1098 ANENCEPHALUS AND SPINA BIFIDA IN OHIO STATE AND IN PA!Nt.SV)[; II
HOSPITAL, OHIO
per 10 000 total white births
Number of Variables the discrimination of vector of means
can
be tested for
signifi-
cance.
A high discrimination between the malformation group and its matched controls appeared within the first 10 of the 24 variables (see accompanying figure). Even with 8 variables a significant discrimination of both groups at 1% level was found. The discrimination of both groups was also possible without the two factors "abortions/stillbirths in mothers family" and "hours of daily work". So, even in a sample with factors each not discriminating significantly between both groups, the linear discriminance analysis makes it possible to discriminate between the malformation group and the matched controls. This might mean that the malformations in our sample can be explained as caused by the combination of many minor factors (extrinsic and intrin-
sic). Institut für Humangenetik, Klinikum der Johann Wolfgang,
Goeth-Universität, Frankfurt am Main, Federal Republic of Germany.
J. KLEINEBRECHT K.-H. DEGENHARDT
CONGENITAL MALFORMATIONS AND VINYL CHLORIDE
SIR,-In March, 1975, a significantly increased rate of central-nervous-system (c.N.s.) malformations was reported in 3 Ohio communities where polyvinyl chloride (P.v.c.) polymerisation plants are located;’ the increase was not uniform and appeared more prominent in the Painesville area. There are two P.v.c. plants in Painesville, one of which began operation in 1949 and the other in 1967. The birth-defect rates were computed from birth-certificate data for 1970-73 and were compared with similar data for the entire State of Ohio. This study suggested a relationship between the higher rates of C.N.S. malformations and the increased risk of exposure to vinyl chloride in these communities. By analysing data collected through the Center for Disease Control’s hospital-based birth defects monitoring programme (B.D.M.P.),2 we examined this relationship. Two hospitals participating in the B.D.M.P. are located in cities with polymerisation plants: one is in Pennsylvania, the other in Painesville, Ohio. c.N.s.-malformation rates for white infants born in these two hospitals in 1970-74 were compared with the rates for white infants in each State. No increase was seen in the Pennsylvania hospital, but an increase, primarily in anencephaly and spina bifida, was noted in the Painesville hospital for the total time 1970-74 (see table). 1.
Infante, P. in Proceedings of the Conference on Occupational Carcinogenesis at the New York Academy of Science, 25 March, 1975. New York (in the press).
2. Center for Disease Control. Congenital Malformations Surveillance Annual Summary 1974. Atlanta, 1975.
The B.D.M.P. hospital data for Painesville were compared with birth-certificate data from the Ohio department of health, and 1 additional case not included in the B.D.M.P. report was added, bringing the total to 15. 30 controls, the first normal white infant born before and after each case, were selected from the hospital birth registry. Medical records for cases and controls were reviewed to confirm the diagnosis and to obtain, among other data, the parents’ occupation and residence at the time of the infant’s birth. In addition, parents of 14 of the affected children were interviewed about previous occupations and residences. The study revealed that none of the interviewed parents of affected infants had ever worked at either of the two P.v.c.-polymerisation plants in Painesville (1 set of parents could not be located, but records show that they did not work at these plants at the time of their infant’s birth); 2 of the fathers of controls had worked at one of the plants at the time of their infants’ births. None of the parents in either group lived within 2 miles of the two plants. The chi-square test of significance was used in comparing the distances from residence and work-place of mothers and fathers to the P.v.c. plants for cases and controls. Comparisons were made at distances of 1 to 10 miles, in 1-mile increments. A significantly larger proportion of control mothers than case mothers worked (including housewives) within a 10-mile radius of the P,v.c. plant, at the 95% confidence level. This is probably a chance occurrence among multiple comparisons. Vinyl chloride is a known carcinogen,3 and concern has arisen over its possible teratogenic effects. This concern stems from recent studies which have shown (a) an increase in mutagenicity in bacterial assay systems4 and (b) increased breakage in chromosomes of P.v.c.-polymerisation workers.’ The Ohio Department of Health studyt is the only report that has suggested that vinyl chloride causes birth defects in man, Although the follow-up study reported here confirmed a moderate increase in c.N.s. malformations in Painesville, Ohio, no association was found with vinyl-chloride exposure. Cancer and Birth Defects Division, Bureau of Epidemiology, Center for Disease Control, Atlanta, Georgia 30333, U.S.A.
