- Email: [email protected]
CIGARETTE SMOKING AND PREGNANCY WEIGHT GAIN
765
suggestion being the great saphenous vein artery. 2-4 anastomosed In 1976-77 eight saphenous-loop fistulas were created in eight patients. Under general anxsthesia, a longitudinal incision was made in the groin. The saphenous vein was dissected are
necessary,
to
one
DISTRIBUTION OF SELECTED HLA ANTIGENS IN CHRONIC SCHIZOPHRENICS AND CONTROLS
the femoral
level about the knee, with preservation of the junction with the femoral vein. A curved subcutaneous tunnel was made and the saphenous vein was brought through, avoiding kinking. End-to-side arteriovenous anastomosis was accomplished with a 6-0 uniterrupted silk suture. All patients were to a
I
given anticoagulation therapy with ’Marcoumar’ (fenprocoumon). The fistulas were used for htmodialysis after a period
Our results
of 3-4 weeks. Because of the thick skin and subcutaneous tissue at the upper thigh this type of fistula gave special problems. Compression and hasmostasis after dialysis treatment required special attention, to avoid bleeding. Even so, five hxmatomas were recorded in four patients-and there were two fatal Case 1.-This 55-year-old woman had been on h2emodiafor a year, the last 3 months via a saphenous loop. Oedema of the leg developed, and during haemodialysis a high venous pressure was regularly recorded (100 mm Hg). One day the patient was found dead on the floor at home. The police deduced that bleeding from the fistula had started while the patient was preparing breakfast. She had tried to stop the bleeding by a compression bandage while sitting in a chair. This had not been effective, and she had bled to death while trying to reach the telephone. Necropsy revealed no other cause of death and the fistula itself was intact. Case 2.-This 58-year-old woman had been on ha:modialysis for 14 months, the last 110 dialyses being via a saphenous loop. She knew about the death of the above patient and was given special instruction in the use of compression bandages in the event of external bleeding. 17 days after the death of case 1 she called an ambulance because of bleeding from the fistula, but she was dead at arrival at hospital. Necropsy revealed that death was due to exsanguination, but there was no damage to the fistula. The saphenous loop arteriovenous fistula is not a satisfactory alternative vascular access procedure. The main complication was bleeding, resulting in five hxmatomas and two deaths. We cannot recommend the saphenous loop arteriovenous fistula-and the two cases of fatal external bleeding call into question the placement of any fistula in the upper thigh.
greater value. The relation between schizophrenia and certain HLA types remains of interest because of the autoimmune hypothesis of schizophreniaand the possible role of the HLA system in determining postsynaptic receptor sensitivity to central neurotransmitters.3 .
Department of Psychiatry, Erasme Hospital, Free University of Brussels, Brussels 1070, Belgium
J. MENDLEWICZ P. LINKOWSKI
CIGARETTE SMOKING AND PREGNANCY WEIGHT GAIN
SIR,-Fetal growth retardation is associated with an increased rate of fetal and neonatal deaths, so many may assume that there is a direct connection between the fetal growth retardation and excessive perinatal mortality rates found in offspring of cigarette smokers. If such a causal relation exists, increasing birthweights by raising maternal food intake in pregnancy and by increasing maternal weight gains might protect fetuses against the unfavourable effects of smoking. Our analysis of data from 45 113 pregnancies show that increasing maternal weight gains affords no such protection. The data base includes mothers, infants, and placentas from the N.I.N.C.C.D.S. Collaborative Perinatal Project.4 The frequencies of abruptio placentas, placenta praevia, and large placental infarcts were determined for various maternal pregnancy weight gains because these three disorders are responsible for most of the increased fetal and neonatal deaths associated with maternal cigarette smoking during pregnancy.s The diagnostic criteria have been published elsewhere.5Maternal pregnancy weight gains were calculated in percent of "optimal" gains.6 Based on an optimal 12-3 kg weight gain at term, Hytten and Leitch found the weight gain at 20 weeks was 3-9 kg and at 30 weeks 8-6 kg. We used these and intermediate values to establish an optimal cumulative weight gain for each week of pregnancy. We then divided each mother’s total pregnancy weight gain by the optimal weight gain value for
JORGEN NORDLING FOLMER LYNGGAARD ROLF IVERSEN HANSEN
HLA ANTIGENS AND SCHIZOPHRENIA
SIR,-Dr Gattaz and Dr Beckmann (Jan. 12,
p. 98) report association with HLA-B27 in chronic or poor prognosis schizophrenia. Using the same diagnostic criteria we have studied HLA antigen frequencies in 64 chronic schizophrenics with poor prognosis and 113 controls. Patients and controls were Whites of Belgian origin. HLA typing was done on peripheral blood lymphocytes by the N.I.H. (N.I.A.I.D.) cytotoxicity test with 120 antisera. We estimated the relative risk and its significance’ (p values being multiplied by the number of an
antigens tested).
