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Hype about glucosamine
retard progressive loss of renal function. Now further improvements can be expected by adjusting renoprotective therapy according to the decline in urinary protein excretion,in the way that antihypertensive therapy has been titrated against level of blood pressure. This approach should be explored in prospective studies. *Paul E De Jong, Gerjan Navis, Dick de Zeeuw Division of Nephrology, Department of Internal Medicine, University Hospital Groningen, 9713 GZ Groningen, Netherlands 1
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The GISEN Group. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997; 349: 1857–63. Navis GJ, de Zeeuw D, de Jong PE. ACE inhibitors: panacea for progressive renal disease? Lancet 1997; 349: 1852–53. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria and the progression of renal disease. Ann Intern Med 1995; 123: 752–62. El Nahas AM, Masters-Thomas A, Brady SA, et al. Selective effects of low protein diets in chronic renal diseases. BMJ 1984; 289: 1337–41. Apperloo AJ, de Zeeuw D, de Jong PE. Short-term antiproteinuric response to antihypertensive therapy predicts long-term GFR decline in patients with non-diabetic renal disease. Kidney Int 1994; 45 (suppl 45): 174–78. Rossing P, Hommel E, Smidt UM, Parving HH. Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment. Diabetologia 1994; 37: 511–16. Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int 1989; 36: 272–79. Buter H, Hemmelder MH, Navis GJ, de Jong PE, de Zeeuw D. Blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transpl 1988; 13: 1682–85. Gansevoort RT, de Zeeuw D, de Jong PE. Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin angiotensin system? Kidney Int 1994; 45: 861–67. Gansevoort RT, de Zeeuw D, de Jong PE. Additive antiproteinuric effect of ACE inhibition and a low protein diet in human renal disease. Nephrol Dial Transpl 1995; 10: 497–504. Heeg JE, de Jong PE, de Zeeuw D. Additive antiproteinuric effect of angiotensin converting enzyme inhibition and non-steroidal antiinflammatory drug therapy: a clue to the mechanism of action. Clin Sci (Colch) 1991; 81: 367–72.
Hype about glucosamine Glucosamine is being extensively marketed as a treatment for osteoarthritis. Books and advertisements in magazines and web pages suggest that glucosamine “cures” osteoarthritis, an implication largely achieved through imagery. But that is what advertisements do for baby food (smiling babies), antidepressants (sad then happy people), and cigarettes and beverages (very happy people socialising), the images suggesting an effect that may be exaggerated or is not necessarily intrinsic to the product. Glucosamine is available as a “nutritional supplement” from health-food stores and via the internet. There are few, if any, meaningful statements about efficacy or any need for caution. It is as if anything “natural” or “organic” cannot be bad. Criticisms of the marketing apart, the scientific questions are: ● Is glucosamine effective and safe in the treatment of osteoarthritis? ● How might it work? ● When, if ever, should it be used? ● How do different preparations compare one with another and with existing therapies? Glucosamine is important in the metabolism of all glycoproteins, including those in cartilage, where one of
THE LANCET • Vol 354 • July 31, 1999
its major roles is in the formation of the glycosaminoglycan chains in aggrecan and other proteoglycans. Aggrecan gives cartilage its hydrophilicity, providing a swelling pressure that is restrained by the tensile forces of collagen fibres. This balance gives cartilage the deformable resilience so necessary for its function. In cartilage affected by osteoarthritis, at least until the disorder is advanced,1 the metabolism is increased, with increased synthesis of collagen, aggrecan, and other structural proteins.1–3 Catabolism is also increased, with elaboration of catalytic cytokines and proteases.4 Chrondrocytes in culture media supplemented with glucosamine do elaborate more aggrecan.5 Thus, if additional aggrecan synthesis is necessary, glucosamine might be beneficial in osteoarthritis, and might slow down disease progression. Whether glucosamine does work this way or by some other method, such as by scavenging free radicals6 or by effects on synthesis of other substances, is unknown. Glucosamine also has a very important role in glucose metabolism; it increases insulin resistance. The mechanism here is complex and not fully understood but could lead to effects ranging from alteration of receptor binding to glycosylation of intracellular proteins.7–9 An analogue of glucosamine, streptozotocin, causes islet-cell death.9 Glucosamine increases glucose resistance in normal and in experimentally diabetic animals.8 Intravenous glucosamine in doses as low as 0·1 mg.kg–1 min–1 results in a 50% reduction in the rate of glucose uptake in skeletal muscle.10 For a 70 kg man this would be an influx of 7 mg/min, a level possibly achieved in vivo with oral doses of 500 mg (calculated from data in ref 11). Patients with osteoarthritis tend to be elderly and obese, and thus prone to type 2 diabetes. A subtle worsening of insulin resistance, even one that might not be seen in a short-term trial with no or only a few mildly diabetic patients, might well have harmful consequences in the long