LARRY D. EDMONDS, HENRY FALK JACK E. NISSIM
LATE COMPLICATIONS OF TUBAL LIGATION
SIR,-Unlike Mr Darwish and Dr Saafan (Nov. 15, p. 97 uncertain as to the aetiology of the late sequelx of female sterilisation, which they refer to as menstrual irreguwe are
larity, but in our study it will be noted we looked specifically at menorrhagia and dysmenorrhoea. It seems unlikely that a psvchosomatic
cause
could be present when
two
different tecl
3. Center for Disease Control. 4.
Morbidity and Mortality Weeklv Report, heb 9, 1974, p. 49. Rannug, U., Johansson, A., Ramel, C., Wachmeister, C. A. Ambio. 1974,3,
5.
Funes-Cravioto, F., Lambert, B., Lindsten, J. Lancet, 1975, i, 459.
194.
1099 to go further into the analysis of the data possible in the formative years of the inquiry.
niques of tubal surgery give rise to such a significant difference
be advisable
in the results. This suggests that there is an anatomical basis to the problem. We hope that use of the Hulka-Clemens clip will limit the amount of tissue destruction and lead to a decrease in these symptoms. A. T. LETCHWORTH Royal Hampshire County Hospital, Winchester A. D. NOBLE
was
Welsh National School of Medicine, Department of Medical Statistics, Heath Park, Cardiff CF4 4XN.
than
R. G. NEWCOMBE HUBERT CAMPBELL IAIN CHALMERS
FATE OF 125I-LABELLED FIBRINOGEN LIVER LESIONS AND ANDROGENIC STEROID THERAPY
SiR,-The finding (Nov. 22, p. 1042) of widespread hyperplastic lesions in the livers of anasmic patients treated with anabolic steroids is an important one, which will help to focus other workers’ attention on changes in the rest of the liver in patients with discrete liver tumours. The suggestion that the term "focal nodular hyperplasia" should be used for such multiple hyperplastic foci is, however, likely to add to the existing confusion. This term is already used for another lesion, in which liver cells, bileducts, fibrous tissue, and blood-vessels form characteristic solitary or sometimes multiple nodules,’ possibly hamartomatous in nature. These, like the quite different liver-cell adenomas which are purely hepatocellular, may be found in patients taking oral contraceptives, although the nature and significance of the association is far from proven.2 Department of Histopathology, Royal Free Hospital, Pond Street, London NW3 2QG.
SIR,-We wish to present some preliminary observations of the fate of 1211-labelled autologous fibrinogen, in response to the report by Edwards and Haynes.’ We have investigated the radioactivity in leg-vein thrombi taken from two patients at necropsy who had earlier received autologous fibrinogen labelled with iodine-125. The material produced in our laboratories has been used in some 70 patients and volunteers2 and is known to have similar properties to native fibrinogen. The semilog plot, loglo% of initial blood radioactivity versus time, is linear with a half-life of 3.95 days in normal volunteers and an estimated extravascular compartment of 24-86%. A kit for the rapid preparation of this radiopharmaceutical is being developed. Autologous I25I-fibrinogen is being used in this centre in a clinical trial designed to assess the efficacy and safety of subcutaneous heparin in prophylaxis against deep-vein thrombosis. The two patients described here were "controls" in this trial, undergoing major gastric surgery and receiving 125I-fibrinogen immediately after the operation.
