- Email: [email protected]
INDOMETHACIN AND GASTRIC PERFORATION IN A NEONATE
1110
financing (insurance) or by public campaign; and your choice seems allow clinicians to make these decisions "based on knowledge of the economic position and on clinical experience". This conclusion raises two related issues which may deserve further consideration-who should decide, and on what basis? These issues are related because, when we have clear criteria which should govern a decision, it is often not so important who applies them-provided that the decision-maker is impartial in the sense of not having a conflict of interest. When substantive criteria are not available the law, at least, will try to achieve a just decision by requiring certain procedural safeguards. Such a procedural approach is founded on the concept of conferring a discretion on decision-makers who are chosen for their ethical or moral characteristics as well as their skill and knowledge, and who must follow a set of procedural rules. The result, it is hoped, will be a decision that is fair and just. To get the best approximation to the "ideal decision maker" we may need a combination of people, skills, disciplines, experience, and relationships to the nature of the decision being taken (e.g., if the decision concerns dialysis, a patient may need to be on the committee). Although committee decision making has problems (such as the diffusion of responsibility and sometimes, with this, the approval of a decision no one member would have taken), in the absence of definitive and widely agreed criteria it is probably the best we can do. The aim is to try to allow as many points of view and values as possible to be weighed in taking decisions that have not only a scientific and medical component but also a much wider value base. In technical legal terms this is an attempt to attain "distributive justice via procedural due process". The substantive criteria you propose for taking decisions on the allocation of haemodialysis are "economic position" (the availability of resources) and "clinical experience". By "clinical experience" I assume that you refer to the medical possibility of prolonging life by haemodialysis and assessment of the quality of that life. You seem to leave the decision entirely to clinicians. I question whether either the criteria you propose or your choice of decision makers represent a wide enough spectrum to reflect the diverse needs, rights, interests, and claims involved in such
to
be
to
decisions.
Further, your editorial seems to address simultaneously the problems involved at both national (or governmental) and individual (or personal) level. For instance, you state that it is wrong that there should be a "geographical inequality (of access to haemodialysis) within the United Kingdom" and that "facilities for dialysis have
to
be made available
uniformly across the country". This is a
the fact that "most units had age limits for acceptance which varied between 45 and 65" probably represents an institutional decision. Or if, as it seems, some individual physicians "disfavoured" certain patients because they were over a certain age, this represents an individual decision. While your editorial finds the governmental decision on the distribution of resources unacceptable you do not criticise the decision not to treat the aged on the basis of age, which is clearly discriminatory. Is this decision felt to be justified as everyone is treated (or not treated) equally? The range of factors which is ethically and legally acceptable in the allocation of a scarce resource may differ, depending on whether a decision is taken at a governmental, institutional, or individual level.’ For instance, while it may be acceptable to take decisions which will increase efficiency, utility, and even medical progress at the governmental and, perhaps, the institutional level, these would not be acceptable criteria in decision making at the individual level. The physician, with his fundamental duty towards his patient must take decisions concerning that patient (or, rather, offer alternatives to that patient), solely on the basis of what is in that patient’s best interests. He cannot decide what treatment to offer or withhold on the basis of what may be in the best interests of others. I suggest that it is only in this way that integrity of the doctor-patient relationship can be preserved2 in what may prove to be the major
governmental level decision. In contrast,
the
1. Fried C Medical experimentation. Personal integrity and social
policy Amsterdam: North Holland Publishing, 1974 2 Somerville MA Randomized controlled trials and randomized control of consent Health Law Canada 1980, 3: 58
legal/ethical/medical problem at the close of the 20th century-the necessity to make hard choices in the allocation of scarce medical resources.
