- Email: [email protected]
Diabetes and Malformation
587 a desirable event. The argument3 that the N.H.S. is in fact providing reasonable value for money ("but could do better") will never satisfy the extreme cutters of public spending or the more excitable private-market enthusiasts. For its part, the medical profession must no longer acquiesce in such numbers in the downgrading of the Service by the present Government. All doctors who feel dejected by what is happening must make their concern plain to their colleagues and to the public.
private medicine as
The State of the N.H.S. THE industrial action which has been jeopardising the National Health Service and its patients for many weeks past could be quickly concluded by a modest concession from the Government. First, give more money now to the lowest paid, on the understanding that this retreat shall brook no argument whatsoever about preservation of differentials. Second, insist on, rather than vaguely offer, further negotiations with the Royal College of Nursing and the unions. After the immediate suspension of all industrial action, discussion could then concentrate on: the mechanism of future pay negotiations between Government, and non-medical N.H.S. nurses, employees; examination of staffing structure and the widely
publicised, though not fully substantiated, allegations of overmanning at certain levels and in some areas; and the prospects for job-sharing (since the Government seems resolved to let unemployment mount) and for no-strike agreements. A Cabinet meeting due to be held on Sept. 9 may conceivably have opened the way to reconciliation with the protesting N.H.S. staff, but the auguries earlier this week were far from favourable, particularly since the Secretary of State for Social Services, Mr NORMAN FOWLER, had painted himself into a corner with his implausible cries of no more money. One root of the dispute lies in the unfairness of across-the-board percentage increases in pay. Unions and Government must recognise the need to agree on a formula which does not leave the lowest paid worse off than they were last year. Lord TAYLOR has proposed one plan and there are others, all of which merit discussion in the efforts to construct fairer pay settlements, not only in the N.H.S. Because of his shrill attribution of blame to all who oppose his views, Mr FOWLER’s reputation has lost even more of its lustre since The Lancet suggested2 last month that he should change course-or resign. His junior, Mr KENNETH CLARKE, the Minister for Health, seems equally devoted to the unyielding line laid down by the Prime Minister. His remarks about the use of troops in support of the N.H.S. were regrettable and needlessly aggravating. It is the future of the declining N.H.S., and not the outcome of the present pay row, which is the cause for gravest concern, though the longer the dispute drags on the worse the ultimate prospects become. The N.H.S. is not, as the Government seems to suppose, a woeful extravagance in need of strict curbing: it is a national asset to be preserved from deprivation at the hand of Mrs THATCHER and those who share her lack of concern over recent events and who see the expansion of 1. 2.
Times, Aug. 25, 1982, p. 9. Lancet, Aug. 14, 1982, p. 365.
Diabetes and Malformation CONGENITAL
malformations
are
unhappily
major defects occurring in around 1 in 40 births. Any possible relation between such a common event and the widely prevalent disease, diabetes mellitus, is therefore difficult to evaluate, particularly when most anomalies in man seem to be produced by the interaction of genetic factors and the environment-including the intrauterine milieu.4 Reviewing the published work, MILLS5 points out the difficulties of deciding whether the diabetic group treated in referral hospitals where malformation common,
studies have been done are typical of all diabetics in the area and, in addition, the importance of the source of the control group, of age matching of pregnancies, and of allowance for the greater medical attention given to infants of diabetic mothers because of their risk of perinatal illness-attention which may result in ascertainment bias for malformation. The definitive study, he concludes, has yet to be done. Of those which do point to an association between diabetes and malformations, one was retrospective6 ind one relied on published reports to determine rates of malformation in the control population.7 Nonetheless, MILLS judges that diabetic mothers have malformation rates two or three times higher than normal. Notable dissenting voices are those of FARQUHAR,,9 of RUBIN and MURPHY,’0 and of GELLIS and HSIA," whose results and reviews were reported in the 1950s and 1960s. Furthermore, NAKAMURA et al. 12 have lately reported negative results in an examination of 1000 perinatal deaths. Almost 10% of the mothers were diabetic, but no malformations were found in their 3. Laurance