variance with those of Gattaz and Beck-
(see table). There is an excess BW16 and a deficit in Al and B7 in schizophrenic patients, but no association with B27. These conflicting results could be linked to methodological problems related to sampling or statistical procedures. HLA studies on small samples of patients run the risk of picking up false associations. This can be avoided by testing new samples of patients and controls, independently from the first samples but originating from the same population. Family studies with segregation analysis and linkage estimation may be of even
lysis
Copenhagen, Denmark
are at
I
mann
bleeding episodes.
Departments of Nephrology and Urology, Hvidovre Hospital,
I
&mid ot;
2. Heath RG, Krupp IM. Schizophrenia as an immunologic disorder. Arch Gen
Psychiat 1967; 16: 1-9. 2. Enderlin F, Harder F, Rittmann WW, Massini MA. Periodische Hämodialyse mit Hilfe der arterialisierten v. Saphena. Helv Chir Acta 1971; 38: 346. 3 Lawton RL, Freeman RM. Unusual intra- and extra-corporeal connections for vascular access. Proc Eur Dial Transpl Assoc 1970; 7: 413-15. 4 Firlit CF, Canning J. Saphenofemoral shunt. Arch Surg 1972; 104: 854-55. 1. Woolf B. On estimating the relation between blood groups and disease. Ann Hum Genet 1955; 19: 251-60.
3. Svejgaard A. The HLA system: An introductory survey. Monogr Hum Genet
1976; no. 7. 4. Niswander RK. The women and their pregnancies. Philadelphia: WB Saunders, 1972. 5. Naeye RL. The duration of maternal cigarette smoking, fetal and placental disorders. Early Hum Develop 1979; 2: 229-37. 6. Hytten FE, Leitch I. The physiology of human pregnancy, ed 2. Oxford:
Blackwell, 1971.
766 MAJOR PREGNANCY DISORDERS
IN RELATION TO MATERNAL
WEIGHT GAIN AND SMOKING
*Non-smokers v. smokers. (When complication rates within smoking categories were compared, the rate for abruptio placentae in <45% weight gain group was the only one significantly different from the corresponding rate for the >75% group, at p<0.05.) Numbers of cases are
shown in italic type.
the length of her pregnancy. The results are seen in the table. The frequencies of abruptio placentae, placenta praevia, and large placental infarcts were greater in smokers than in nonsmokers and changed little as pregnancy weight gains increased. We conclude that increasing maternal food intake during pregnancy is unlikely to protect the fetus and neonate against the deleterious effects of the mother’s smoking cigarettes. Department of Pathology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033, U.S.A.