Faculty of Law, University, Montreal, Quebec, Canada H3A 1W9; and Faculty of Medicine, McGill
McGill University
MARGARET A. SOMERVILLE
SIR,-Chronic ambulatory peritoneal dialysis (CAPD) is an exciting new method of chronic dialysis. Nevertheless, there is a substantial morbidity with a 30-40% drop-out rate worldwide.Iisis therefore essential that patients, who are started on CAPD, are also assessed for alternative treatments. We arrange an arteriovenous fistula and transplant assessment for most CAPD patients at the beginning of dialysis, so that a rapid transfer to haemodialysis can be undertaken if needed. While we agree with Dr Gabriel (April 18, p. 896) that much CAPD could be supervised outside renal units, CAPD should be part of an integrated service of renal replacement which also provides haemodialysis and transplantation. L. R. SOLOMON R. A. COWARD N. P. MALLICK
Department of Renal Medicine, Manchester Royal Infirmary, Manchester M 13 9WL
LIFE-THREATENING ILLNESS IN THOSE WITH SEVERE MENTAL HANDICAP
SIR,-The dilemma referred to by the Medical Services Study Group of the Royal College of Physicians (April 18, p. 837) should be amplified. In my experience a physician who is also the father or grandfather of a severely handicapped or disabled child is often suspicious that something untoward will occur while his child is being cared for by others. This attitude is often an obvious contrast to his previously expressed views concerning other patients which have stated that too much has been done to prolong already impaired existences. Double standards of care are always difficult to justify. In this instance one is for the able and temporarily ill and another for the disabled and chronically impaired. It has long been clear that the lowest level of care in a clinic, hospital, or other institution is determined by the treatment and concern given to those who are at least able to manage on their own behalf. A multiply handicapped child who has no advocate is one of the most vulnerable individuals in our "modern" society. As long as it is someone else’s child a decision appears easier than it is. The concept that some are more equal than others is difficult and unacceptable for most physicians who provide service, attempt to teach, and contribute worthwhile research. Department of Pediatrics, Temple University School of Medicine, and St Christopher’s Hospital for Children, Philadelphia, Pennsylvania 19133, U.S.A.
HENRY W. BAIRD
INDOMETHACIN AND GASTRIC PERFORATION IN A NEONATE
SIR,-Indomethacin has been given to neonates to close a symptomatic persistent ductus arteriosus since 1975 when its use was first suggested. We recently had in our regional neonatal unit a baby of 28 weeks’ gestation weighing 1075 g. She had severe respiratory distress syndrome which responded well to ventilation, but at 72 hours of age cardiac failure developed due to a persistent ductus arteriosus, with high oxygen requirements. Her response to restricted fluids, digoxin, and diuretics was poor, so three doses of indomethacin (0’2mg/kg) were given by the nasogastric tube 8 hourly. 8 hours after the last dose, despite a marked improvement cardiologically, nasogastric aspirates suddenly became bloodstained and severe abdominal distension developed. A decubitus film showed a large pneumoperitoneum. Laparotomy revealed a single ragged perforation in the lesser curvature of the stomach which was 1
Peritoneal Dialysis Bull 1980; 1(3): 18-19.
2.
Sharpe GL
Indomethacin and closure of the ductus
arteriosus
Lancet 1975, 693
1111 INDEX* AND COMPARISON
She died of a large intraventricular haemorrhage but at further abdominal lesion was noted. necropsy Spontaneous neonatal gastric perforation is a well recognised phenomenon especially in preterm babies, and several possible causative factors have been described,3 including birth trauma, gastric distension, and congenital muscular deficiency. However, indomethacin can cause gastric ulceration in babies4 and gastric perforation in adults.5 In the absence of predisposing factors the occurrence of gastric perforation in our patient soon after indomethacin therapy suggests a causal link. We feel that the risk of gastric perforation should be added to the already recognised serious complications of indomethacin therapy when considering how best to close a symptomatic persistent ductus arteriosus in a preterm infant. oversewn.
*Died
A. N. CAMPBELL J. R. BEASLEY A. P. KENNA
Children’s Department, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE
ARE VINCA ALKALOIDS ASSOCIATED WITH MYOCARDIAL INFARCTION?