J. New Society, Aug. 26, 1982, p. 331.
4. Berry CL. Congenital malformations. In: Berry CL, ed. Paediatric pathology. London, Heidelberg, New York: Springer Verlag, 1981: 67-86. 5. Mills JL. Malformations in infants of diabetic mothers. Teratology 1982; 25: 385-94. 6. Molsted-Pedersen L, Tygstrup I, Pedersen J. Congenital malformations in newborn infants of diabetic women. Lancet 1964; i: 1124-26. 7. Kucera J. Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 1971; 7: 61-70. 8. Farquhar JW. The child of the diabetic woman. Arch Dis Childh 1959; 34: 76-96. 9. Farquhar JW. Prognosis for babies born to diabetic mothers in Edinburgh. Arch Dis Childh 1969; 44: 36-47. 10. Rubin A, Murphy DP. Studies in human reproduction III. The frequency of congenital malformation in the offspring of non-diabetic and diabetic individuals. J Pediatr 1958; 33: 579. 11. Gellis SS, Hsia DY. The infant of the diabetic mother. AMA J Dis Child 1959; 97: 1-41. 12. Nakamura Y, Hosokawa Y, Yano H, Nakashima N, Nakashima T, Komatsu Y, Nakashima H, Fakuda S, Kuyama M, Hashimoto T, Nagasue N, Aiko Y, Kabashima S. Primary causes of perinatal death. An autopsy study of1000 cases in Japanese infants. Human Pathol 1982; 13: 54-61.
588
necropsy. The difficulties of defining malformation (hydroceles are included in some studies, only major anomalies in others), the choice of patients and controls, and problems in ascertainment where necropsies have not been done lead to variable interpretation of results and differing views on their meaning. However MILLS does argue persuasively that malformations in general are more frequent in the children of diabetic mothers. What might be the mechanism? Further analysis of KUCERA’s data by MILLS et al. 13 suggests that the abnormalities have their origin before the 7th week of development-a noteworthy observation in view of the reports by PEDERSEN and MOLSTED-PEDERSEN of early growth delay14 and increased loss of small fetuses15 in diabetic pregnancies. If this is so then diabetes can be set alongside various and fetal growth other factors which reduce of in the and which, opinion SPIERS, 16 may contribute substantially to malformation in man. Specific associations of malformations with diabetes have not been confirmed with the exception of the caudal regression syndrome (agenesis or hypoplasia of the femora with agenesis of low vertebrae), for which the relative risk in infants of diabetic mothers is over 200. There are some areas of general agreement about risk of malformation in diabetes mellitus. Diabetic fathers do not have more malformed children than the male population at large, 17 suggesting that the malformation-enhancing effect of diabetes is not a result of diabetes-associated genes. Prediabetic women do not seem to be at increased risk of producing malformed infants and studies which have purported to find this show obvious selection bias. Women with gestational diabetes do not show an increased malformation risk-a matter studied in detail in the prospective Collaborative Perinatal Project.’8 As to whose diabetes is controlled by oral women hypoglycaemic agents, some positive findings have been reported,19 but the number of studies is small and the weight of the data suggests no additional hazard. 20 , How might diabetes hamper development? The disease is complex in biochemical terms: all aspects of intermediary metabolism may be altered, as well as levels of circulating hormones. As in much experimental teratogenesis, extrapolation from laboratory animal to man can be misleading; for
offspring
,
at
embryonic
13. Mills 14.
15. 16. 17.
18. 19. 20.
