- Email: [email protected]
“Adiposity rebound”: reality or epiphenomenon?
COMMENTARY
“fully informed” consent may be a misleading term that would be better replaced by “best feasible” consent. On the basis of a careful interpretation of their findings, Mason and colleagues suggest several potential strategies to promote the best feasible consent. They emphasise that investigators need greater guidance on the legal and ethical constraints governing consent. However, exactly what these constraints should be remains highly controversial.1,5,6 A fundamental issue is whether standards for consent should differ according to whether an unproven therapy is used in a randomised trial or in clinical practice. Use of unproven treatments has been designated as experimentation, whether or not given under research circumstances.7 The principle of respect for individuals is not well served by the current double standard that encourages routine clinical use but discourages proper clinical trials of unproven and possibly hazardous therapies,1,8,9 especially emergency therapies that are widely given without consent.5,6 The staunch parental support for consent reported by Mason and colleagues should not be interpreted as supporting this double standard. Parents were not specifically asked about trials of emergency therapies or other therapies given in routine care without consent; they may not have known that unproven therapies are commonly used in clinical practice; and neither they nor the neonatologists may have been aware of the growing evidence that outcome is improved by participation in clinical trials.10 Further study is needed to define parental views about consent for unproven therapies within and outside clinical trials and to assess new approaches to seeking the best feasible consent in difficult clinical circumstances. When it is not possible to obtain consent and the trial does not involve research procedures that increase risk to patients, the principle of respect for individuals would not preclude enrolment in a randomised trial—especially if the institutional review board concludes that risk is likely to be decreased by the monitoring, supportive care, or follow-up assessments afforded by the trial. Consent to remain in the trial could then be obtained as soon as feasible. *Jon E Tyson, Paula L Knudson *Center for Population Health and Evidence-Based Medicine, and Institutional Review Board, University of Texas-Houston Medical School, Houston TX 77030, USA
The term “adiposity rebound” was first used by RollandCachera and her coworkers1 to describe the period around 6 years of age when body mass index (BMI) begins to increase after a nadir (figure). The suggestion was that children with an early “adiposity rebound” were at increased risk of obesity when they became adults.1–3 Since those original reports, at least four other publications have confirmed that early “adiposity rebound” is associated with an increased BMI in adulthood.4–7 The period of “adiposity rebound” may be a criticial period for the development of obesity in adults,8 and this rebound may account for about 30% of that proportion of adult obesity that begins in childhood.6 Nonetheless, several concerns remain. These concerns include the lack of evidence both that the rebound in BMI is attributable to body fat and that the increased BMI observed in adults who have had early adiposity rebound is associated with an increase in body fat. If the BMI rebound is driven by increased body fat, what is driving the early adiposity rebound that precedes it? Finally, although adiposity rebound may define a period of risk in childhood for obesity in adulthood, the limited ability to determine early BMI rebound for individuals may limit its applicability in clinical settings. Few studies of adiposity rebound1–6 have included simultaneous examination of a measure other than BMI at the time of adiposity rebound or in adulthood, even though such measures do seem to have been available in some of the studies.2,4 The only study with measures of subscapular skinfold thickness,2 a direct measure of truncal subcutaneous fat, revealed modest differences in both BMI and skinfold thickness that were more pronounced among young adults who had early rather than late rebound.2 Although differences in skinfold thickness were observed for young men and young women, the sample sizes were small (14–21 per group) and few were obese, as defined by a BMI of 30 or more. Since the children with higher BMIs had an earlier rebound (figure), the period of adiposity rebound could represent an epiphenomenon. Whether age at rebound or the BMI at rebound has a greater influence on adult BMI cannot be answered unequivocally. The BMI at rebound