SIR,-A report in The Lancetof myocardial infarction in
a
after vinblastine treatment for Hodgkin’s disease (HD) prompted us to examine the possibility of vinca alkaloid associated myocardial infarction among such patients reported to the Connecticut Tumor Registry between 1960 and 1969 and followed up to 1977. 7 of 827 patients with newly diagnosed HD died of myocardial infarction after surviving HD for at least a week; on the basis of general population rates, 5-77 deaths from myocardial infarction were expected. These 7 index HD patients, who ranged in age from 33 to 70 years at diagnosis of HD, were each matched to 3 HD controls with respect to sex, race, age (± 5 years), year of diagnosis (± 2 years), and survival (at least equal to that of the index patient), to compare therapy histories collected. The completeness of the Connecticut Tumor Registry’s therapy histories has not been documented, but is believed to be similar for all patients. None of the index HD patients had received vinblastine, as compared with 14% of the controls (table). Myocardial infarction has been reported after vincristine injections in patients with nonHodgkin’s lymphoma treated without radiotherapy,1,8but none of the index patients in our series received this drug. Although an equal percentage of index and comparison patients in our series received radiotherapy which included a mediastinal port, the proportions in the two study groups are higher than observed for the entire Connecticut Tumor Registry’s HD series (table). It has been suggested that mediastinal irradiation may cause or contribute to3 myocardial infarction in certain patients with other risk factors? -13 The small series reported here suggests that factors other than vinblastine and vincristine would more directly explain the occurrence of fatal myocardial infarction in patients with HD. Difficulties in assuming causality between drug exposure and a
37-year-old man
3 Vreede AA, Prasarn V. Gastric
perforation
in
premature
new
born.
NY State J Med
1972, 72: 2895-97. 4 Seal WA, Kyle JM, Mullett MD Failure of indomethacin therapy to induce closure of patent ductus arteriosus in premature infants with respiratory distress syndrome. J Pediat 1977; 91: 621. 5 Clark GM. Indomethacin in rheumatoid arthritis. Arthritis Rheum 1964; 7: 300. 6 Lejonc JL, Vernant JP, Macquin I, Castaigne A. Myocardial infarction following vinblastine treatment. Lancet 1980; ii: 692. Mandel EM, Lewinski U, Djaldetti M. Vincristine-induced myocardial infarction. Cancer 1975, 36: 1979-82. 8 Somers G, Abramow M, Wittek M, Naets JP. Myocardial infarction: a complication of vincristine treatment? Lancet 1976; ii: 690. 9 Stewart JR, Fajardo LF. Radiation-induced heart disease. Radiol Clins N Am 1971; 9: 511-31. Tracy GP, Brown DE, Johnson LW, Gottheb AJ. Radiation-induced coronary artery disease. JAMA 1974, 228: 1660-62. McReynolds RA, Gold GL, Roberts WC. Coronary heart disease after mediastinal irradiation for Hodgkin’s disease. Am J Med 1976; 60: 39-45. - Weinstein P, Greenwald ES, Grossman J. Unusual cardiac reaction to chemotherapy following mediastinal irradiation in a patient with Hodgkin’s disease. AmJ Med 1976, 60: 152-56. Rodgers DL Precocious myocardial infarction after radiation treatment for Hodgkin’s disease Chest 1976, 70: 675-7. - Vogelzang NJ, Frenning DH, Kennedy BJ. Coronary artery disease after treatment with bleomycin and vinblastine. Cancer Treat Rep 1980; 64: 1159-60.
tHODGKIN’S
DISEASE
PATIENTS, BY
TREATMENT
no
of myocardial infarction.
t Matched to index patients by age, sex,
race, year of diagnosis, and survival.
