- Email: [email protected]
Gestational diabetes and beyond
COMMENTARY
the Seven Countries Study Remarkable as it may seem, a study initiated almost 40 years ago and involving some 10000 middle-aged men from fourteen cohorts in seven countries is still studying survivors, processing data, analysing material, and producing important reports. Three recent books‘-3 describe, from different perspectives, how Ancel Keys and his collaborators in the Seven Countries Study have influenced our understanding of the nature of cardiovascular disease in general and of coronary heart disease in particular. The Seven Countries Study was the first of the major epidemiological investigations of heart disease deliberately to pursue a specific nutritional hypothesis; it also set a pattern for standardising methods
Reflections
on
of examination in numerous other international and national studies. The main hypothesis was that atherosclerosis and coronary heart disease are essentially nutritional problems, related primarily to the composition of fat intake. The findings of the study showed that saturated fatty acids played a leading part in raising blood cholesterol and that other factors such as hypertension, cigarette smoking, diabetes, and physical inactivity were additional, acting on the coronary vessels only when they were rendered susceptible by the presence of
hypercholesterolaemia. The Stamlers and others in the USA supported this nutritional-metabolic concept and, through programmes such as the Multiple Risk Factor Intervention Trial (MRFIT), moved the findings of the epidemiological studies into the field of prevention. It would be rash to attribute the striking decline in cardiovascular disease mortality in the USA entirely to the widespread acceptance and partial implementation of public health measures designed to lower blood cholesterol, but, as predicted, average US blood cholesterol concentrations have fallen considerably during the past two decades at the same time as the heart disease death rate has declined. As in many other western countries with declining cardiovascular death rates, the prevalence of obesity in the USA has risen, but obesity associated with lower blood cholesterol is not a major hazard to the coronary arteries. In the UK, acceptance that nutritional factors are important in cardiovascular disease was slow and cautious, major rearguard reactions being fought throughout the 1960s and 70s. To the British cardiologists of that time, Keys and cholesterol represented an American intrusion that had overtones of prohibition. There is still a substantial body of opinion, much of it connected with the food industry, which does not accept an essential role for dietary fats in coronary heart disease. Participants at an international symposium held in Japan in 1993 to celebrate the 35th anniversary of the Seven Countries Study and the 90th birthday of Ancel Keys reported on recent trends in cardiovascular disease in these countries and also discussed methods of food intake assessment and the current status of dietary saturated fatty acids, serum cholesterol, and coronary heart disease.’ The failure of this study as well as others to find associations between dietary factors and serum cholesterol at the individual level is attributed to measurement error; when repeatedly collected data are used, the associations are found. Overall, the original
208
is strongly supported by the findings in the seven countries over the ensuing 35 years.3 And none of this worldwide adventure in cardiovascular epidemiology the steadfast would have come about without commitment and enthusiasm of Keys and his successor in Minneapolis, Henry Blackburn.2 In terms of future strategies, the late Fred Epstein, in reviewing the strong relations seen in the seven countries between coronary heart disease risk factors and other chronic disease,’ leaves a clear message: "There is a need to step up prevention programs for all chronic diseases with a potential for prevention. It would clearly be wasteful and inefficient to launch campaigns for each of these disorders separately, and people in the population would resent being exposed to parallel and uncoordinated demands on their attention". Perhaps it is time to get our
hypothesis
acts
A G Royal
together. Shaper Free
Hospital School of Medicine, London, UK
1
Toshima H, Koga Y, Blackburn H, eds. Lessons for science from the Seven Countries Study: a 35-year collaborative experience in cardiovascular disease epidemiology. Tokyo: Springer-Verlag, 1994. Pp 243. (Available from Springer-Verlag, 175 Fifth Avenue, NY
2
Blackburn H. On the trail of heart attacks in seven countries. University of Minnesota, 1995. Pp 148. (Available from Division of Epidemiology, University of Minnesota, 1300 South 2nd Street, Suite 300, Minneapolis, MN 55454, USA. $20.00.) Kromhout D, Menotti A, Blackburn H, eds. The Seven Countries Study: a scientific adventure in cardiovascular epidemiology. Utrecht: Brouwer Offset, 1994. Pp 219. (Available from RIVM, PO Box 1, 3720 BA Bilthoven, Netherlands. $25.00.)