needed 50 000 IU, but she is now taking 100 000 IU daily. Vitamin E alone has proved worthless. The reason for this remarkable response to vitamin A in this case is obscure, as are the biological implications. Serum concentrations of vitamin A were normal (0.8-4.1 p.mol/1) both after 3 months of treatment (2.5 mol/1) and after a 3-week period without the drug (1.2 mol/1) during which the patient lost about 3 kg in weight. To see if intestinal permeability was involved we did polyethyleneglycol (PEG, 400) studies.2,J Before treatment the permeability pattern was similar to that found in other patients with Crohn’s disease. Although urinary recovery of PEG 400 was decreased overall, the intestinal permeability barrier against the larger molecules in the polymeric mixture was impaired. After treatment with vitamin A the permeability characteristics resembled those found in healthy individuals, and the effect of vitamin A in this case was similar to the change in the abnormal profile in patients with coeliac disease who responded to gluten-free diet.2 Retinoids, including retinol, profoundly affect the metabolism and differentiation of epithelial tissues, among them the intestinal mucosa: changes include increases in goblet cell numbers, production of glycoproteins, secretion of mucus, and formation of glycocalyx.4.5 It could be that vitamin A restored some previously impaired intestinal-barrier function. If so and if, as is suspected, the essential abnormality in Crohn’s disease is impaired function of the intestinal barrier, other Crohn’s patients might benefit from vitamin A. Certain systemic diseases associated with gut changes (e.g., dermatitis herpetiformis, other dermatoses, and inflammatory joint disease might also respond to vitamin A or other retinoids-indeed a pilot study on dermatitis herpetiformis looks promising. Departments of Dermatology, Medical Microbiology, and Clinical Chemistry, University Hospital, S-581 85
M. SKOGH T. SUNDQUIST C. TAGESSON
Linköping, Sweden
RICHARD L. NAEYE NUTRITIONAL ŒDEMA
SIR,- The paper from the Tropical Metabolism Research Unit, Jamaica (Jan. 19, p. 114) provides some objective evi-
VITAMIN A IN CROHN’S DISEASE
SIR,-In the search for derivatives of vitamin A (retinol) with a better therapeutic ratio than the natural .vitamin, many retinoids have been tested. The driving force has been their use in the prevention and treatment of cancer, but retinoids have also been tried in skin conditions with disordered keratinisation. We decided to test the alleged potentiating effect of vitamin E on the action of vitamin A’ in a small series of patients with psoriasis. Among the patients investigated was a 31-year-old woman with Crohn’s disease. She had had an ileocaecal resection with considerable improvement, but she still had moderate diarrhoea about twice a day. At the end of July, 1979, oral treatment with vitamin A (retinol palmitate 50 000 IU thrice daily) combined with vitamin E (d-a-tocopheryl acetate 100 rhg thrice daily) was started. The psoriatic lesions healed within 2 weeks, which the patient felt could have been due to chance because improvement usually took place at about that time of the year. But the most striking effect was a return to normal bowel function. Soon after starting the new treatment the patient found she could eat any food, even plums, without any ill-effects and with no diarrhoea. She agreed to continue treatment with one of the two vitamins, and after a time switch over to the other. After interrupting and reinstituting treatment several times it has become quite clear that the gut symptoms reeur within a couple of days of stopping the vitamin A, but that the bowel returns to normal function within days of the reintroduction of vitamin A. At the start she
2
1. Ayres
S, Jr., Mihan R, Scribner MD. Synergism of vitamins A and E dermatologic applications. Cutis 1979; 23: 600-90.
with
dence for the suggestion often made before that nutritional oedema is not primarily caused by a fall in serum albumin. However, the removal of one effete theory of causation is always more easily accomplished if another can be suggested. In their discussion, Dr Golden and his colleagues do not suggest an alternative, but I think there are some recent developments which may point the way to a better hypothesis. Oedema is the clinical manifestation of sodium retention. There must, therefore, be an abnormality in the renal mechanisms responsible for sodium homoeostasis yet, as Golden et at. argue, alterations in renal haemodynamics and mineralocorticoids are not different in oedematous and non-oedematous cases of severe malnutrition. What is lacking in the child with kwashiorkor is the elusive "third factor"—or whatever it is that mediates the normally precise renal response to a saline load-since this too is independent of glomerular filtration rate and mineralocorticoid concentrations. This important 2. Chadwick
VS, Phillips SF, Hofmann AF. Measurement of intestinal permealow molecular weight glycols (PEG 400) II: Application to
bility using
normal and abnormal permeability states in terology 1977; 73: 247-51.
man
and animals. Gastroen-
3.
Sundqvist T, Magnusson K-E, Sjödahl R, Stjernström I, Tagesson C. Passage of molecules through the wall of the gastrointestinal tract II Application of low-molecular weight polyethyleneglycol and a deterministic mathematical model for determining the intestinal permeability in man Gut (in press). 4. De Luca L, Schumacher M, Wolf G, Newberne PM. Biosynthesis of a fucosecontaining glycopeptide from rat small intestine in normal and vitamin A-deficinet conditions. J Biol Chem 1970; 245: 4551-558. 5. Orfanos CE, Pullman H, Runne U, et al. Behandlung der Psoriasis mit Vitamin A, Vitamin-A-Säure und oralen Retinoiden. Hautarzt 1979, 30: 124-33.