disorder such as myocardial infarction based upon case reporting of patients with known or suspected risk factors (e.g., smoking, previous infarct, mediastinal irradiation),6,17,14 indicate the need for an epidemiological study designed to reveal multiple common
risk factors and their interactions. While vinca alkaloids may on occasion be associated with myocardial infarction, it is not clear that the relation is causal; Mandel et al. were unable to cause myocardial infarction or detectable coronary artery injury in mice after daily administration of high doses of vincristine.Our series suggests that the number of deaths, if any, attributable to such an association is likely to be small. ARLENE F. KANTOR Environmental Epidemiology Branch, MARK H. GREENE National Cancer Institute, JOHN D. BOICE National Institutes of Health, JOSEPH F. FRAUMENI, JR Bethesda, Maryland 20205, U.S.A. _
Connecticut Tumor Registry, Connecticut State Department of Health, Hartford, Connecticut
__
JOHN T. FLANNERY
SALIVARY OESTRIOL IN NORMAL PREGNANCY
SIR,-Oestrogen assays are widely used for assessing fetal wellbeing, although the clinical value of such assays is still being debated. With daily sample collections the results are encouraging but in routine practice maternal blood samples are collected only once or twice a week and the results are disappointing.’ Urinary oestrogen determinations are complicated by "completeness of collection" problems and the validity of the "correction for creatinine" factor. Daily blood sampling is time consuming and not readily tolerated by patients. In contrast, saliva is easily collected by the patient herself. We have established the clinical usefulness of salivary sampling for other steroids,2and it seemed worthwhile to consider the application of these techniques to the assessment of fetal wellbeing. A conventional radioimmunoassay for salivary free oestriol was established with a liquid-phase antiserum and tritiated oestriol as radioligand, antibody-bound and free steroid being separated by dextran-coated charcoal, and oestriol extracted from saliva with ether. The standard curve covered the range l. 75-l7’ 50 nmol/l and its sensitivity allowed the determination of oestriol concentrations in small volumes (200 1) of saliva. Replicate assays (n = 12) of high, medium, and low quality control samples showed that within and between assay coefficients of variation did not exceed 9 - 0 and 9 - 4%, respectively. Saliva samples were collected throughout pregnancy from 30 weeks to term. The samples were stored (-20°C) and assayed only when it was known that the pregnancy had ended in the birth of a normal infant. These data allowed the construction of a normal range for salivary free oestriol concentrations throughout the last trimester of pregnancy (figure). Oestriol concentrations in single daily samples of plasma and urine, even in normal pregnancy, may be associated with coefficients of variation exceeding 30%, and 1 Goebelsmann U The 6: 223-44
2.
uses
of oestriol
as
a monitoring tool. Clins Obstet Gynaecol 1979;
Riad-Fahmy D, Read GF, Joyce BG, Walker RF Steroid Immunoassays in endocrinology. In. Voller A, ed Immunoassay for the 80’s. Lancaster- MTP (in press)
financing (insurance) or by public campaign; and your choice seems allow clinicians to make these decisions "based on knowledge of the economic position and on clinical experience". This conclusion raises two related issues which may deserve further consideration-who should decide, and on what basis? These issues are related because, when we have clear criteria which should govern a decision, it is often not so important who applies them-provided that the decision-maker is impartial in the sense of not having a conflict of interest. When substantive criteria are not available the law, at least, will try to achieve a just decision by requiring certain procedural safeguards. Such a procedural approach is founded on the concept of conferring a discretion on decision-makers who are chosen for their ethical or moral characteristics as well as their skill and knowledge, and who must follow a set of procedural rules. The result, it is hoped, will be a decision that is fair and just. To get the best approximation to the "ideal decision maker" we may need a combination of people, skills, disciplines, experience, and relationships to the nature of the decision being taken (e.g., if the decision concerns dialysis, a patient may need to be on the committee). Although committee decision making has problems (such as the diffusion of responsibility and sometimes, with this, the approval of a decision no one member would have taken), in the absence of definitive and widely agreed criteria it is probably the best we can do. The aim is to try to allow as many points of view and values as possible to be weighed in taking decisions that have not only a scientific and medical component but also a much wider value base. In technical legal terms this is an attempt to attain "distributive justice via procedural due process". The substantive criteria you propose for taking decisions on the allocation of haemodialysis are "economic position" (the availability of resources) and "clinical experience". By "clinical experience" I assume that you refer to the medical possibility of prolonging life by haemodialysis and assessment of the quality of that life. You seem to leave the decision entirely to clinicians. I question whether either the criteria you propose or your choice of decision makers represent a wide enough spectrum to reflect the diverse needs, rights, interests, and claims involved in such
to
be
to
decisions.