1
THE LANCET • Vol 356 • December 16, 2000
BMI percentiles on the US Centers for Disease and Prevention growth charts 35 95th
30
25
50th
BMI
Tyson J. Use of unproven therapies in clinical practice and research: How can we better serve our patients and their families. Sem Perinatol 1995; 19: 98–111. 2 Eidelman AI, Hoffmann NW, Kaitz M. Cognitive deficits in women after childbirth. Obstet Gynecol 1993; 81: 764–67. 3 Oakley A. Experiments in knowing: gender and method in the social sciences. Cambridge: Polity Press, 2000: 26–27. 4 Giacomini MK, Cook DJ for the Evidence-Based Medicine Working Group. User’s Guide to the Medical Literature. XXIII. Qualitative research in health care: are the results of the study valid JAMA 2000; 284: 357–62. 5 Collins R, Doll R, Peto R. Ethics of clinical trials. In: Williams CJ. Introducing new treatments for cancer: practical, ethical, and legal problems. New York :John Wiley, 1992. 6 Truog RD, Robinson W, Randolph A, Morris A. Is informed consent always necessary for randomized controlled trials? N Engl J Med 1999; 340: 804–07. 7 United States Department of Health and Human Research. OPRR NIH. Protecting human research subjects. Institutional review board guidebook. US Government Printing Office; 1993: G4. 8 Chalmers I, Silverman WA. Professional and public double standards on clinical experimentation. Controlled Clin Trials 1987; 8: 388–91. 9 Rogers CG, Tyson JE, Kennedy KA, Broyles RS, Hickman J. Conventional consent with opting in versus simplified consent with opting out: an exploratory trial for studies that do not increase patient risk. J Pediatr 1998; 132: 606–11. 10 Lantos JD. The “inclusion benefit” in clinical trials. J Pediatr 1999; 134: 130–31.
"Adiposity rebound": reality or epiphenomenon?
20
5th
15
10 2
4
6
8
10 12 14 Age (years)
16
18
20
Earlier rebound of BMI occurs at higher percentiles
2027
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
seems to have an effect on adult BMI that is independent of the time of rebound.6 However, the correlations between BMI at age 7 and adult BMI and between age at rebound and adult BMI are much the same. BMI at age 7 may thus be a more practical criterion for the determination of risk.7 Because BMI is weight (kg) divided by height (m2), an increased BMI can reflect either increased weight or decreased height, and it is not known whether children or adults with early increases in BMI are heavier or have a reduced height velocity compared with children with later increases in BMI. Even if the differences in BMI in childhood can be attributed to increased weight, whether the increase is in body fat rather than bone or muscle mass remains unclear. A similar argument applies to adults. The factors that predispose to early BMI rebound also remain uncertain. Television viewing by American children has been linked to obesity,9 but there is no evidence that children with early rebound are more sedentary than children with later rebound. Two small studies have suggested that early protein intake predicts an increase in BMI10,11 or subscapular skinfold thickness10 at the time of adiposity rebound11 or at age 8 years.10 In a larger sample of children for whom 3-day prospective household measures were collected at ages 8 and 18 months, no significant association was found between protein, fat, or carbohydrate intake and the timing of BMI rebound.12 Furthermore, how would increased protein intake lead to early rebound? Nor do children always eat what their parents urge them to. For example, encouragement to eat certain foods may reduce intake of that food13 whereas restrictions on a food item may lead to increased consumption of it when the restriction is removed.14 In a cross-sectional study, increased parental control over food intake was associated with an impaired capacity of children to regulate their own intake15 but this study cannot tell whether this finding indicated cause and effect or effect and cause. Adiposity rebound has been based on population measures. In an individual this rebound may be difficult to judge. Measurement error will probably confound assessment of early BMI rebound in young children. For example, a measurement error of 2 cm in a child who weighs 20 kg and is 115 cm tall will account for an error of 0·5 of a BMI unit. Furthermore, few children are likely to be seen frequently enough for the period of rebound to be identified—and because the period of rebound can be identified only retrospectively, early rebound may not be preventable. William H Dietz Division of Nutrition and Physical Activity, Centers for Disease Control and Prevention, Atlanta, GA 30341,USA