10010, USA. $60.00)
3
Gestational diabetes and beyond See page 227 Pregnancy is characterised by several factors that act to alter the blood glucose concentration.’ Hormones such as human placental lactogen, progesterone, prolactin, and cortisol have diabetogenic properties; their tendency to increase maternal blood glucose is counterbalanced by an increase in insulin to almost twice the nonpregnant concentration. The rise in insulin is itself offset by increasing insulin resistance, the mechanism of which is not clearly understood. Irrespective of these changes, the vast majority of pregnant women manage to maintain their blood glucose within normal limits. In a few women, the capacity for insulin secretion is exceeded as a consequence of increasing insulin resistance, and gestational diabetes develops, usually late in the second trimester. Most women with non-insulin-dependent diabetes (NIDDM) probably have an unrecognised degree of glucose intolerance during their pregnancies, and most women with a history of gestational diabetes are likely to develop NIDDM. The evidence for these assertions comes from follow-up studies over several years,2 and
epidemiological investigations which show that the frequency of gestational diabetes within a certain population is similar to that for impaired glucose from
tolerance and NIDDM in women who are 10 years older.3 This deterioration of glucose tolerance following gestational diabetes is especially associated with factors related to insulin sensitivity: obesity and weight gain double the risk of developing abnormal glucose tolerance.’ Other important factors include the mother’s
ethnic group, the need for insulin during pregnancy, and family history of NIDDM. There is no convincing evidence that parity alone is a risk factor for the development ofNIDDM.’ In this issue, Peters and her colleagues report that a single pregnancy complicated by gestational diabetes may accelerate the development of NIDDM in women with a high prevalence of pancreatic p-cell dysfunction, independent of the effects of weight gain. They followed a
666 Latino women with gestational diabetes, but normal glucose tolerance immediately post partum, for up to 7-5 years. 87 (13%) of the women completed an additional pregnancy, with 80 remaining non-diabetic immediately following that pregnancy. The annual incidence of NIDDM in the women was 2-5 times that in the overall cohort. Proportional hazard regression analysis confirmed that the relative risk of NIDDM was increased three-fold by an additional pregnancy, even after adjustment for other potential diabetic risk factors, compared with those women who did not have another pregnancy. Weight gain was shown to be an associated risk for NIDDM, the relative risk being almost double for each 4-5 kg gained during the follow-up period. What are the likely explanations for these findings and how important are they for women developing gestational diabetes? It seems that women who get gestational diabetes do indeed have limited (3-cell capacity to compensate for the insulin resistance of pregnancy and, not
surprisingly, they
go
on
to
develop gestational
diabetes during a subsequent pregnancy. What has not been appreciated previously is that such women then progress to NIDDM at a much higher rate than women who do not have a further pregnancy. This observation suggests that the additional pregnancy is another metabolic insult to the islet cells. This effect is
compounded by weight gain. These findings underline the importance of surveying all women with gestational diabetes in anticipation that they will eventually develop NIDDM, and in the expectation that an additional pregnancy and increasing body weight will accelerate this process. The observations also highlight the need to improve communication between hospital and family practice and to establish effective systems for education about healthy eating, contraceptive methods, and awareness of the likelihood of future diabetes. Any system of surveillance should ensure a postnatal oral glucose tolerance test (OGTT) and include a programme of annual monitoring with, at the very least, urine analysis and a random blood glucose estimation. Women from certain ethnic populations are at even
greater risk of diabetes, and educational programmes
be comprehensible and culturally relevant, and bear clear message about the importance of follow-up.6 What about screening policies for gestational diabetes? Such a policy must be well defined, easily administered, inexpensive, and reproducible, it should also have a high sensitivity to identify most individuals with the disorder. Many alternatives, including a fasting or random blood glucose and 50 g, 75 g, or 100 g OGTT, have been suggested, but without universal agreement. 7,8 In the UK, most centres use a 75 g OGTT as the final measure, but the blood glucose values recommended as diagnostic by WHO have not yet been validated against any outcome of pregnancy.""I In predominantly white populations, must a
screening policies for gestational diabetes
may not be seen the best allocation of obstetric resources because the number of white/Europid women likely to be affected is small. However, the benefits of screening ethnic groups with a high prevalence of both impaired glucose tolerance and NIDDM are clear. The implications of gestational diabetes extend far beyond pregnancy; for this reason, the potential benefits of a structured screening system during and after pregnancy should be reassessed to take account of both public health and obstetric outcomes. as
Peter
Kopelman
Medical Unit, 1 2 3
4
Royal London Hospital, London, UK
Kuhl C.