Further, your editorial seems to address simultaneously the problems involved at both national (or governmental) and individual (or personal) level. For instance, you state that it is wrong that there should be a "geographical inequality (of access to haemodialysis) within the United Kingdom" and that "facilities for dialysis have
to
be made available
uniformly across the country". This is a
the fact that "most units had age limits for acceptance which varied between 45 and 65" probably represents an institutional decision. Or if, as it seems, some individual physicians "disfavoured" certain patients because they were over a certain age, this represents an individual decision. While your editorial finds the governmental decision on the distribution of resources unacceptable you do not criticise the decision not to treat the aged on the basis of age, which is clearly discriminatory. Is this decision felt to be justified as everyone is treated (or not treated) equally? The range of factors which is ethically and legally acceptable in the allocation of a scarce resource may differ, depending on whether a decision is taken at a governmental, institutional, or individual level.’ For instance, while it may be acceptable to take decisions which will increase efficiency, utility, and even medical progress at the governmental and, perhaps, the institutional level, these would not be acceptable criteria in decision making at the individual level. The physician, with his fundamental duty towards his patient must take decisions concerning that patient (or, rather, offer alternatives to that patient), solely on the basis of what is in that patient’s best interests. He cannot decide what treatment to offer or withhold on the basis of what may be in the best interests of others. I suggest that it is only in this way that integrity of the doctor-patient relationship can be preserved2 in what may prove to be the major
governmental level decision. In contrast,
the
1. Fried C Medical experimentation. Personal integrity and social
policy Amsterdam: North Holland Publishing, 1974 2 Somerville MA Randomized controlled trials and randomized control of consent Health Law Canada 1980, 3: 58
legal/ethical/medical problem at the close of the 20th century-the necessity to make hard choices in the allocation of scarce medical resources.
Faculty of Law, University, Montreal, Quebec, Canada H3A 1W9; and Faculty of Medicine, McGill
McGill University
MARGARET A. SOMERVILLE
SIR,-Chronic ambulatory peritoneal dialysis (CAPD) is an exciting new method of chronic dialysis. Nevertheless, there is a substantial morbidity with a 30-40% drop-out rate worldwide.Iisis therefore essential that patients, who are started on CAPD, are also assessed for alternative treatments. We arrange an arteriovenous fistula and transplant assessment for most CAPD patients at the beginning of dialysis, so that a rapid transfer to haemodialysis can be undertaken if needed. While we agree with Dr Gabriel (April 18, p. 896) that much CAPD could be supervised outside renal units, CAPD should be part of an integrated service of renal replacement which also provides haemodialysis and transplantation. L. R. SOLOMON R. A. COWARD N. P. MALLICK
Department of Renal Medicine, Manchester Royal Infirmary, Manchester M 13 9WL
LIFE-THREATENING ILLNESS IN THOSE WITH SEVERE MENTAL HANDICAP
SIR,-The dilemma referred to by the Medical Services Study Group of the Royal College of Physicians (April 18, p. 837) should be amplified. In my experience a physician who is also the father or grandfather of a severely handicapped or disabled child is often suspicious that something untoward will occur while his child is being cared for by others. This attitude is often an obvious contrast to his previously expressed views concerning other patients which have stated that too much has been done to prolong already impaired existences. Double standards of care are always difficult to justify. In this instance one is for the able and temporarily ill and another for the disabled and chronically impaired. It has long been clear that the lowest level of care in a clinic, hospital, or other institution is determined by the treatment and concern given to those who are at least able to manage on their own behalf. A multiply handicapped child who has no advocate is one of the most vulnerable individuals in our "modern" society. As long as it is someone else’s child a decision appears easier than it is. The concept that some are more equal than others is difficult and unacceptable for most physicians who provide service, attempt to teach, and contribute worthwhile research. Department of Pediatrics, Temple University School of Medicine, and St Christopher’s Hospital for Children, Philadelphia, Pennsylvania 19133, U.S.A.