1
2
3
4
5
Rolland-Cachera M-F, Deheeger M, Bellisle F, Sempe M, GuilloudBataille M, Patois E. Adiposity rebound in children: a simple indicator for predicting adiposity. Am J Clin Nutr 1984; 39: 129–35. Rolland-Cachera MF, Avons P, Patois E, Sempe M. Tracking the development of adiposity from one month of age to adulthood. Ann Human Biol 1987; 14: 219–29. Rolland-Cachwera M-F, Bellisle F, Deheeger M, Guilloud-Bataille M, Pequignot F, Sempe, M. Adiposity development and prediction during growth in humans: a two decade follow-up study. In: Bjorntorp P, Rossner S, eds. Obesity in Europe 88. London: John Libbey, 1988. Siervogel RM, Roche AF, Guo S, Mukherjee D, Chumlea WC. Patterns of change in weight/stature2 from 2 to 18 years: findings from long-term serial data for children in the Fels longitudinal growth study. Int J Obesity 1991; 15: 479–85. Prokopec M, Bellisle F. Adiposity in Czech children followed from 1 month of age to adulthood: analysis of individual BMI
2028
6
7
8 9
10
11
12
13
14
15
patterns. Ann Human Biol 1993; 20: 517–25. Whitaker RC, Pepe MS, Wright JA, Seidel KD, Dietz WH. Early adiposity rebound and the risk of adult obesity. Pediatrics 1998; 101(electronic pages)/3/e5. Williams S, Davie G, Lam F. Predicting BMI in young adults from childhood data using two approaches to modeling adiposity rebound. Int J Obes Relat Metab Disord 1999; 23: 348–54. Dietz WH. Critical periods in childhood for the development of obesity. Am J Clin Nutr 1994; 59: 995–99. Dietz WH, Gortmaker SL. Do we fatten our children at the TV set? obesity and television viewing in children and adolescents. Pediatrics 1985; 75: 807–12. Rolland-Cachera MF, Deheeger M, Akrout M, Bellisle F. Influence of macronutrients on adiposity development. Int J Obesity 1995; 19: 573–78. Scaglioni S, Agostini C, De Notarus R, et al. Early macronutrient intake and overweight at five years of age. Int J Obesity 2000; 24: 777–81. Dorosty AR, Emmett PM, Cowin IS, Reilly JJ, ALSPAC Study Team. Factors associated with early adiposity rebound. Pediatrics 2000; 105: 1115–18. Birch LL, Marlin DW, Rotter J. Eating as the “means” activity in a contingency: effects on young children’s food preference. Child Dev 1985; 55: 431–39. Fisher JO, Birch LL. Restricting access to palatable foods affects children’s behavioral response, food selection and intake. Am J Clin Nutr 1999; 69: 1264–72. Johnson SL, Birch LL. Parents’ and children’s adiposity and eating style. Pediatrics 1994; 94: 653–61.
Thrombolytic therapy in the elderly A recent observational study by Thiemann et al1 of 7864 Medicare patients treated for acute myocardial infarction in the USA has been widely interpreted as meaning that the use of thrombolytic therapy in patients over 75 may do more harm than good.2 30-day mortality in patients aged 76-86 was significantly higher in those who received thrombolytic therapy within 4 h of admission than in those who did not (18·0% vs 13·6%, p=0·003). These results appear to contradict the Fibrinolytic Therapy Trialists’ (FTT) overview3 of 58 600 patients randomised into thrombolytic trials, which concluded that the 35-day mortality rate in the 5788 patients aged over 75 was lower in those who received thrombolytic therapy than in those who did not (24·3% vs 25·3%). The difference was not significant and the 95% CI was -16% to +36%). However, the absolute mortality reduction in patients over 75 (10 potential lives saved per 1000 treated) was similar to that of patients under 55 (11 per 1000). What can the clinician conclude from such disparate reports, and how much credence can be given to observational studies? In the Thiemann study, there were significant imbalances between the groups in terms of prognostic factors, and the analysis was adjusted for these. However, even with such adjustment, selection of treatments based on physicians’ preferences can affect outcomes that are not due to the treatment itself. The only way to ensure that unknown factors are balanced between treatment groups is by randomised treatment assignment.4 The fact that only 34% of electrocardiographically eligible patients were included in the Thiemann study suggests that there was indeed a selection bias. Another confounding factor is that a large proportion of the patients aged 76–86 who did receive thrombolytic therapy had relative contraindications; for example, 12% had a systolic blood pressure of over 180 mm Hg and 18·0% had a history of trauma, peptic ulceration, or internal bleeding—all of which would have increased the risk of intracranial and systemic bleeding.
