- Email: [email protected]
CHLORPROPAMIDE IN DIABETIC PREGNANCY
32
than upon complement activation3 or lymphocytedependent antibodies.4 Nevertheless, her experimentally induced lesions show differences from those of coeliac disease, in that plasma cells in the intestinal infiltrate are fewer and epithelial-cell changes less Thus it seems that cell-mediated reactions severe. may be involved in the pathogenesis of coeliac disease, but the exact mechanisms remain to be revealed.
CHLORPROPAMIDE IN DIABETIC PREGNANCY PREGNANCY in the insulin-independent diabetic may pose a difficult therapeutic problem. Increasing
impairment of carbohydrate tolerance is likely as pregnancy progresses, simple dietary measures may fail to control hyperglycsemia, and yet physician and patient alike are reluctant to start insulin injections if a safe alternative exists in tablet form. The temptation to prescribe a sulphonylurea (either de novo or by increasing the dose in pregnancy) must be weighed against the adequacy of control that these drugs can achieve and the potential hazards for fetal health inherent in a substance which crosses the placenta with ease and is a potent stimulant of pancreatic islet tissue. How safe is chlorpropamide for the fetus ? Early reports from South Africa suggested particular dangers in this context: Jackson et al. reported an overall fetal/infant mortality of 64% in a series of 25 chlorpropamide-treated pregnancies, the mortality being more than double that in pregnancies where the maternal diabetes was controlled with tolbutamide, diet, or insulin; and Campbell 6 raised the question of drug-induced malformation among surviving infants. These frightening figures were not, however, reproduced by clinicians in Britain (overall mortality 15% in 26 chlorpropamide-treated pregnancies 7), in Jamaica (mortality 12% in 34 pregnancies 8), or indeed by a later study from South Africa (mortality 14% in 58 pregnancies 9). None of these reports suggests a teratogenic effect of chlorpropamide : all lead to the suspicion that the outcome of pregnancy has been governed by the severity of maternal diabetes (which determines the dose of sulphonylurea), rather than by any specific morbid effect of chlorpropamide itself. This suspicion seems to be confirmed by a report from Aberdeen. 10 Sutherland and his colleagues review their experience with chlorpropamide, in daily dosage of at least 200 mg., in 19 pregnant diabetics, and correlate drug usage with diabetic control and fetal Good control of maternal diabetes was defined strictly as a mid-afternoon blood-glucose below 135 mg. per 100 ml. at all stages of pregnancy, and bad control likewise as a blood-glucose above 170 mg. per 100 ml. No constant relation was found
outcome.
3. Ballard, J., Shiner, M. Lancet, 1972, i, 1202. 4. Fakhri, O., Hobbs, J. R. ibid. 1972, ii, 403. 5. Jackson, W. P. U., Campbell, G. D., Notelovitz, M., Blumsohn, D. Diabetes, 1962, 11, suppl. p. 98. 6. Campbell, G. D. Br. med. J. 1963, i, 59. 7. Malins, J. M., Cooke, A. M., Pyke, D. A., Fitzgerald, M. G. ibid. 1964, ii, 187. 8. Douglas, C. P., Richards, R. Diabetes, 1967, 16, 60. 9. Notelovitz, M. S. Afr. med. J. 1971, 45, 226. 10. Sutherland, H. W., Bewsher, P. D., Cormack, J. D., Hughes, C. R. T., Reid, A., Russell, G., Stowers, J. M. Archs Dis. Childh. 1974, 49, 283.
daily dose of chlorpropamide, the total ingested during pregnancy, and the fetal outcome; the two intrauterine deaths were in badly controlled pregnancies where increased doses of chlorpropamide (500 mg. a day) had been used in the third trimester.