term. Double-blind, placebo-controlled randomised trials show that glucosamine is mildly effective for relieving the pain of osteoarthritis.6,12,13 The trials lasted 4–6 weeks. There were few adverse events. One trial compared glucosamine with half the maximum dose of ibuprofen. Glucosamine showed less efficacy at 1 week and the same efficacy at 4 weeks, interpreted as meaning that glucosamine is a “slow-acting drug” for osteoarthritis, and that it will continue to act long after 4 weeks. These trials clearly do not meet the requirements of the Osteoarthritis Research Society for slow-acting drugs,14 which recommends trials of 3–12 months for such products, nor did they impress the editors of the Medical Letter.15 Recently, all trials for glucosamine and chondroitin for treating osteoarthritis have been subjected to a meta-analysis.16 The quality assessment for these studies ranged from 8–36, where 33 or less is poor and 34–45 is moderate. The conclusion was that, although these treatments also show effects, there is insufficient information about trial design to allow a definitive evaluation. No treatment for osteoarthritis has been proved to affect structural changes in the joint or the rate of progression. Treatments are for symptomatic relief, and since osteoarthritis is a chronic disease lasting 10–30 years, longer-term studies of efficacy and safety are needed. Such studies have not been done for glucosamine, nor for many other treatments for this 353
disorder, except as postmarketing surveys. Furthermore, glucosamine is marketed as a nutritional supplement, and the testing of “nutritional substances” required by most regulatory agencies is minimal. There is also little quality control, and products from various suppliers may differ widely in content of both presumed active product and excipients. The main problem with glucosamine is that its longterm efficacy and safety are unknown. Study of these effects would require large numbers of patients followed up for a very long time, and would be expensive. On June 8, 1998, the US National Institutes of Health in the USA issued a Request for Proposals to study the efficacy and safety of glucosamine and glycosaminoglycans in osteoarthritis. It will be a long time before any of the studies that are funded will be completed. Till then, what should patients be advised? Many of them will probably take glucosamine whatever they are told. Perhaps all, but especially those who are overweight or have diabetes, should be urged caution and have their attention drawn to the short duration of the studies. Mark E Adams Department of Rheumatic Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada 1 Mankin HJ, Lippiello L. Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. J Bone Joint Surg [Am] 1970; 52: 424–34. 2 Adams ME, Dourado GS, Matyas JR, Huang D. mRNA expression of biglycan, decorin, and fibromodulin in experimental osteoarthritis. Osteoarthritis Cartilage 1994; 45 (abstr). 3 Matyas JR, Adams ME, Huang D, Sandell LJ. Discoordinate gene expression of aggrecan and type II collagen in experimental osteoarthritis. Arthritis Rheum 1995; 38: 420–25. 4 Malemud CJ, Hering TM. Regulation of chrondrocytes in osteoarthrosis. In: Adolphe M, ed. Biological regulation of the chondrocytes. Boca Raton, Florida: CRC Press, 1992: 295–319. 5 Bassleer C, Rovati L, Franchimont P. Stimulation of proteoglycan production by glucosamine sulfate in chrondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage 1998; 6: 427–34. 6 Müller-Fabbender H, Bach GL, Haase W, Rovati LC, Setnikar I. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage 1994; 2: 61–69. 7 Roos MD, Han IO, Paterson AJ, Kudlow JE. Role of glucosamine synthesis in the stimulation of TGF-a gene transcription by glucose and EGF. Am J Physiol Cell Physiol 1996; 270: C803–11. 8 McClain DA, Crook ED. Hexosamines and insulin resistance. Diabetes 1996; 45: 1003–09. 9 Poos MD, Xie W, Kaihong S, et al. Streptozotocin, an analog of Nacetylglucosamine, blocks the removal of O-GlcNAc from intracellular proteins. Proc Assoc Am Phys 1998; 110: 422–32. 10 Baron AD, Zhu J, Weldon H, Mainnu L, Garvy WT. Glucosamine induces insulin resistance in vivo by affecting GLUC4 translocation in skeletal muscle. J Clin Invest 1995; 96: 2792–801. 11 Setnikar I, Giacchetti C, Zanolo G. Pharmacokinetics of glucosamine in the dog and in man. Arzneimittelforsgung 1986; 36: 729–35. 12 Reichelt A, Förster KK, Fischer M, Rovati LC, Setnikar I. Efficacy and safety of intramuscular glucosamine sulfate in osteoarthritis of the knee: a randomised, placebo-controlled, double-blind study. Arzneimittelforsgung 1994; 44: 75–80. 13 Noack W, Fischer M, Förster KK, Rovati LC, Setnikar I. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage 1994; 2: 51–59. 14 Altman R, Brandt K, Hochberg M, Moskowitz R. Design and conduct of clinical trials in patients with osteoarthritis: recommendation from a task force of the Osteoarthritis Research Society. Osteoarthritis Cartilage 1996; 4: 217–43. 15 Quackwatch. Glucosamine for arthritis. (http://www.quackwatch.com /01QuackeryRelatedTopics/DSH/glucosamine.html; accessed on July 26, 1999. 16 McAlindon TE, Guilin J, Felson DT. Glucosamine (GL) and chondroitin (CH) treatment for osteoarthritis (OA) of the knee or hip: a meta-analysis and quality of assessment of clinical trials. Arthritis Rheum 1998; S198 (abstr).