THE LANCET • Vol 356 • December 16, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
“fully informed” consent may be a misleading term that would be better replaced by “best feasible” consent. On the basis of a careful interpretation of their findings, Mason and colleagues suggest several potential strategies to promote the best feasible consent. They emphasise that investigators need greater guidance on the legal and ethical constraints governing consent. However, exactly what these constraints should be remains highly controversial.1,5,6 A fundamental issue is whether standards for consent should differ according to whether an unproven therapy is used in a randomised trial or in clinical practice. Use of unproven treatments has been designated as experimentation, whether or not given under research circumstances.7 The principle of respect for individuals is not well served by the current double standard that encourages routine clinical use but discourages proper clinical trials of unproven and possibly hazardous therapies,1,8,9 especially emergency therapies that are widely given without consent.5,6 The staunch parental support for consent reported by Mason and colleagues should not be interpreted as supporting this double standard. Parents were not specifically asked about trials of emergency therapies or other therapies given in routine care without consent; they may not have known that unproven therapies are commonly used in clinical practice; and neither they nor the neonatologists may have been aware of the growing evidence that outcome is improved by participation in clinical trials.10 Further study is needed to define parental views about consent for unproven therapies within and outside clinical trials and to assess new approaches to seeking the best feasible consent in difficult clinical circumstances. When it is not possible to obtain consent and the trial does not involve research procedures that increase risk to patients, the principle of respect for individuals would not preclude enrolment in a randomised trial—especially if the institutional review board concludes that risk is likely to be decreased by the monitoring, supportive care, or follow-up assessments afforded by the trial. Consent to remain in the trial could then be obtained as soon as feasible. *Jon E Tyson, Paula L Knudson *Center for Population Health and Evidence-Based Medicine, and Institutional Review Board, University of Texas-Houston Medical School, Houston TX 77030, USA
The term “adiposity rebound” was first used by RollandCachera and her coworkers1 to describe the period around 6 years of age when body mass index (BMI) begins to increase after a nadir (figure). The suggestion was that children with an early “adiposity rebound” were at increased risk of obesity when they became adults.1–3 Since those original reports, at least four other publications have confirmed that early “adiposity rebound” is associated with an increased BMI in adulthood.4–7 The period of “adiposity rebound” may be a criticial period for the development of obesity in adults,8 and this rebound may account for about 30% of that proportion of adult obesity that begins in childhood.6 Nonetheless, several concerns remain. These concerns include the lack of evidence both that the rebound in BMI is attributable to body fat and that the increased BMI observed in adults who have had early adiposity rebound is associated with an increase in body fat. If the BMI rebound is driven by increased body fat, what is driving the early adiposity rebound that precedes it? Finally, although adiposity rebound may define a period of risk in childhood for obesity in adulthood, the limited ability to determine early BMI rebound for individuals may limit its applicability in clinical settings. Few studies of adiposity rebound1–6 have included simultaneous examination of a measure other than BMI at the time of adiposity rebound or in adulthood, even though such measures do seem to have been available in some of the studies.2,4 The only study with measures of subscapular skinfold thickness,2 a direct measure of truncal subcutaneous fat, revealed modest differences in both BMI and skinfold thickness that were more pronounced among young adults who had early rather than late rebound.2 Although differences in skinfold thickness were observed for young men and young women, the sample sizes were small (14–21 per group) and few were obese, as defined by a BMI of 30 or more. Since the children with higher BMIs had an earlier rebound (figure), the period of adiposity rebound could represent an epiphenomenon. Whether age at rebound or the BMI at rebound has a greater influence on adult BMI cannot be answered unequivocally. The BMI at rebound