between the
The condition of the newborn infants reflected the control of diabetes during pregnancy: all infants from badly controlled pregnancies showed clinical or biochemical abnormalities, whereas half those from well controlled pregnancies showed no abnormality other than the plump and plethoric appearance typical in the infant of a diabetic mother. Intravenous 6 infants tests were on glucose-tolerance performed shortly after birth, and showed a brisker insulin response and rate of glucose disposal than in infants of untreated mothers with less severe diabetes. The Aberdeen findings provide strong evidence that in pregnancy is harmless to the fetus or infant and that good control of maternal diabetes, however this is achieved, is the most important contribution towards a successful outcome. A similar conclusion was drawn by White at the Joslin Clinic 11 in the pre-sulphonylurea era. But it would be unwise to suggest, merely because the drug is safe, that highdose chlorpropamide is an appropriate treatment in diabetic pregnancy: very high blood-sugar in such women is much better controlled with insulin. Chlorpropamide therapy is best confined to pregnant women with mild diabetes, in whom good control can be attained with small doses; and Sutherland et all have already documented its value in the treatchemical " diabetes in pregnancy. Chlorment of propamide in this context seems sensible and worthy of wider usage, provided it is combined with strict attention to other aspects of diabetic control and expert obstetric management.
chlorpropamide
"
tcPo2 HAVING to measure various blood-levels repeatedly in the care of certain critically ill patients is a nightmare for all concerned, and non-invasive techniques are a cherished dream. The blood-gases are a good case in point. To be valuable, arterial sampling usually has to be frequent, and the lot of patients on ventilatory support can undoubtedly be made easier if end-tidal Pco2 can be monitored instead of PaC02. The newborn baby with respiratory distress poses special difficulties. Carbon dioxide takes second place to oxygen, which must be maintained within normal limits. Either too little or too much may do permanent damage, and the only arbiter of what is right is the oxygen tension in the arterial blood. Frequent sampling is technically difficult and not without risk. The Clark electrode and micro-methods were great advances, but heel stabs, arterial punctures, and umbilical-artery cannulation-the neonatologist’s present stock-in-tradeare all invasive methods with their disadvantages. Capillary Po2 is not necessarily a good indication of Pao2; crying distorts the findings in samples obtained 11. 12.
White, P. Am. J. Med. 1949, 7, 609. Sutherland, H. W., Stowers, J. M., Cormack, J. D., Bewsher, P. D. Br. med. J. 1973, iii, 9.
than upon complement activation3 or lymphocytedependent antibodies.4 Nevertheless, her experimentally induced lesions show differences from those of coeliac disease, in that plasma cells in the intestinal infiltrate are fewer and epithelial-cell changes less Thus it seems that cell-mediated reactions severe. may be involved in the pathogenesis of coeliac disease, but the exact mechanisms remain to be revealed.
CHLORPROPAMIDE IN DIABETIC PREGNANCY PREGNANCY in the insulin-independent diabetic may pose a difficult therapeutic problem. Increasing
impairment of carbohydrate tolerance is likely as pregnancy progresses, simple dietary measures may fail to control hyperglycsemia, and yet physician and patient alike are reluctant to start insulin injections if a safe alternative exists in tablet form. The temptation to prescribe a sulphonylurea (either de novo or by increasing the dose in pregnancy) must be weighed against the adequacy of control that these drugs can achieve and the potential hazards for fetal health inherent in a substance which crosses the placenta with ease and is a potent stimulant of pancreatic islet tissue. How safe is chlorpropamide for the fetus ? Early reports from South Africa suggested particular dangers in this context: Jackson et al. reported an overall fetal/infant mortality of 64% in a series of 25 chlorpropamide-treated pregnancies, the mortality being more than double that in pregnancies where the maternal diabetes was controlled with tolbutamide, diet, or insulin; and Campbell 6 raised the question of drug-induced malformation among surviving infants. These frightening figures were not, however, reproduced by clinicians in Britain (overall mortality 15% in 26 chlorpropamide-treated pregnancies 7), in Jamaica (mortality 12% in 34 pregnancies 8), or indeed by a later study from South Africa (mortality 14% in 58 pregnancies 9). None of these reports suggests a teratogenic effect of chlorpropamide : all lead to the suspicion that the outcome of pregnancy has been governed by the severity of maternal diabetes (which determines the dose of sulphonylurea), rather than by any specific morbid effect of chlorpropamide itself. This suspicion seems to be confirmed by a report from Aberdeen. 10 Sutherland and his colleagues review their experience with chlorpropamide, in daily dosage of at least 200 mg., in 19 pregnant diabetics, and correlate drug usage with diabetic control and fetal Good control of maternal diabetes was defined strictly as a mid-afternoon blood-glucose below 135 mg. per 100 ml. at all stages of pregnancy, and bad control likewise as a blood-glucose above 170 mg. per 100 ml. No constant relation was found
outcome.