suggestion being the great saphenous vein artery. 2-4 anastomosed In 1976-77 eight saphenous-loop fistulas were created in eight patients. Under general anxsthesia, a longitudinal incision was made in the groin. The saphenous vein was dissected are
necessary,
to
one
DISTRIBUTION OF SELECTED HLA ANTIGENS IN CHRONIC SCHIZOPHRENICS AND CONTROLS
the femoral
level about the knee, with preservation of the junction with the femoral vein. A curved subcutaneous tunnel was made and the saphenous vein was brought through, avoiding kinking. End-to-side arteriovenous anastomosis was accomplished with a 6-0 uniterrupted silk suture. All patients were to a
I
given anticoagulation therapy with ’Marcoumar’ (fenprocoumon). The fistulas were used for htmodialysis after a period
Our results
of 3-4 weeks. Because of the thick skin and subcutaneous tissue at the upper thigh this type of fistula gave special problems. Compression and hasmostasis after dialysis treatment required special attention, to avoid bleeding. Even so, five hxmatomas were recorded in four patients-and there were two fatal Case 1.-This 55-year-old woman had been on h2emodiafor a year, the last 3 months via a saphenous loop. Oedema of the leg developed, and during haemodialysis a high venous pressure was regularly recorded (100 mm Hg). One day the patient was found dead on the floor at home. The police deduced that bleeding from the fistula had started while the patient was preparing breakfast. She had tried to stop the bleeding by a compression bandage while sitting in a chair. This had not been effective, and she had bled to death while trying to reach the telephone. Necropsy revealed no other cause of death and the fistula itself was intact. Case 2.-This 58-year-old woman had been on ha:modialysis for 14 months, the last 110 dialyses being via a saphenous loop. She knew about the death of the above patient and was given special instruction in the use of compression bandages in the event of external bleeding. 17 days after the death of case 1 she called an ambulance because of bleeding from the fistula, but she was dead at arrival at hospital. Necropsy revealed that death was due to exsanguination, but there was no damage to the fistula. The saphenous loop arteriovenous fistula is not a satisfactory alternative vascular access procedure. The main complication was bleeding, resulting in five hxmatomas and two deaths. We cannot recommend the saphenous loop arteriovenous fistula-and the two cases of fatal external bleeding call into question the placement of any fistula in the upper thigh.
greater value. The relation between schizophrenia and certain HLA types remains of interest because of the autoimmune hypothesis of schizophreniaand the possible role of the HLA system in determining postsynaptic receptor sensitivity to central neurotransmitters.3 .
Department of Psychiatry, Erasme Hospital, Free University of Brussels, Brussels 1070, Belgium
J. MENDLEWICZ P. LINKOWSKI
CIGARETTE SMOKING AND PREGNANCY WEIGHT GAIN
SIR,-Fetal growth retardation is associated with an increased rate of fetal and neonatal deaths, so many may assume that there is a direct connection between the fetal growth retardation and excessive perinatal mortality rates found in offspring of cigarette smokers. If such a causal relation exists, increasing birthweights by raising maternal food intake in pregnancy and by increasing maternal weight gains might protect fetuses against the unfavourable effects of smoking. Our analysis of data from 45 113 pregnancies show that increasing maternal weight gains affords no such protection. The data base includes mothers, infants, and placentas from the N.I.N.C.C.D.S. Collaborative Perinatal Project.4 The frequencies of abruptio placentas, placenta praevia, and large placental infarcts were determined for various maternal pregnancy weight gains because these three disorders are responsible for most of the increased fetal and neonatal deaths associated with maternal cigarette smoking during pregnancy.s The diagnostic criteria have been published elsewhere.5Maternal pregnancy weight gains were calculated in percent of "optimal" gains.6 Based on an optimal 12-3 kg weight gain at term, Hytten and Leitch found the weight gain at 20 weeks was 3-9 kg and at 30 weeks 8-6 kg. We used these and intermediate values to establish an optimal cumulative weight gain for each week of pregnancy. We then divided each mother’s total pregnancy weight gain by the optimal weight gain value for
JORGEN NORDLING FOLMER LYNGGAARD ROLF IVERSEN HANSEN
HLA ANTIGENS AND SCHIZOPHRENIA
SIR,-Dr Gattaz and Dr Beckmann (Jan. 12,
p. 98) report association with HLA-B27 in chronic or poor prognosis schizophrenia. Using the same diagnostic criteria we have studied HLA antigen frequencies in 64 chronic schizophrenics with poor prognosis and 113 controls. Patients and controls were Whites of Belgian origin. HLA typing was done on peripheral blood lymphocytes by the N.I.H. (N.I.A.I.D.) cytotoxicity test with 120 antisera. We estimated the relative risk and its significance’ (p values being multiplied by the number of an
antigens tested).