1
THE LANCET • Vol 356 • December 16, 2000
BMI percentiles on the US Centers for Disease and Prevention growth charts 35 95th
30
25
50th
BMI
Tyson J. Use of unproven therapies in clinical practice and research: How can we better serve our patients and their families. Sem Perinatol 1995; 19: 98–111. 2 Eidelman AI, Hoffmann NW, Kaitz M. Cognitive deficits in women after childbirth. Obstet Gynecol 1993; 81: 764–67. 3 Oakley A. Experiments in knowing: gender and method in the social sciences. Cambridge: Polity Press, 2000: 26–27. 4 Giacomini MK, Cook DJ for the Evidence-Based Medicine Working Group. User’s Guide to the Medical Literature. XXIII. Qualitative research in health care: are the results of the study valid JAMA 2000; 284: 357–62. 5 Collins R, Doll R, Peto R. Ethics of clinical trials. In: Williams CJ. Introducing new treatments for cancer: practical, ethical, and legal problems. New York :John Wiley, 1992. 6 Truog RD, Robinson W, Randolph A, Morris A. Is informed consent always necessary for randomized controlled trials? N Engl J Med 1999; 340: 804–07. 7 United States Department of Health and Human Research. OPRR NIH. Protecting human research subjects. Institutional review board guidebook. US Government Printing Office; 1993: G4. 8 Chalmers I, Silverman WA. Professional and public double standards on clinical experimentation. Controlled Clin Trials 1987; 8: 388–91. 9 Rogers CG, Tyson JE, Kennedy KA, Broyles RS, Hickman J. Conventional consent with opting in versus simplified consent with opting out: an exploratory trial for studies that do not increase patient risk. J Pediatr 1998; 132: 606–11. 10 Lantos JD. The “inclusion benefit” in clinical trials. J Pediatr 1999; 134: 130–31.
"Adiposity rebound": reality or epiphenomenon?
20
5th
15
10 2
4
6
8
10 12 14 Age (years)
16
18
20
Earlier rebound of BMI occurs at higher percentiles
2027
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
seems to have an effect on adult BMI that is independent of the time of rebound.6 However, the correlations between BMI at age 7 and adult BMI and between age at rebound and adult BMI are much the same. BMI at age 7 may thus be a more practical criterion for the determination of risk.7 Because BMI is weight (kg) divided by height (m2), an increased BMI can reflect either increased weight or decreased height, and it is not known whether children or adults with early increases in BMI are heavier or have a reduced height velocity compared with children with later increases in BMI. Even if the differences in BMI in childhood can be attributed to increased weight, whether the increase is in body fat rather than bone or muscle mass remains unclear. A similar argument applies to adults. The factors that predispose to early BMI rebound also remain uncertain. Television viewing by American children has been linked to obesity,9 but there is no evidence that children with early rebound are more sedentary than children with later rebound. Two small studies have suggested that early protein intake predicts an increase in BMI10,11 or subscapular skinfold thickness10 at the time of adiposity rebound11 or at age 8 years.10 In a larger sample of children for whom 3-day prospective household measures were collected at ages 8 and 18 months, no significant association was found between protein, fat, or carbohydrate intake and the timing of BMI rebound.12 Furthermore, how would increased protein intake lead to early rebound? Nor do children always eat what their parents urge them to. For example, encouragement to eat certain foods may reduce intake of that food13 whereas restrictions on a food item may lead to increased consumption of it when the restriction is removed.14 In a cross-sectional study, increased parental control over food intake was associated with an impaired capacity of children to regulate their own intake15 but this study cannot tell whether this finding indicated cause and effect or effect and cause. Adiposity rebound has been based on population measures. In an individual this rebound may be difficult to judge. Measurement error will probably confound assessment of early BMI rebound in young children. For example, a measurement error of 2 cm in a child who weighs 20 kg and is 115 cm tall will account for an error of 0·5 of a BMI unit. Furthermore, few children are likely to be seen frequently enough for the period of rebound to be identified—and because the period of rebound can be identified only retrospectively, early rebound may not be preventable. William H Dietz Division of Nutrition and Physical Activity, Centers for Disease Control and Prevention, Atlanta, GA 30341,USA