Aetiology of gestational diabetes. Baillières Clin Obstet Gynaecol 1991; 5: 279-92. O’Sullivan JB. Diabetes mellitus after gestational diabetes. Diabetes 1991; 40 (suppl): 131-35. Harris MI. Gestational diabetes may represent discovery of pre-existing glucose intolerance. Diabetes Care 1988; 11: 402-11. O’Sullivan JB. Body weight and subsequent diabetes mellitus. JAMA 1982; 248: 949-52.
5
6
JE, Rimm EB, Colditz GA, et al. Parity and incidence of noninsulin-dependent diabetes mellitus. Am J Med 1992; 93: 13-18. Dornhorst A, Paterson CM, Nicholls JSD, et al. High prevalence of gestational diabetes in women from ethnic minority groups. Diabetic Manson
Med 1992; 9: 820-25. Ales KL, Santini DL. Should all pregnant women be screened for gestational glucose intolerance? Lancet 1989 i: 1187-90. 8 Nelson-Piercy C, Gale EA. Do we know how to screen for gestational diabetes? Current practice in one regional health authority. Diabetic Med 1994; 11: 493-98. 9 World Health Organization. Diabetes mellitus. WHO Tech Rep Ser 1985; 729: 9-17. 10 Dornhurst A, Beard RW. Gestational diabetes: a challenge for the future. Diabetic Med 1993; 10: 897-905. 11 Nasrat HA, Sabbagh SA, Salleh M, Ardai M. New criteria for interpretation of the 75 g oral glucose tolerance test in pregnancy. Metabolism 1990; 39: 51-57. 7
Acellular pertussis vaccines: vaccines for an old disease
new
Bordetella pertussis infection remains a disease of international importance, causing about 500 000 deaths and affecting more than 50 million people world wide each year.’ Despite this, immunisation rates in many countries have declined as a result of perceived serious adverse events ascribed to whole-cell vaccines. Acellular pertussis vaccines were developed in response to concerns about fever, febrile seizures, persistent crying, hypotonichyporesponsive episodes, encephalopathy, and sudden infant death syndrome (SIDS). The main impediment to development and evaluation of acellular vaccines has been lack of knowledge about which pertussis vaccine components-pertussis toxin (PT), pertactin (PRN), filamentous haemagglutinin (FHA), or fimbrial antigens (FIM)-stimulate an immune response that correlates with protection against disease. Existing acellular vaccines contain PT alone or with other components; this reflects the presumed major role of PT in producing disease. However, the minimum protective level of PT antibody is unclear, the clinical relevance of antibody produced by each of the various components is unknown, and disease continues to occur in the presence of high levels of post-immunisation PT
antibody. 2,3 Recently published clinical trials document the safety and short-term efficacy of candidate acellular pertussis vaccines. The phase 1/11 Nationwide Multicenter 209
the Seven Countries Study Remarkable as it may seem, a study initiated almost 40 years ago and involving some 10000 middle-aged men from fourteen cohorts in seven countries is still studying survivors, processing data, analysing material, and producing important reports. Three recent books‘-3 describe, from different perspectives, how Ancel Keys and his collaborators in the Seven Countries Study have influenced our understanding of the nature of cardiovascular disease in general and of coronary heart disease in particular. The Seven Countries Study was the first of the major epidemiological investigations of heart disease deliberately to pursue a specific nutritional hypothesis; it also set a pattern for standardising methods
Reflections
on
of examination in numerous other international and national studies. The main hypothesis was that atherosclerosis and coronary heart disease are essentially nutritional problems, related primarily to the composition of fat intake. The findings of the study showed that saturated fatty acids played a leading part in raising blood cholesterol and that other factors such as hypertension, cigarette smoking, diabetes, and physical inactivity were additional, acting on the coronary vessels only when they were rendered susceptible by the presence of