JL, Baker L, Goldman AS. Malformation in infants of diabetic mothers occur before the seventh gestational week. Diabetes 1979; 28: 292-93. Pedersen JF, Molsted-Pedersen L. Early fetal growth delay detected by ultrasound marks increased risk of congenital malformation in diabetic pregnancy Br Med J 1981; 283: 269-71. Pedersen JF, Molsted-Pedersen L. Early growth delay predisposes the fetus in diabetic pregnancy to congenital malformation. Lancet 1982; i: 737. Spiers SP. Does growth retardation predispose the fetus to congenital malformation? Lancet 1982; i: 312-14. Bennet PH, Webner C, Miller M. Congenital anomalies and the diabetic pregnancy In: Pregnancy, metabolism, diabetes and the fetus (Ciba Found Symp 63). Amsterdam: Excerpta Medica, 1979. Chung CS, Myrianthopolus NC. I. Factors affecting risks of congenital malformations. II. Effect of maternal diabetes. Birth Defects Orig Art Series XI no. 10; 1975. Soler N, Walsh C, Malus J. Congenital malformations in newborn infants of diabetic mothers. Quart J Med 1976; 178: 303-13. Day R, Insley J. Maternal diabetes and congenital malformations Arch Dis Childh 1976; 51: 935-38.
example, DURAISW AMI21 produced limb anomalies in chick embryos with insulin, but later work suggests that metabolic disturbance is more important than the hormone.22 REID,23 in 1970, suggested that certain fetal cells may be especially sensitive to exogenous glucose levels. They may be switched by high maternal blood glucose to a glycolytic pattern of metabolism and repress mitochondrial biogenesis, thus affecting growth rates of cells, preventing them from meeting their "spatio-temporal commitments" during organogenesis. Reversion to normal blood glucose might further decrease the energy supply, and fluctuations would be particularly dangerous-a suggestion supported by the apparently higher malformation rates in severely affected mothers.24 In the investigations reported so far, a major problem is that few workers have studied the relevant phase of human gestation. The period before 7-8 weeks is clearly critical and is the time when fetal wastage is greatest and most anomalies have their origins.4 No insulin is produced by the fetus in this time25 and maternal insulin does not cross the placenta until later in pregnancy-further support for an effect not directly dependent on insulin. LESLIE and his colleagues26 have used haemoglobin A levels as an integrated measure of blood glucose over the preceding weeks, in insulin-dependent diabetic mothers. In three offive cases with raised levels at first medical contact in pregnancy, malformations occurred; there were none in eighteen babies whose mothers had a normal HbA,. Of course, these observations tell us nothing about the effects of concurrent changes in metabolism. If better control of diabetes offers a reduction of hazard to the embryo and fetus, it must clearly be started before conception.2’ By the time of the first antenatal visit the damage may be done.
Renal THE first FRIEDREICH
Papillary Necrosis account of renal papillary necrosis, by
1877,1I concerned patients with prostatic hypertrophy and secondary hydronephrosis. in
In MANDEL’s 1952 report,2 60% of cases were attributed to diabetes, 3007o to urinary-tract obstruction, and 9’ 4% to both, urinary-tract infection has been found in up to 95% of cases seen at necropsy. It was in the late 1950s and early 1960s that analgesic 21. Duraiswami PK. Insulin induced skeletal abnormalities in developing chickens. Br Med J 1952, ii: 384-90. 22. Horrii K, Watanable, G, Ingalls TH. Experimental diabetes in pregnant mice. Prevention of congenital malformations in offspring by insulin. Diabetes 1966, 15: 192-204. 23. Reid RA. Diabetes and congenital abnormalities. Lancet 1970, i: 1030-31. 24 Molsted-Pedersen L, Tygstrup I, Pedersen J. Congenital malformation in newborn infants of diabetic women. Lancet 1964; i: 1124-26. 25 Like A, Orci L. Embryogenesis of the human pancreatic islets A light and electron microscopic study Diabetes 1972; 21: 511-34. 26. Leslie RDG, Pyke DA, John PN, White JN. Haemoglobin A1in diabetic pregnancy Lancet 1978; ii: 958-59. 27 Steel JM, Johnstone FD, Smith AF, Duncan LJP Five years’ experience of a "prepregnancy" clinic for insulin-dependent diabetics Br Med J 1982; 285: 353-56 1. Friedreich N Ueber Necrose der Nierenpapillen bei Hydronephrose. Virchows Arch Pathol Anat 1877, 69: 308. 2 Mandel EE. Renal medullary necrosis. Am J Med 1952, 13: 322.