They were not given heparin. postoperative day patient A had a 20% increase in actiadjacent points in his left calf which persisted until death, and this was regarded as fulfilling the criteria for the presence of deep-venous thrombosis.3 He developed bronchopneumonia from which he died on the 4th postoperative day, at which time scanning showed high activity in both legs below the knees. At necropsy careful dissection of veins in both legs revealed the presence of ante-mortem thrombi, particularly within the soleal plexus and popliteal veins. Organisation of the thrombi appeared more advanced on the left side. A small peripheral pulmonary embolus was also noted. Patient B showed no evidence of venous thrombosis on leg scanning for the first 8 postoperative days. 17 days after the initial operation, a second operation was performed, and the patient progressively deteriorated, dying 9 days later from peritonitis and bronchopneumonia with multiple pulmonary emboli. Both femoral veins and On the 3rd
PETER
J. SCHEUER
MATERNAL DEATHS editorial SIR,-Your (Nov. 15, p. 963) comments on the seventh triennial Report on Confidential Enquiries into Maternal Deaths in England and Wales, covering the years 1970-72. A continuing fall in the number of deaths and in the maternal mortality-rate is recorded. During the nine years 1964—72 there were large changes in the age and parity of parturients, an increasing proportion of deliveries took place in hospital, and the Termination of Pregnancy Act 1967 came into effect. Although the report contains analyses which standardise for some of these variables, there is no assessment of the overall effect of these social and medical changes. Where the data have been standardised, real improvement seems to have been
patchy. We have standardised the mortality-rates for age and parity between 1964-66 and 1970-72 and we find that, whereas the ratio of the crude rates for "true" maternal mortality was 0.69, the S.M.R. when adjusted for age was 0.76 and when adjusted for parity was 0.77. When adjusted for age and parity simultaneously it was 0-80. It is clear, therefore, that there has been a real improvement of about 20% in maternal mortality, possibly attributable to the factors mentioned in the editorial. However, at least one-third of the observed improvement is due to the changing age and parity of the parturients. Similar effects may be due to changes in social class, and particularly in the gestational age at which abortions occur. The Department of Health no doubt has information which would allow proportional allocation of the observed fall to changes in the characteristics of pregnant women and the supposed effectiveness of medical intervention, but until this is done it cannot be said that a critical self-appraisal of the effectiveness of the work of obstetricians has been completed. We agree that this inquiry has for twenty-one years been an admirable example of critical self-appraisal, but it would now 1. Edmonson, H. A. Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology; section vii, fascicle 25. Washington, 1958. 2 Anthony, P. P. Lancet, 1975, i, 685.
vity
over two
smaller veins of the left calf contained adherent ante-mortem thrombi. Sections of thrombi taken from veins in various sites in both patients were studied by autoradiography. In patient A, who had been given labelled autologous fibrinogen 4 days before death, radioactivity was exclusively attached to fibrinogen and arranged in the form of strands. Edwards and Haynes’ found that at 60 hours the "majority of radioactivity was in relation to white blood-cells", and it must be recalled that these workers had used homologous commercially produced fibrinogen.
The purpose of our study has been to demonstrate the precise localisation of autologous fibrinogen produced in our laboratory, when taken up in a fresh thrombus. Fibrinogen obtained from commercial sources is not recommended for use in metabolic studies, being not reproducible between batches4 and containing degraded and denatured material as well as free iodine. McFarlane’ suggested that
fibrin/fibrinogen degradation products
are
phagocytosed by
cellular components in, or close to, the intravascular compartment. This pinocytosis by polymorphonuclear leucocytes has been observed experimentally by Bocci and his colleagues6 for other plasma-proteins, and there is positive chemotaxis of these cells for components of plasmin-digested fibrinogen.’ The degraded material present in the fibrinogen preparation administered to the patient of Edwards and Haynes, and certainly found in the second of our two patients at auto-radio1. 2.
Edwards, D. H., Haynes, D. W. Lancet, 1974, ii, 220. Hawker, R. J., Hawker, L. M. Unpublished.
3. Kakkar, V. V. m Thromboembolism: Diagnosis and Treatment (edited by V. V. Kakkar and A. J. Jouhar); p. 101. Edinburgh, 1972. 4. Hickman, J. A. Br. J. Hæmat. 1971, 20, 611. 5. McFarlane, A. S. Clin. Sci. 1964, 26, 415. 6. Bocci, V., Masti, L., Pacini, A., Viti, A. Exp. Cell Res. 1968, 52, 129. 7. McKenzie, R., Pepper, D. S., Kay, A. B. Thromb. Res. 1975, 6, 1.