variance with those of Gattaz and Beck-
(see table). There is an excess BW16 and a deficit in Al and B7 in schizophrenic patients, but no association with B27. These conflicting results could be linked to methodological problems related to sampling or statistical procedures. HLA studies on small samples of patients run the risk of picking up false associations. This can be avoided by testing new samples of patients and controls, independently from the first samples but originating from the same population. Family studies with segregation analysis and linkage estimation may be of even
lysis
Copenhagen, Denmark
are at
I
mann
bleeding episodes.
Departments of Nephrology and Urology, Hvidovre Hospital,
I
&mid ot;
2. Heath RG, Krupp IM. Schizophrenia as an immunologic disorder. Arch Gen
Psychiat 1967; 16: 1-9. 2. Enderlin F, Harder F, Rittmann WW, Massini MA. Periodische Hämodialyse mit Hilfe der arterialisierten v. Saphena. Helv Chir Acta 1971; 38: 346. 3 Lawton RL, Freeman RM. Unusual intra- and extra-corporeal connections for vascular access. Proc Eur Dial Transpl Assoc 1970; 7: 413-15. 4 Firlit CF, Canning J. Saphenofemoral shunt. Arch Surg 1972; 104: 854-55. 1. Woolf B. On estimating the relation between blood groups and disease. Ann Hum Genet 1955; 19: 251-60.
3. Svejgaard A. The HLA system: An introductory survey. Monogr Hum Genet
1976; no. 7. 4. Niswander RK. The women and their pregnancies. Philadelphia: WB Saunders, 1972. 5. Naeye RL. The duration of maternal cigarette smoking, fetal and placental disorders. Early Hum Develop 1979; 2: 229-37. 6. Hytten FE, Leitch I. The physiology of human pregnancy, ed 2. Oxford:
Blackwell, 1971.
766 MAJOR PREGNANCY DISORDERS
IN RELATION TO MATERNAL
WEIGHT GAIN AND SMOKING
*Non-smokers v. smokers. (When complication rates within smoking categories were compared, the rate for abruptio placentae in <45% weight gain group was the only one significantly different from the corresponding rate for the >75% group, at p<0.05.) Numbers of cases are
shown in italic type.
the length of her pregnancy. The results are seen in the table. The frequencies of abruptio placentae, placenta praevia, and large placental infarcts were greater in smokers than in nonsmokers and changed little as pregnancy weight gains increased. We conclude that increasing maternal food intake during pregnancy is unlikely to protect the fetus and neonate against the deleterious effects of the mother’s smoking cigarettes. Department of Pathology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033, U.S.A.