private medicine as
The State of the N.H.S. THE industrial action which has been jeopardising the National Health Service and its patients for many weeks past could be quickly concluded by a modest concession from the Government. First, give more money now to the lowest paid, on the understanding that this retreat shall brook no argument whatsoever about preservation of differentials. Second, insist on, rather than vaguely offer, further negotiations with the Royal College of Nursing and the unions. After the immediate suspension of all industrial action, discussion could then concentrate on: the mechanism of future pay negotiations between Government, and non-medical N.H.S. nurses, employees; examination of staffing structure and the widely
publicised, though not fully substantiated, allegations of overmanning at certain levels and in some areas; and the prospects for job-sharing (since the Government seems resolved to let unemployment mount) and for no-strike agreements. A Cabinet meeting due to be held on Sept. 9 may conceivably have opened the way to reconciliation with the protesting N.H.S. staff, but the auguries earlier this week were far from favourable, particularly since the Secretary of State for Social Services, Mr NORMAN FOWLER, had painted himself into a corner with his implausible cries of no more money. One root of the dispute lies in the unfairness of across-the-board percentage increases in pay. Unions and Government must recognise the need to agree on a formula which does not leave the lowest paid worse off than they were last year. Lord TAYLOR has proposed one plan and there are others, all of which merit discussion in the efforts to construct fairer pay settlements, not only in the N.H.S. Because of his shrill attribution of blame to all who oppose his views, Mr FOWLER’s reputation has lost even more of its lustre since The Lancet suggested2 last month that he should change course-or resign. His junior, Mr KENNETH CLARKE, the Minister for Health, seems equally devoted to the unyielding line laid down by the Prime Minister. His remarks about the use of troops in support of the N.H.S. were regrettable and needlessly aggravating. It is the future of the declining N.H.S., and not the outcome of the present pay row, which is the cause for gravest concern, though the longer the dispute drags on the worse the ultimate prospects become. The N.H.S. is not, as the Government seems to suppose, a woeful extravagance in need of strict curbing: it is a national asset to be preserved from deprivation at the hand of Mrs THATCHER and those who share her lack of concern over recent events and who see the expansion of 1. 2.
Times, Aug. 25, 1982, p. 9. Lancet, Aug. 14, 1982, p. 365.
Diabetes and Malformation CONGENITAL
malformations
are
unhappily
major defects occurring in around 1 in 40 births. Any possible relation between such a common event and the widely prevalent disease, diabetes mellitus, is therefore difficult to evaluate, particularly when most anomalies in man seem to be produced by the interaction of genetic factors and the environment-including the intrauterine milieu.4 Reviewing the published work, MILLS5 points out the difficulties of deciding whether the diabetic group treated in referral hospitals where malformation common,
studies have been done are typical of all diabetics in the area and, in addition, the importance of the source of the control group, of age matching of pregnancies, and of allowance for the greater medical attention given to infants of diabetic mothers because of their risk of perinatal illness-attention which may result in ascertainment bias for malformation. The definitive study, he concludes, has yet to be done. Of those which do point to an association between diabetes and malformations, one was retrospective6 ind one relied on published reports to determine rates of malformation in the control population.7 Nonetheless, MILLS judges that diabetic mothers have malformation rates two or three times higher than normal. Notable dissenting voices are those of FARQUHAR,,9 of RUBIN and MURPHY,’0 and of GELLIS and HSIA," whose results and reviews were reported in the 1950s and 1960s. Furthermore, NAKAMURA et al. 12 have lately reported negative results in an examination of 1000 perinatal deaths. Almost 10% of the mothers were diabetic, but no malformations were found in their 3. Laurance