HOSPITAL, OHIO
per 10 000 total white births
Number of Variables the discrimination of vector of means
can
be tested for
signifi-
cance.
A high discrimination between the malformation group and its matched controls appeared within the first 10 of the 24 variables (see accompanying figure). Even with 8 variables a significant discrimination of both groups at 1% level was found. The discrimination of both groups was also possible without the two factors "abortions/stillbirths in mothers family" and "hours of daily work". So, even in a sample with factors each not discriminating significantly between both groups, the linear discriminance analysis makes it possible to discriminate between the malformation group and the matched controls. This might mean that the malformations in our sample can be explained as caused by the combination of many minor factors (extrinsic and intrin-
sic). Institut für Humangenetik, Klinikum der Johann Wolfgang,
Goeth-Universität, Frankfurt am Main, Federal Republic of Germany.
J. KLEINEBRECHT K.-H. DEGENHARDT
CONGENITAL MALFORMATIONS AND VINYL CHLORIDE
SIR,-In March, 1975, a significantly increased rate of central-nervous-system (c.N.s.) malformations was reported in 3 Ohio communities where polyvinyl chloride (P.v.c.) polymerisation plants are located;’ the increase was not uniform and appeared more prominent in the Painesville area. There are two P.v.c. plants in Painesville, one of which began operation in 1949 and the other in 1967. The birth-defect rates were computed from birth-certificate data for 1970-73 and were compared with similar data for the entire State of Ohio. This study suggested a relationship between the higher rates of C.N.S. malformations and the increased risk of exposure to vinyl chloride in these communities. By analysing data collected through the Center for Disease Control’s hospital-based birth defects monitoring programme (B.D.M.P.),2 we examined this relationship. Two hospitals participating in the B.D.M.P. are located in cities with polymerisation plants: one is in Pennsylvania, the other in Painesville, Ohio. c.N.s.-malformation rates for white infants born in these two hospitals in 1970-74 were compared with the rates for white infants in each State. No increase was seen in the Pennsylvania hospital, but an increase, primarily in anencephaly and spina bifida, was noted in the Painesville hospital for the total time 1970-74 (see table). 1.
Infante, P. in Proceedings of the Conference on Occupational Carcinogenesis at the New York Academy of Science, 25 March, 1975. New York (in the press).
2. Center for Disease Control. Congenital Malformations Surveillance Annual Summary 1974. Atlanta, 1975.
The B.D.M.P. hospital data for Painesville were compared with birth-certificate data from the Ohio department of health, and 1 additional case not included in the B.D.M.P. report was added, bringing the total to 15. 30 controls, the first normal white infant born before and after each case, were selected from the hospital birth registry. Medical records for cases and controls were reviewed to confirm the diagnosis and to obtain, among other data, the parents’ occupation and residence at the time of the infant’s birth. In addition, parents of 14 of the affected children were interviewed about previous occupations and residences. The study revealed that none of the interviewed parents of affected infants had ever worked at either of the two P.v.c.-polymerisation plants in Painesville (1 set of parents could not be located, but records show that they did not work at these plants at the time of their infant’s birth); 2 of the fathers of controls had worked at one of the plants at the time of their infants’ births. None of the parents in either group lived within 2 miles of the two plants. The chi-square test of significance was used in comparing the distances from residence and work-place of mothers and fathers to the P.v.c. plants for cases and controls. Comparisons were made at distances of 1 to 10 miles, in 1-mile increments. A significantly larger proportion of control mothers than case mothers worked (including housewives) within a 10-mile radius of the P,v.c. plant, at the 95% confidence level. This is probably a chance occurrence among multiple comparisons. Vinyl chloride is a known carcinogen,3 and concern has arisen over its possible teratogenic effects. This concern stems from recent studies which have shown (a) an increase in mutagenicity in bacterial assay systems4 and (b) increased breakage in chromosomes of P.v.c.-polymerisation workers.’ The Ohio Department of Health studyt is the only report that has suggested that vinyl chloride causes birth defects in man, Although the follow-up study reported here confirmed a moderate increase in c.N.s. malformations in Painesville, Ohio, no association was found with vinyl-chloride exposure. Cancer and Birth Defects Division, Bureau of Epidemiology, Center for Disease Control, Atlanta, Georgia 30333, U.S.A.