hypercholesterolaemia. The Stamlers and others in the USA supported this nutritional-metabolic concept and, through programmes such as the Multiple Risk Factor Intervention Trial (MRFIT), moved the findings of the epidemiological studies into the field of prevention. It would be rash to attribute the striking decline in cardiovascular disease mortality in the USA entirely to the widespread acceptance and partial implementation of public health measures designed to lower blood cholesterol, but, as predicted, average US blood cholesterol concentrations have fallen considerably during the past two decades at the same time as the heart disease death rate has declined. As in many other western countries with declining cardiovascular death rates, the prevalence of obesity in the USA has risen, but obesity associated with lower blood cholesterol is not a major hazard to the coronary arteries. In the UK, acceptance that nutritional factors are important in cardiovascular disease was slow and cautious, major rearguard reactions being fought throughout the 1960s and 70s. To the British cardiologists of that time, Keys and cholesterol represented an American intrusion that had overtones of prohibition. There is still a substantial body of opinion, much of it connected with the food industry, which does not accept an essential role for dietary fats in coronary heart disease. Participants at an international symposium held in Japan in 1993 to celebrate the 35th anniversary of the Seven Countries Study and the 90th birthday of Ancel Keys reported on recent trends in cardiovascular disease in these countries and also discussed methods of food intake assessment and the current status of dietary saturated fatty acids, serum cholesterol, and coronary heart disease.’ The failure of this study as well as others to find associations between dietary factors and serum cholesterol at the individual level is attributed to measurement error; when repeatedly collected data are used, the associations are found. Overall, the original
208
is strongly supported by the findings in the seven countries over the ensuing 35 years.3 And none of this worldwide adventure in cardiovascular epidemiology the steadfast would have come about without commitment and enthusiasm of Keys and his successor in Minneapolis, Henry Blackburn.2 In terms of future strategies, the late Fred Epstein, in reviewing the strong relations seen in the seven countries between coronary heart disease risk factors and other chronic disease,’ leaves a clear message: "There is a need to step up prevention programs for all chronic diseases with a potential for prevention. It would clearly be wasteful and inefficient to launch campaigns for each of these disorders separately, and people in the population would resent being exposed to parallel and uncoordinated demands on their attention". Perhaps it is time to get our
hypothesis
acts
A G Royal
together. Shaper Free
Hospital School of Medicine, London, UK
1
Toshima H, Koga Y, Blackburn H, eds. Lessons for science from the Seven Countries Study: a 35-year collaborative experience in cardiovascular disease epidemiology. Tokyo: Springer-Verlag, 1994. Pp 243. (Available from Springer-Verlag, 175 Fifth Avenue, NY
2
Blackburn H. On the trail of heart attacks in seven countries. University of Minnesota, 1995. Pp 148. (Available from Division of Epidemiology, University of Minnesota, 1300 South 2nd Street, Suite 300, Minneapolis, MN 55454, USA. $20.00.) Kromhout D, Menotti A, Blackburn H, eds. The Seven Countries Study: a scientific adventure in cardiovascular epidemiology. Utrecht: Brouwer Offset, 1994. Pp 219. (Available from RIVM, PO Box 1, 3720 BA Bilthoven, Netherlands. $25.00.)