needed 50 000 IU, but she is now taking 100 000 IU daily. Vitamin E alone has proved worthless. The reason for this remarkable response to vitamin A in this case is obscure, as are the biological implications. Serum concentrations of vitamin A were normal (0.8-4.1 p.mol/1) both after 3 months of treatment (2.5 mol/1) and after a 3-week period without the drug (1.2 mol/1) during which the patient lost about 3 kg in weight. To see if intestinal permeability was involved we did polyethyleneglycol (PEG, 400) studies.2,J Before treatment the permeability pattern was similar to that found in other patients with Crohn’s disease. Although urinary recovery of PEG 400 was decreased overall, the intestinal permeability barrier against the larger molecules in the polymeric mixture was impaired. After treatment with vitamin A the permeability characteristics resembled those found in healthy individuals, and the effect of vitamin A in this case was similar to the change in the abnormal profile in patients with coeliac disease who responded to gluten-free diet.2 Retinoids, including retinol, profoundly affect the metabolism and differentiation of epithelial tissues, among them the intestinal mucosa: changes include increases in goblet cell numbers, production of glycoproteins, secretion of mucus, and formation of glycocalyx.4.5 It could be that vitamin A restored some previously impaired intestinal-barrier function. If so and if, as is suspected, the essential abnormality in Crohn’s disease is impaired function of the intestinal barrier, other Crohn’s patients might benefit from vitamin A. Certain systemic diseases associated with gut changes (e.g., dermatitis herpetiformis, other dermatoses, and inflammatory joint disease might also respond to vitamin A or other retinoids-indeed a pilot study on dermatitis herpetiformis looks promising. Departments of Dermatology, Medical Microbiology, and Clinical Chemistry, University Hospital, S-581 85
M. SKOGH T. SUNDQUIST C. TAGESSON
Linköping, Sweden
RICHARD L. NAEYE NUTRITIONAL ŒDEMA
SIR,- The paper from the Tropical Metabolism Research Unit, Jamaica (Jan. 19, p. 114) provides some objective evi-
VITAMIN A IN CROHN’S DISEASE
SIR,-In the search for derivatives of vitamin A (retinol) with a better therapeutic ratio than the natural .vitamin, many retinoids have been tested. The driving force has been their use in the prevention and treatment of cancer, but retinoids have also been tried in skin conditions with disordered keratinisation. We decided to test the alleged potentiating effect of vitamin E on the action of vitamin A’ in a small series of patients with psoriasis. Among the patients investigated was a 31-year-old woman with Crohn’s disease. She had had an ileocaecal resection with considerable improvement, but she still had moderate diarrhoea about twice a day. At the end of July, 1979, oral treatment with vitamin A (retinol palmitate 50 000 IU thrice daily) combined with vitamin E (d-a-tocopheryl acetate 100 rhg thrice daily) was started. The psoriatic lesions healed within 2 weeks, which the patient felt could have been due to chance because improvement usually took place at about that time of the year. But the most striking effect was a return to normal bowel function. Soon after starting the new treatment the patient found she could eat any food, even plums, without any ill-effects and with no diarrhoea. She agreed to continue treatment with one of the two vitamins, and after a time switch over to the other. After interrupting and reinstituting treatment several times it has become quite clear that the gut symptoms reeur within a couple of days of stopping the vitamin A, but that the bowel returns to normal function within days of the reintroduction of vitamin A. At the start she
2
1. Ayres
S, Jr., Mihan R, Scribner MD. Synergism of vitamins A and E dermatologic applications. Cutis 1979; 23: 600-90.
with
dence for the suggestion often made before that nutritional oedema is not primarily caused by a fall in serum albumin. However, the removal of one effete theory of causation is always more easily accomplished if another can be suggested. In their discussion, Dr Golden and his colleagues do not suggest an alternative, but I think there are some recent developments which may point the way to a better hypothesis. Oedema is the clinical manifestation of sodium retention. There must, therefore, be an abnormality in the renal mechanisms responsible for sodium homoeostasis yet, as Golden et at. argue, alterations in renal haemodynamics and mineralocorticoids are not different in oedematous and non-oedematous cases of severe malnutrition. What is lacking in the child with kwashiorkor is the elusive "third factor"—or whatever it is that mediates the normally precise renal response to a saline load-since this too is independent of glomerular filtration rate and mineralocorticoid concentrations. This important 2. Chadwick
VS, Phillips SF, Hofmann AF. Measurement of intestinal permealow molecular weight glycols (PEG 400) II: Application to
bility using
normal and abnormal permeability states in terology 1977; 73: 247-51.
man
and animals. Gastroen-
3.
Sundqvist T, Magnusson K-E, Sjödahl R, Stjernström I, Tagesson C. Passage of molecules through the wall of the gastrointestinal tract II Application of low-molecular weight polyethyleneglycol and a deterministic mathematical model for determining the intestinal permeability in man Gut (in press). 4. De Luca L, Schumacher M, Wolf G, Newberne PM. Biosynthesis of a fucosecontaining glycopeptide from rat small intestine in normal and vitamin A-deficinet conditions. J Biol Chem 1970; 245: 4551-558. 5. Orfanos CE, Pullman H, Runne U, et al. Behandlung der Psoriasis mit Vitamin A, Vitamin-A-Säure und oralen Retinoiden. Hautarzt 1979, 30: 124-33.