59 were of short gestation (less than 36 weeks), 141 light for dates (weight less than the 10th centile for gestational age), and 187 controls (term babies of appropriate weight). The two abnormal groups represent 10% of births then; mean birth-weights of the groups were 2415 g (short gestation) and 2537 g (light for dates). At ages 5, 6, and 7 years these children were assessed by conventional neurological, anthropometric, and psychometric methods and by reports on their behaviour from mothers, teachers, and psychiatrists. Care was taken to allow for distorting factors such as clinical abnormalities of pregnancy and labour, biological factors (sex and birth rank), and postnatal environmental influences such as social class. The conclusions are clear: the growth and performance of the short-gestation and the light-for-dates children were worse than those of the term children. Moreover, if the light-for-dates group is divided into rather light for dates (weight 5th to 10th centiles) and very light for dates (less than 5th centile) the degree of impairment of school-age performance was proportional to the severity of intrauterine growth retardation, since the scores of rather-light-for-dates children were intermediate between the very-light-for-dates and control children. The most crucial finding was that the overall attainment of the very-light-for-dates group was significantly worse than that of the short-gestation group-in other words, it is clearly better to be born too soon than too small. What is the import of these results today, when some of the study children will already have left school? The risks from being born prematurely are being reduced. Prenatal therapeutics may help (steroids to prevent hyaline membrane disease; phenobarbitone for jaundice) and neonatal intensive care has improved the survival of very-low-birth-weight infants without appreciably increasing handicap .2,3 Much remains to be done; even the choice of food for very small babies is still controversial.4,5 The major adverse influences on the light-fordates infant cease after birth and the benefits from improvement in neonatal care for this group will be marginal. Efforts must be directed towards early screening of all pregnancies for the risk baby6 and to the 1 Born too Soon or Born too Small (Clinics in Developmental Medicine no. 61). by G. A. NELIGAN, I. KOLVIN, D. SCOTT, and R. F. GARSIDE. 1976. 2 3
London: Heinemann. Philadelphia: Lippincott. Pp. 101. £4.50. Marriage, K. J, Davies, P. A. Archs Dis. Child., 1977, 52, 176. Stewart, A. L., Turcan, D. M., Rawlings, G. R., Reynolds, E. O.
R. ibid.
p. 97. Wald, N, Cuckle, H., Stirrat, G. M., Bennett, M. J., Turnbull, A. C. Lancet, 1977, ii, 268. 5. Fomon, S. J., Ziegler, E. E., Vazquez, H. D. Am. J. Dis. Child. 1977, 131,
4
463. 6
Davies, D. P. Archs Dis. Child. 1977, 52, 296.
prompt diagnosis of placental insufficiency by observing growth and placental function. When this happens, labour may be induced before serious growth failure occurs, or, more enticingly, intrauterine nutrition may be enhanced and the baby allowed to thrive in its natural incubator. These remedies are expensive, especially for a service whose funds are threatened. The Lancet has consistently warned7,8 against complacency about the results of British perinatal practice and we welcome the formation of the British Psediatric Perinatal Group to foster research and education and as a pressure group. The Department of Health9 has promised support for services concerned with prevention: how much more evidence must be offered before prevention of handicap is rated as important as maternal and perinatal mortality, and maternity and neonatal services are developed to an acceptable and uniform standard?
COUNCIL OF WAR ON ALIMENTARY CANCER THE task of the Medical Research Council in deciding which projects to support with its shrinking finances is far from easy. Even in palmier times the Council had to try to do more than make arbitrary judgments between competing claims. Today it sees a great need to define worthwhile objectives-not only worthwhile in the desirability of their goal but also justified in the likelihood of yielding fruitful results. The Council also has a responsibility to guide medical researchers in Britain towards promising areas and to point them towards unexplored territory which deserves investigation. Cancer research is not short of enthusiasts in any of its aspects, and throughout Britain cancer epidemiology, immunology, clinical management, and diagnosis has been explored for a long time. Yet, while the results in some
areas-lymph-node lymphoma, leuksemia, epider-
mal neoplasms, head-and-neck cancer-have shown useful benefit from research, gastrointestinal cancer still presents a doleful picture. About 1 person in 5 in the United Kingdom dies of cancer, and alimentary neoplasms account for 28% of all these deaths. Even the five-year survival(not a particularly stringent test of therapy) is only 6% for gastric carcinoma and 27% for colorectal cancer. One of the few bright spots is a declining incidence of gastric carcinoma in the United Kingdom, though the reason for this is a mystery. It was this gloomy state, with no sign of improvement, which encouraged the Council to hold a review meeting in April, 1977, at which workers, well informed about different aspects of alimentary malignancy, might pool their information, discuss it, and thereby enable the Council to point the way forward and direct its resources aright. A readable summary of that meeting has been published’ and deserves careful consideration. It was written by a small group of participants with feet firmly on the ground. While picking out promising directions of research, it equally emphasises the problems likely to arise in their exploitation. Thus, though point7. Lancet, 1976, i, 729. 8. ibid. 1976, ii, 941. 9. Priorities for Health and Personal Social Services in England. Department of Health and Social Security, 1976. 1. Review of Gastric and Colo-rectal Cancers: report of a conference held on 2 and 3 April, 1977, in Edinburgh. Copies available free from the Medical Research Council, 20 Park Crescent, London W1N 4AL.