10010, USA. $60.00)
3
Gestational diabetes and beyond See page 227 Pregnancy is characterised by several factors that act to alter the blood glucose concentration.’ Hormones such as human placental lactogen, progesterone, prolactin, and cortisol have diabetogenic properties; their tendency to increase maternal blood glucose is counterbalanced by an increase in insulin to almost twice the nonpregnant concentration. The rise in insulin is itself offset by increasing insulin resistance, the mechanism of which is not clearly understood. Irrespective of these changes, the vast majority of pregnant women manage to maintain their blood glucose within normal limits. In a few women, the capacity for insulin secretion is exceeded as a consequence of increasing insulin resistance, and gestational diabetes develops, usually late in the second trimester. Most women with non-insulin-dependent diabetes (NIDDM) probably have an unrecognised degree of glucose intolerance during their pregnancies, and most women with a history of gestational diabetes are likely to develop NIDDM. The evidence for these assertions comes from follow-up studies over several years,2 and
epidemiological investigations which show that the frequency of gestational diabetes within a certain population is similar to that for impaired glucose from
tolerance and NIDDM in women who are 10 years older.3 This deterioration of glucose tolerance following gestational diabetes is especially associated with factors related to insulin sensitivity: obesity and weight gain double the risk of developing abnormal glucose tolerance.’ Other important factors include the mother’s
ethnic group, the need for insulin during pregnancy, and family history of NIDDM. There is no convincing evidence that parity alone is a risk factor for the development ofNIDDM.’ In this issue, Peters and her colleagues report that a single pregnancy complicated by gestational diabetes may accelerate the development of NIDDM in women with a high prevalence of pancreatic p-cell dysfunction, independent of the effects of weight gain. They followed a
666 Latino women with gestational diabetes, but normal glucose tolerance immediately post partum, for up to 7-5 years. 87 (13%) of the women completed an additional pregnancy, with 80 remaining non-diabetic immediately following that pregnancy. The annual incidence of NIDDM in the women was 2-5 times that in the overall cohort. Proportional hazard regression analysis confirmed that the relative risk of NIDDM was increased three-fold by an additional pregnancy, even after adjustment for other potential diabetic risk factors, compared with those women who did not have another pregnancy. Weight gain was shown to be an associated risk for NIDDM, the relative risk being almost double for each 4-5 kg gained during the follow-up period. What are the likely explanations for these findings and how important are they for women developing gestational diabetes? It seems that women who get gestational diabetes do indeed have limited (3-cell capacity to compensate for the insulin resistance of pregnancy and, not
surprisingly, they
go
on
to
develop gestational
diabetes during a subsequent pregnancy. What has not been appreciated previously is that such women then progress to NIDDM at a much higher rate than women who do not have a further pregnancy. This observation suggests that the additional pregnancy is another metabolic insult to the islet cells. This effect is
compounded by weight gain. These findings underline the importance of surveying all women with gestational diabetes in anticipation that they will eventually develop NIDDM, and in the expectation that an additional pregnancy and increasing body weight will accelerate this process. The observations also highlight the need to improve communication between hospital and family practice and to establish effective systems for education about healthy eating, contraceptive methods, and awareness of the likelihood of future diabetes. Any system of surveillance should ensure a postnatal oral glucose tolerance test (OGTT) and include a programme of annual monitoring with, at the very least, urine analysis and a random blood glucose estimation. Women from certain ethnic populations are at even
greater risk of diabetes, and educational programmes
be comprehensible and culturally relevant, and bear clear message about the importance of follow-up.6 What about screening policies for gestational diabetes? Such a policy must be well defined, easily administered, inexpensive, and reproducible, it should also have a high sensitivity to identify most individuals with the disorder. Many alternatives, including a fasting or random blood glucose and 50 g, 75 g, or 100 g OGTT, have been suggested, but without universal agreement. 7,8 In the UK, most centres use a 75 g OGTT as the final measure, but the blood glucose values recommended as diagnostic by WHO have not yet been validated against any outcome of pregnancy.""I In predominantly white populations, must a
screening policies for gestational diabetes
may not be seen the best allocation of obstetric resources because the number of white/Europid women likely to be affected is small. However, the benefits of screening ethnic groups with a high prevalence of both impaired glucose tolerance and NIDDM are clear. The implications of gestational diabetes extend far beyond pregnancy; for this reason, the potential benefits of a structured screening system during and after pregnancy should be reassessed to take account of both public health and obstetric outcomes. as
Peter
Kopelman
Medical Unit, 1 2 3
4
Royal London Hospital, London, UK
Kuhl C.