HENRY W. BAIRD
INDOMETHACIN AND GASTRIC PERFORATION IN A NEONATE
SIR,-Indomethacin has been given to neonates to close a symptomatic persistent ductus arteriosus since 1975 when its use was first suggested. We recently had in our regional neonatal unit a baby of 28 weeks’ gestation weighing 1075 g. She had severe respiratory distress syndrome which responded well to ventilation, but at 72 hours of age cardiac failure developed due to a persistent ductus arteriosus, with high oxygen requirements. Her response to restricted fluids, digoxin, and diuretics was poor, so three doses of indomethacin (0’2mg/kg) were given by the nasogastric tube 8 hourly. 8 hours after the last dose, despite a marked improvement cardiologically, nasogastric aspirates suddenly became bloodstained and severe abdominal distension developed. A decubitus film showed a large pneumoperitoneum. Laparotomy revealed a single ragged perforation in the lesser curvature of the stomach which was 1
Peritoneal Dialysis Bull 1980; 1(3): 18-19.
2.
Sharpe GL
Indomethacin and closure of the ductus
arteriosus
Lancet 1975, 693
1111 INDEX* AND COMPARISON
She died of a large intraventricular haemorrhage but at further abdominal lesion was noted. necropsy Spontaneous neonatal gastric perforation is a well recognised phenomenon especially in preterm babies, and several possible causative factors have been described,3 including birth trauma, gastric distension, and congenital muscular deficiency. However, indomethacin can cause gastric ulceration in babies4 and gastric perforation in adults.5 In the absence of predisposing factors the occurrence of gastric perforation in our patient soon after indomethacin therapy suggests a causal link. We feel that the risk of gastric perforation should be added to the already recognised serious complications of indomethacin therapy when considering how best to close a symptomatic persistent ductus arteriosus in a preterm infant. oversewn.
*Died
A. N. CAMPBELL J. R. BEASLEY A. P. KENNA
Children’s Department, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE
ARE VINCA ALKALOIDS ASSOCIATED WITH MYOCARDIAL INFARCTION?
SIR,-A report in The Lancetof myocardial infarction in
a
after vinblastine treatment for Hodgkin’s disease (HD) prompted us to examine the possibility of vinca alkaloid associated myocardial infarction among such patients reported to the Connecticut Tumor Registry between 1960 and 1969 and followed up to 1977. 7 of 827 patients with newly diagnosed HD died of myocardial infarction after surviving HD for at least a week; on the basis of general population rates, 5-77 deaths from myocardial infarction were expected. These 7 index HD patients, who ranged in age from 33 to 70 years at diagnosis of HD, were each matched to 3 HD controls with respect to sex, race, age (± 5 years), year of diagnosis (± 2 years), and survival (at least equal to that of the index patient), to compare therapy histories collected. The completeness of the Connecticut Tumor Registry’s therapy histories has not been documented, but is believed to be similar for all patients. None of the index HD patients had received vinblastine, as compared with 14% of the controls (table). Myocardial infarction has been reported after vincristine injections in patients with nonHodgkin’s lymphoma treated without radiotherapy,1,8but none of the index patients in our series received this drug. Although an equal percentage of index and comparison patients in our series received radiotherapy which included a mediastinal port, the proportions in the two study groups are higher than observed for the entire Connecticut Tumor Registry’s HD series (table). It has been suggested that mediastinal irradiation may cause or contribute to3 myocardial infarction in certain patients with other risk factors? -13 The small series reported here suggests that factors other than vinblastine and vincristine would more directly explain the occurrence of fatal myocardial infarction in patients with HD. Difficulties in assuming causality between drug exposure and a
37-year-old man
3 Vreede AA, Prasarn V. Gastric
perforation
in
premature
new
born.