LARRY D. EDMONDS, HENRY FALK JACK E. NISSIM
LATE COMPLICATIONS OF TUBAL LIGATION
SIR,-Unlike Mr Darwish and Dr Saafan (Nov. 15, p. 97 uncertain as to the aetiology of the late sequelx of female sterilisation, which they refer to as menstrual irreguwe are
larity, but in our study it will be noted we looked specifically at menorrhagia and dysmenorrhoea. It seems unlikely that a psvchosomatic
cause
could be present when
two
different tecl
3. Center for Disease Control. 4.
Morbidity and Mortality Weeklv Report, heb 9, 1974, p. 49. Rannug, U., Johansson, A., Ramel, C., Wachmeister, C. A. Ambio. 1974,3,
5.
Funes-Cravioto, F., Lambert, B., Lindsten, J. Lancet, 1975, i, 459.
194.
1099 to go further into the analysis of the data possible in the formative years of the inquiry.
niques of tubal surgery give rise to such a significant difference
be advisable
in the results. This suggests that there is an anatomical basis to the problem. We hope that use of the Hulka-Clemens clip will limit the amount of tissue destruction and lead to a decrease in these symptoms. A. T. LETCHWORTH Royal Hampshire County Hospital, Winchester A. D. NOBLE
was
Welsh National School of Medicine, Department of Medical Statistics, Heath Park, Cardiff CF4 4XN.
than
R. G. NEWCOMBE HUBERT CAMPBELL IAIN CHALMERS
FATE OF 125I-LABELLED FIBRINOGEN LIVER LESIONS AND ANDROGENIC STEROID THERAPY
SiR,-The finding (Nov. 22, p. 1042) of widespread hyperplastic lesions in the livers of anasmic patients treated with anabolic steroids is an important one, which will help to focus other workers’ attention on changes in the rest of the liver in patients with discrete liver tumours. The suggestion that the term "focal nodular hyperplasia" should be used for such multiple hyperplastic foci is, however, likely to add to the existing confusion. This term is already used for another lesion, in which liver cells, bileducts, fibrous tissue, and blood-vessels form characteristic solitary or sometimes multiple nodules,’ possibly hamartomatous in nature. These, like the quite different liver-cell adenomas which are purely hepatocellular, may be found in patients taking oral contraceptives, although the nature and significance of the association is far from proven.2 Department of Histopathology, Royal Free Hospital, Pond Street, London NW3 2QG.
SIR,-We wish to present some preliminary observations of the fate of 1211-labelled autologous fibrinogen, in response to the report by Edwards and Haynes.’ We have investigated the radioactivity in leg-vein thrombi taken from two patients at necropsy who had earlier received autologous fibrinogen labelled with iodine-125. The material produced in our laboratories has been used in some 70 patients and volunteers2 and is known to have similar properties to native fibrinogen. The semilog plot, loglo% of initial blood radioactivity versus time, is linear with a half-life of 3.95 days in normal volunteers and an estimated extravascular compartment of 24-86%. A kit for the rapid preparation of this radiopharmaceutical is being developed. Autologous I25I-fibrinogen is being used in this centre in a clinical trial designed to assess the efficacy and safety of subcutaneous heparin in prophylaxis against deep-vein thrombosis. The two patients described here were "controls" in this trial, undergoing major gastric surgery and receiving 125I-fibrinogen immediately after the operation.