Aetiology of gestational diabetes. Baillières Clin Obstet Gynaecol 1991; 5: 279-92. O’Sullivan JB. Diabetes mellitus after gestational diabetes. Diabetes 1991; 40 (suppl): 131-35. Harris MI. Gestational diabetes may represent discovery of pre-existing glucose intolerance. Diabetes Care 1988; 11: 402-11. O’Sullivan JB. Body weight and subsequent diabetes mellitus. JAMA 1982; 248: 949-52.
5
6
JE, Rimm EB, Colditz GA, et al. Parity and incidence of noninsulin-dependent diabetes mellitus. Am J Med 1992; 93: 13-18. Dornhorst A, Paterson CM, Nicholls JSD, et al. High prevalence of gestational diabetes in women from ethnic minority groups. Diabetic Manson
Med 1992; 9: 820-25. Ales KL, Santini DL. Should all pregnant women be screened for gestational glucose intolerance? Lancet 1989 i: 1187-90. 8 Nelson-Piercy C, Gale EA. Do we know how to screen for gestational diabetes? Current practice in one regional health authority. Diabetic Med 1994; 11: 493-98. 9 World Health Organization. Diabetes mellitus. WHO Tech Rep Ser 1985; 729: 9-17. 10 Dornhurst A, Beard RW. Gestational diabetes: a challenge for the future. Diabetic Med 1993; 10: 897-905. 11 Nasrat HA, Sabbagh SA, Salleh M, Ardai M. New criteria for interpretation of the 75 g oral glucose tolerance test in pregnancy. Metabolism 1990; 39: 51-57. 7
Acellular pertussis vaccines: vaccines for an old disease
new
Bordetella pertussis infection remains a disease of international importance, causing about 500 000 deaths and affecting more than 50 million people world wide each year.’ Despite this, immunisation rates in many countries have declined as a result of perceived serious adverse events ascribed to whole-cell vaccines. Acellular pertussis vaccines were developed in response to concerns about fever, febrile seizures, persistent crying, hypotonichyporesponsive episodes, encephalopathy, and sudden infant death syndrome (SIDS). The main impediment to development and evaluation of acellular vaccines has been lack of knowledge about which pertussis vaccine components-pertussis toxin (PT), pertactin (PRN), filamentous haemagglutinin (FHA), or fimbrial antigens (FIM)-stimulate an immune response that correlates with protection against disease. Existing acellular vaccines contain PT alone or with other components; this reflects the presumed major role of PT in producing disease. However, the minimum protective level of PT antibody is unclear, the clinical relevance of antibody produced by each of the various components is unknown, and disease continues to occur in the presence of high levels of post-immunisation PT
antibody. 2,3 Recently published clinical trials document the safety and short-term efficacy of candidate acellular pertussis vaccines. The phase 1/11 Nationwide Multicenter 209