1
2
3
4
5
Rolland-Cachera M-F, Deheeger M, Bellisle F, Sempe M, GuilloudBataille M, Patois E. Adiposity rebound in children: a simple indicator for predicting adiposity. Am J Clin Nutr 1984; 39: 129–35. Rolland-Cachera MF, Avons P, Patois E, Sempe M. Tracking the development of adiposity from one month of age to adulthood. Ann Human Biol 1987; 14: 219–29. Rolland-Cachwera M-F, Bellisle F, Deheeger M, Guilloud-Bataille M, Pequignot F, Sempe, M. Adiposity development and prediction during growth in humans: a two decade follow-up study. In: Bjorntorp P, Rossner S, eds. Obesity in Europe 88. London: John Libbey, 1988. Siervogel RM, Roche AF, Guo S, Mukherjee D, Chumlea WC. Patterns of change in weight/stature2 from 2 to 18 years: findings from long-term serial data for children in the Fels longitudinal growth study. Int J Obesity 1991; 15: 479–85. Prokopec M, Bellisle F. Adiposity in Czech children followed from 1 month of age to adulthood: analysis of individual BMI
2028
6
7
8 9
10
11
12
13
14
15
patterns. Ann Human Biol 1993; 20: 517–25. Whitaker RC, Pepe MS, Wright JA, Seidel KD, Dietz WH. Early adiposity rebound and the risk of adult obesity. Pediatrics 1998; 101(electronic pages)/3/e5. Williams S, Davie G, Lam F. Predicting BMI in young adults from childhood data using two approaches to modeling adiposity rebound. Int J Obes Relat Metab Disord 1999; 23: 348–54. Dietz WH. Critical periods in childhood for the development of obesity. Am J Clin Nutr 1994; 59: 995–99. Dietz WH, Gortmaker SL. Do we fatten our children at the TV set? obesity and television viewing in children and adolescents. Pediatrics 1985; 75: 807–12. Rolland-Cachera MF, Deheeger M, Akrout M, Bellisle F. Influence of macronutrients on adiposity development. Int J Obesity 1995; 19: 573–78. Scaglioni S, Agostini C, De Notarus R, et al. Early macronutrient intake and overweight at five years of age. Int J Obesity 2000; 24: 777–81. Dorosty AR, Emmett PM, Cowin IS, Reilly JJ, ALSPAC Study Team. Factors associated with early adiposity rebound. Pediatrics 2000; 105: 1115–18. Birch LL, Marlin DW, Rotter J. Eating as the “means” activity in a contingency: effects on young children’s food preference. Child Dev 1985; 55: 431–39. Fisher JO, Birch LL. Restricting access to palatable foods affects children’s behavioral response, food selection and intake. Am J Clin Nutr 1999; 69: 1264–72. Johnson SL, Birch LL. Parents’ and children’s adiposity and eating style. Pediatrics 1994; 94: 653–61.
Thrombolytic therapy in the elderly A recent observational study by Thiemann et al1 of 7864 Medicare patients treated for acute myocardial infarction in the USA has been widely interpreted as meaning that the use of thrombolytic therapy in patients over 75 may do more harm than good.2 30-day mortality in patients aged 76-86 was significantly higher in those who received thrombolytic therapy within 4 h of admission than in those who did not (18·0% vs 13·6%, p=0·003). These results appear to contradict the Fibrinolytic Therapy Trialists’ (FTT) overview3 of 58 600 patients randomised into thrombolytic trials, which concluded that the 35-day mortality rate in the 5788 patients aged over 75 was lower in those who received thrombolytic therapy than in those who did not (24·3% vs 25·3%). The difference was not significant and the 95% CI was -16% to +36%). However, the absolute mortality reduction in patients over 75 (10 potential lives saved per 1000 treated) was similar to that of patients under 55 (11 per 1000). What can the clinician conclude from such disparate reports, and how much credence can be given to observational studies? In the Thiemann study, there were significant imbalances between the groups in terms of prognostic factors, and the analysis was adjusted for these. However, even with such adjustment, selection of treatments based on physicians’ preferences can affect outcomes that are not due to the treatment itself. The only way to ensure that unknown factors are balanced between treatment groups is by randomised treatment assignment.4 The fact that only 34% of electrocardiographically eligible patients were included in the Thiemann study suggests that there was indeed a selection bias. Another confounding factor is that a large proportion of the patients aged 76–86 who did receive thrombolytic therapy had relative contraindications; for example, 12% had a systolic blood pressure of over 180 mm Hg and 18·0% had a history of trauma, peptic ulceration, or internal bleeding—all of which would have increased the risk of intracranial and systemic bleeding.
THE LANCET • Vol 356 • December 16, 2000
For personal use only. Not to be reproduced without permission of The Lancet.