3. Ballard, J., Shiner, M. Lancet, 1972, i, 1202. 4. Fakhri, O., Hobbs, J. R. ibid. 1972, ii, 403. 5. Jackson, W. P. U., Campbell, G. D., Notelovitz, M., Blumsohn, D. Diabetes, 1962, 11, suppl. p. 98. 6. Campbell, G. D. Br. med. J. 1963, i, 59. 7. Malins, J. M., Cooke, A. M., Pyke, D. A., Fitzgerald, M. G. ibid. 1964, ii, 187. 8. Douglas, C. P., Richards, R. Diabetes, 1967, 16, 60. 9. Notelovitz, M. S. Afr. med. J. 1971, 45, 226. 10. Sutherland, H. W., Bewsher, P. D., Cormack, J. D., Hughes, C. R. T., Reid, A., Russell, G., Stowers, J. M. Archs Dis. Childh. 1974, 49, 283.
daily dose of chlorpropamide, the total ingested during pregnancy, and the fetal outcome; the two intrauterine deaths were in badly controlled pregnancies where increased doses of chlorpropamide (500 mg. a day) had been used in the third trimester.
between the
The condition of the newborn infants reflected the control of diabetes during pregnancy: all infants from badly controlled pregnancies showed clinical or biochemical abnormalities, whereas half those from well controlled pregnancies showed no abnormality other than the plump and plethoric appearance typical in the infant of a diabetic mother. Intravenous 6 infants tests were on glucose-tolerance performed shortly after birth, and showed a brisker insulin response and rate of glucose disposal than in infants of untreated mothers with less severe diabetes. The Aberdeen findings provide strong evidence that in pregnancy is harmless to the fetus or infant and that good control of maternal diabetes, however this is achieved, is the most important contribution towards a successful outcome. A similar conclusion was drawn by White at the Joslin Clinic 11 in the pre-sulphonylurea era. But it would be unwise to suggest, merely because the drug is safe, that highdose chlorpropamide is an appropriate treatment in diabetic pregnancy: very high blood-sugar in such women is much better controlled with insulin. Chlorpropamide therapy is best confined to pregnant women with mild diabetes, in whom good control can be attained with small doses; and Sutherland et all have already documented its value in the treatchemical " diabetes in pregnancy. Chlorment of propamide in this context seems sensible and worthy of wider usage, provided it is combined with strict attention to other aspects of diabetic control and expert obstetric management.
chlorpropamide
"
tcPo2 HAVING to measure various blood-levels repeatedly in the care of certain critically ill patients is a nightmare for all concerned, and non-invasive techniques are a cherished dream. The blood-gases are a good case in point. To be valuable, arterial sampling usually has to be frequent, and the lot of patients on ventilatory support can undoubtedly be made easier if end-tidal Pco2 can be monitored instead of PaC02. The newborn baby with respiratory distress poses special difficulties. Carbon dioxide takes second place to oxygen, which must be maintained within normal limits. Either too little or too much may do permanent damage, and the only arbiter of what is right is the oxygen tension in the arterial blood. Frequent sampling is technically difficult and not without risk. The Clark electrode and micro-methods were great advances, but heel stabs, arterial punctures, and umbilical-artery cannulation-the neonatologist’s present stock-in-tradeare all invasive methods with their disadvantages. Capillary Po2 is not necessarily a good indication of Pao2; crying distorts the findings in samples obtained 11. 12.
White, P. Am. J. Med. 1949, 7, 609. Sutherland, H. W., Stowers, J. M., Cormack, J. D., Bewsher, P. D. Br. med. J. 1973, iii, 9.