They were not given heparin. postoperative day patient A had a 20% increase in actiadjacent points in his left calf which persisted until death, and this was regarded as fulfilling the criteria for the presence of deep-venous thrombosis.3 He developed bronchopneumonia from which he died on the 4th postoperative day, at which time scanning showed high activity in both legs below the knees. At necropsy careful dissection of veins in both legs revealed the presence of ante-mortem thrombi, particularly within the soleal plexus and popliteal veins. Organisation of the thrombi appeared more advanced on the left side. A small peripheral pulmonary embolus was also noted. Patient B showed no evidence of venous thrombosis on leg scanning for the first 8 postoperative days. 17 days after the initial operation, a second operation was performed, and the patient progressively deteriorated, dying 9 days later from peritonitis and bronchopneumonia with multiple pulmonary emboli. Both femoral veins and On the 3rd
PETER
J. SCHEUER
MATERNAL DEATHS editorial SIR,-Your (Nov. 15, p. 963) comments on the seventh triennial Report on Confidential Enquiries into Maternal Deaths in England and Wales, covering the years 1970-72. A continuing fall in the number of deaths and in the maternal mortality-rate is recorded. During the nine years 1964—72 there were large changes in the age and parity of parturients, an increasing proportion of deliveries took place in hospital, and the Termination of Pregnancy Act 1967 came into effect. Although the report contains analyses which standardise for some of these variables, there is no assessment of the overall effect of these social and medical changes. Where the data have been standardised, real improvement seems to have been
patchy. We have standardised the mortality-rates for age and parity between 1964-66 and 1970-72 and we find that, whereas the ratio of the crude rates for "true" maternal mortality was 0.69, the S.M.R. when adjusted for age was 0.76 and when adjusted for parity was 0.77. When adjusted for age and parity simultaneously it was 0-80. It is clear, therefore, that there has been a real improvement of about 20% in maternal mortality, possibly attributable to the factors mentioned in the editorial. However, at least one-third of the observed improvement is due to the changing age and parity of the parturients. Similar effects may be due to changes in social class, and particularly in the gestational age at which abortions occur. The Department of Health no doubt has information which would allow proportional allocation of the observed fall to changes in the characteristics of pregnant women and the supposed effectiveness of medical intervention, but until this is done it cannot be said that a critical self-appraisal of the effectiveness of the work of obstetricians has been completed. We agree that this inquiry has for twenty-one years been an admirable example of critical self-appraisal, but it would now 1. Edmonson, H. A. Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology; section vii, fascicle 25. Washington, 1958. 2 Anthony, P. P. Lancet, 1975, i, 685.
vity
over two
smaller veins of the left calf contained adherent ante-mortem thrombi. Sections of thrombi taken from veins in various sites in both patients were studied by autoradiography. In patient A, who had been given labelled autologous fibrinogen 4 days before death, radioactivity was exclusively attached to fibrinogen and arranged in the form of strands. Edwards and Haynes’ found that at 60 hours the "majority of radioactivity was in relation to white blood-cells", and it must be recalled that these workers had used homologous commercially produced fibrinogen.
The purpose of our study has been to demonstrate the precise localisation of autologous fibrinogen produced in our laboratory, when taken up in a fresh thrombus. Fibrinogen obtained from commercial sources is not recommended for use in metabolic studies, being not reproducible between batches4 and containing degraded and denatured material as well as free iodine. McFarlane’ suggested that
fibrin/fibrinogen degradation products
are
phagocytosed by
cellular components in, or close to, the intravascular compartment. This pinocytosis by polymorphonuclear leucocytes has been observed experimentally by Bocci and his colleagues6 for other plasma-proteins, and there is positive chemotaxis of these cells for components of plasmin-digested fibrinogen.’ The degraded material present in the fibrinogen preparation administered to the patient of Edwards and Haynes, and certainly found in the second of our two patients at auto-radio1. 2.
Edwards, D. H., Haynes, D. W. Lancet, 1974, ii, 220. Hawker, R. J., Hawker, L. M. Unpublished.
3. Kakkar, V. V. m Thromboembolism: Diagnosis and Treatment (edited by V. V. Kakkar and A. J. Jouhar); p. 101. Edinburgh, 1972. 4. Hickman, J. A. Br. J. Hæmat. 1971, 20, 611. 5. McFarlane, A. S. Clin. Sci. 1964, 26, 415. 6. Bocci, V., Masti, L., Pacini, A., Viti, A. Exp. Cell Res. 1968, 52, 129. 7. McKenzie, R., Pepper, D. S., Kay, A. B. Thromb. Res. 1975, 6, 1.