J. New Society, Aug. 26, 1982, p. 331.
4. Berry CL. Congenital malformations. In: Berry CL, ed. Paediatric pathology. London, Heidelberg, New York: Springer Verlag, 1981: 67-86. 5. Mills JL. Malformations in infants of diabetic mothers. Teratology 1982; 25: 385-94. 6. Molsted-Pedersen L, Tygstrup I, Pedersen J. Congenital malformations in newborn infants of diabetic women. Lancet 1964; i: 1124-26. 7. Kucera J. Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 1971; 7: 61-70. 8. Farquhar JW. The child of the diabetic woman. Arch Dis Childh 1959; 34: 76-96. 9. Farquhar JW. Prognosis for babies born to diabetic mothers in Edinburgh. Arch Dis Childh 1969; 44: 36-47. 10. Rubin A, Murphy DP. Studies in human reproduction III. The frequency of congenital malformation in the offspring of non-diabetic and diabetic individuals. J Pediatr 1958; 33: 579. 11. Gellis SS, Hsia DY. The infant of the diabetic mother. AMA J Dis Child 1959; 97: 1-41. 12. Nakamura Y, Hosokawa Y, Yano H, Nakashima N, Nakashima T, Komatsu Y, Nakashima H, Fakuda S, Kuyama M, Hashimoto T, Nagasue N, Aiko Y, Kabashima S. Primary causes of perinatal death. An autopsy study of1000 cases in Japanese infants. Human Pathol 1982; 13: 54-61.
588
necropsy. The difficulties of defining malformation (hydroceles are included in some studies, only major anomalies in others), the choice of patients and controls, and problems in ascertainment where necropsies have not been done lead to variable interpretation of results and differing views on their meaning. However MILLS does argue persuasively that malformations in general are more frequent in the children of diabetic mothers. What might be the mechanism? Further analysis of KUCERA’s data by MILLS et al. 13 suggests that the abnormalities have their origin before the 7th week of development-a noteworthy observation in view of the reports by PEDERSEN and MOLSTED-PEDERSEN of early growth delay14 and increased loss of small fetuses15 in diabetic pregnancies. If this is so then diabetes can be set alongside various and fetal growth other factors which reduce of in the and which, opinion SPIERS, 16 may contribute substantially to malformation in man. Specific associations of malformations with diabetes have not been confirmed with the exception of the caudal regression syndrome (agenesis or hypoplasia of the femora with agenesis of low vertebrae), for which the relative risk in infants of diabetic mothers is over 200. There are some areas of general agreement about risk of malformation in diabetes mellitus. Diabetic fathers do not have more malformed children than the male population at large, 17 suggesting that the malformation-enhancing effect of diabetes is not a result of diabetes-associated genes. Prediabetic women do not seem to be at increased risk of producing malformed infants and studies which have purported to find this show obvious selection bias. Women with gestational diabetes do not show an increased malformation risk-a matter studied in detail in the prospective Collaborative Perinatal Project.’8 As to whose diabetes is controlled by oral women hypoglycaemic agents, some positive findings have been reported,19 but the number of studies is small and the weight of the data suggests no additional hazard. 20 , How might diabetes hamper development? The disease is complex in biochemical terms: all aspects of intermediary metabolism may be altered, as well as levels of circulating hormones. As in much experimental teratogenesis, extrapolation from laboratory animal to man can be misleading; for
offspring
,
at
embryonic
13. Mills 14.
15. 16. 17.
18. 19. 20.