NY State J Med
1972, 72: 2895-97. 4 Seal WA, Kyle JM, Mullett MD Failure of indomethacin therapy to induce closure of patent ductus arteriosus in premature infants with respiratory distress syndrome. J Pediat 1977; 91: 621. 5 Clark GM. Indomethacin in rheumatoid arthritis. Arthritis Rheum 1964; 7: 300. 6 Lejonc JL, Vernant JP, Macquin I, Castaigne A. Myocardial infarction following vinblastine treatment. Lancet 1980; ii: 692. Mandel EM, Lewinski U, Djaldetti M. Vincristine-induced myocardial infarction. Cancer 1975, 36: 1979-82. 8 Somers G, Abramow M, Wittek M, Naets JP. Myocardial infarction: a complication of vincristine treatment? Lancet 1976; ii: 690. 9 Stewart JR, Fajardo LF. Radiation-induced heart disease. Radiol Clins N Am 1971; 9: 511-31. Tracy GP, Brown DE, Johnson LW, Gottheb AJ. Radiation-induced coronary artery disease. JAMA 1974, 228: 1660-62. McReynolds RA, Gold GL, Roberts WC. Coronary heart disease after mediastinal irradiation for Hodgkin’s disease. Am J Med 1976; 60: 39-45. - Weinstein P, Greenwald ES, Grossman J. Unusual cardiac reaction to chemotherapy following mediastinal irradiation in a patient with Hodgkin’s disease. AmJ Med 1976, 60: 152-56. Rodgers DL Precocious myocardial infarction after radiation treatment for Hodgkin’s disease Chest 1976, 70: 675-7. - Vogelzang NJ, Frenning DH, Kennedy BJ. Coronary artery disease after treatment with bleomycin and vinblastine. Cancer Treat Rep 1980; 64: 1159-60.
tHODGKIN’S
DISEASE
PATIENTS, BY
TREATMENT
no
of myocardial infarction.
t Matched to index patients by age, sex,
race, year of diagnosis, and survival.
disorder such as myocardial infarction based upon case reporting of patients with known or suspected risk factors (e.g., smoking, previous infarct, mediastinal irradiation),6,17,14 indicate the need for an epidemiological study designed to reveal multiple common
risk factors and their interactions. While vinca alkaloids may on occasion be associated with myocardial infarction, it is not clear that the relation is causal; Mandel et al. were unable to cause myocardial infarction or detectable coronary artery injury in mice after daily administration of high doses of vincristine.Our series suggests that the number of deaths, if any, attributable to such an association is likely to be small. ARLENE F. KANTOR Environmental Epidemiology Branch, MARK H. GREENE National Cancer Institute, JOHN D. BOICE National Institutes of Health, JOSEPH F. FRAUMENI, JR Bethesda, Maryland 20205, U.S.A. _
Connecticut Tumor Registry, Connecticut State Department of Health, Hartford, Connecticut
__
JOHN T. FLANNERY
SALIVARY OESTRIOL IN NORMAL PREGNANCY
SIR,-Oestrogen assays are widely used for assessing fetal wellbeing, although the clinical value of such assays is still being debated. With daily sample collections the results are encouraging but in routine practice maternal blood samples are collected only once or twice a week and the results are disappointing.’ Urinary oestrogen determinations are complicated by "completeness of collection" problems and the validity of the "correction for creatinine" factor. Daily blood sampling is time consuming and not readily tolerated by patients. In contrast, saliva is easily collected by the patient herself. We have established the clinical usefulness of salivary sampling for other steroids,2and it seemed worthwhile to consider the application of these techniques to the assessment of fetal wellbeing. A conventional radioimmunoassay for salivary free oestriol was established with a liquid-phase antiserum and tritiated oestriol as radioligand, antibody-bound and free steroid being separated by dextran-coated charcoal, and oestriol extracted from saliva with ether. The standard curve covered the range l. 75-l7’ 50 nmol/l and its sensitivity allowed the determination of oestriol concentrations in small volumes (200 1) of saliva. Replicate assays (n = 12) of high, medium, and low quality control samples showed that within and between assay coefficients of variation did not exceed 9 - 0 and 9 - 4%, respectively. Saliva samples were collected throughout pregnancy from 30 weeks to term. The samples were stored (-20°C) and assayed only when it was known that the pregnancy had ended in the birth of a normal infant. These data allowed the construction of a normal range for salivary free oestriol concentrations throughout the last trimester of pregnancy (figure). Oestriol concentrations in single daily samples of plasma and urine, even in normal pregnancy, may be associated with coefficients of variation exceeding 30%, and 1 Goebelsmann U The 6: 223-44
2.
uses
of oestriol
as
a monitoring tool. Clins Obstet Gynaecol 1979;
Riad-Fahmy D, Read GF, Joyce BG, Walker RF Steroid Immunoassays in endocrinology. In. Voller A, ed Immunoassay for the 80’s. Lancaster- MTP (in press)