JL, Baker L, Goldman AS. Malformation in infants of diabetic mothers occur before the seventh gestational week. Diabetes 1979; 28: 292-93. Pedersen JF, Molsted-Pedersen L. Early fetal growth delay detected by ultrasound marks increased risk of congenital malformation in diabetic pregnancy Br Med J 1981; 283: 269-71. Pedersen JF, Molsted-Pedersen L. Early growth delay predisposes the fetus in diabetic pregnancy to congenital malformation. Lancet 1982; i: 737. Spiers SP. Does growth retardation predispose the fetus to congenital malformation? Lancet 1982; i: 312-14. Bennet PH, Webner C, Miller M. Congenital anomalies and the diabetic pregnancy In: Pregnancy, metabolism, diabetes and the fetus (Ciba Found Symp 63). Amsterdam: Excerpta Medica, 1979. Chung CS, Myrianthopolus NC. I. Factors affecting risks of congenital malformations. II. Effect of maternal diabetes. Birth Defects Orig Art Series XI no. 10; 1975. Soler N, Walsh C, Malus J. Congenital malformations in newborn infants of diabetic mothers. Quart J Med 1976; 178: 303-13. Day R, Insley J. Maternal diabetes and congenital malformations Arch Dis Childh 1976; 51: 935-38.
example, DURAISW AMI21 produced limb anomalies in chick embryos with insulin, but later work suggests that metabolic disturbance is more important than the hormone.22 REID,23 in 1970, suggested that certain fetal cells may be especially sensitive to exogenous glucose levels. They may be switched by high maternal blood glucose to a glycolytic pattern of metabolism and repress mitochondrial biogenesis, thus affecting growth rates of cells, preventing them from meeting their "spatio-temporal commitments" during organogenesis. Reversion to normal blood glucose might further decrease the energy supply, and fluctuations would be particularly dangerous-a suggestion supported by the apparently higher malformation rates in severely affected mothers.24 In the investigations reported so far, a major problem is that few workers have studied the relevant phase of human gestation. The period before 7-8 weeks is clearly critical and is the time when fetal wastage is greatest and most anomalies have their origins.4 No insulin is produced by the fetus in this time25 and maternal insulin does not cross the placenta until later in pregnancy-further support for an effect not directly dependent on insulin. LESLIE and his colleagues26 have used haemoglobin A levels as an integrated measure of blood glucose over the preceding weeks, in insulin-dependent diabetic mothers. In three offive cases with raised levels at first medical contact in pregnancy, malformations occurred; there were none in eighteen babies whose mothers had a normal HbA,. Of course, these observations tell us nothing about the effects of concurrent changes in metabolism. If better control of diabetes offers a reduction of hazard to the embryo and fetus, it must clearly be started before conception.2’ By the time of the first antenatal visit the damage may be done.
Renal THE first FRIEDREICH
Papillary Necrosis account of renal papillary necrosis, by
1877,1I concerned patients with prostatic hypertrophy and secondary hydronephrosis. in
In MANDEL’s 1952 report,2 60% of cases were attributed to diabetes, 3007o to urinary-tract obstruction, and 9’ 4% to both, urinary-tract infection has been found in up to 95% of cases seen at necropsy. It was in the late 1950s and early 1960s that analgesic 21. Duraiswami PK. Insulin induced skeletal abnormalities in developing chickens. Br Med J 1952, ii: 384-90. 22. Horrii K, Watanable, G, Ingalls TH. Experimental diabetes in pregnant mice. Prevention of congenital malformations in offspring by insulin. Diabetes 1966, 15: 192-204. 23. Reid RA. Diabetes and congenital abnormalities. Lancet 1970, i: 1030-31. 24 Molsted-Pedersen L, Tygstrup I, Pedersen J. Congenital malformation in newborn infants of diabetic women. Lancet 1964; i: 1124-26. 25 Like A, Orci L. Embryogenesis of the human pancreatic islets A light and electron microscopic study Diabetes 1972; 21: 511-34. 26. Leslie RDG, Pyke DA, John PN, White JN. Haemoglobin A1in diabetic pregnancy Lancet 1978; ii: 958-59. 27 Steel JM, Johnstone FD, Smith AF, Duncan LJP Five years’ experience of a "prepregnancy" clinic for insulin-dependent diabetics Br Med J 1982; 285: 353-56 1. Friedreich N Ueber Necrose der Nierenpapillen bei Hydronephrose. Virchows Arch Pathol Anat 1877, 69: 308. 2 Mandel EE. Renal medullary necrosis. Am J Med 1952, 13: 322.