354
Survival after being born too soon, but at what cost? The survival rate of very preterm infants has been increasing steadily in recent decades.1,2 Although the remarkable advances in medical care and technology that have permitted this secular trend are commendable, there are undercurrents of concern about the quality of life for such children in later life.3 Many have learning difficulties or behavioural problems when they get to school, and up to half require additional help or facilities.4,5 Yet there has been no consensus among published studies, even those of high-risk groups of extremely low birthweight infants (<1000 g) (eg, ref 6). This situation may reflect variation in study design rather than real differences in reproductive casualty. Nevertheless, it is important to establish benchmarks for the success of neonatal intensive care in representative samples. Many studies of intellectual abilities, educational success, and behavioural adjustment of individuals born much too soon or too small have included too few individuals or have lacked control groups. The generalisability of their findings is thus open to question. Methods used to assess cognitive and adaptive functioning at school age have been variable in thoroughness.7,8 To address deficiencies in previous research D Wolke and colleagues9 undertook the ambitious Bavarian Longitudinal Study of preterm infants. They have recently published data on outcome at school entry.9 This impressive body of work combines both a prospective survey of a large number of at-risk infants, together with innovative assessments of their developmental attainments. The survey results add to the sum of knowledge on the long-term consequences of preterm birth, although they do not provide a startling contrast to the consensus of previous work. 70 600 babies were enrolled in Bavaria over a 14 month period in 1985/86. Cases were defined as those having a gestation of less than 32 weeks (and 78% had birthweight under 1500 g). 75% (264) of all eligible births were assessed between the ages of 5 months and 6 years 3 months. There were 264 full-term controls, born in the same area over the same period. The team employed a wide variety of outcome measures, such as intelligence (based on Kaufman-ABC test10), receptive and expressive language, speech articulation, and prereading and number skills. The Kaufman-ABC test yields mental-processing subscales that are arguably more predictive of educational success than are conventional IQ measures, although this point is controversial. The psychological tests were standardised against a large random sample of the German population. The Kaufman-ABC test draws a distinction between “sequential” mental processing (eg, repeating numbers spoken by an examiner) and “simultaneous” mental processing (eg, recalling the spatial locations of stimuli). The former is thought to be important for skills such as reading, the latter for problem solving. At follow-up the proportion of infants born preterm who had significant problems with sequential information processing (12·1%) was more than ten times greater than that of controls. The proportion with simultaneous information processing problems (34·8%) was 30 times greater. Language problems were also much commoner among the preterm group. They had a poorer quality of speech, and poorer grammatical constructions in expressive
THE LANCET • Vol 354 • July 31, 1999
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The GISEN Group. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997; 349: 1857–63. Navis GJ, de Zeeuw D, de Jong PE. ACE inhibitors: panacea for progressive renal disease? Lancet 1997; 349: 1852–53. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria and the progression of renal disease. Ann Intern Med 1995; 123: 752–62. El Nahas AM, Masters-Thomas A, Brady SA, et al. Selective effects of low protein diets in chronic renal diseases. BMJ 1984; 289: 1337–41. Apperloo AJ, de Zeeuw D, de Jong PE. Short-term antiproteinuric response to antihypertensive therapy predicts long-term GFR decline in patients with non-diabetic renal disease. Kidney Int 1994; 45 (suppl 45): 174–78. Rossing P, Hommel E, Smidt UM, Parving HH. Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment. Diabetologia 1994; 37: 511–16. Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int 1989; 36: 272–79. Buter H, Hemmelder MH, Navis GJ, de Jong PE, de Zeeuw D. Blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transpl 1988; 13: 1682–85. Gansevoort RT, de Zeeuw D, de Jong PE. Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin angiotensin system? Kidney Int 1994; 45: 861–67. Gansevoort RT, de Zeeuw D, de Jong PE. Additive antiproteinuric effect of ACE inhibition and a low protein diet in human renal disease. Nephrol Dial Transpl 1995; 10: 497–504. Heeg JE, de Jong PE, de Zeeuw D. Additive antiproteinuric effect of angiotensin converting enzyme inhibition and non-steroidal antiinflammatory drug therapy: a clue to the mechanism of action. Clin Sci (Colch) 1991; 81: 367–72.
Hype about glucosamine Glucosamine is being extensively marketed as a treatment for osteoarthritis. Books and advertisements in magazines and web pages suggest that glucosamine “cures” osteoarthritis, an implication largely achieved through imagery. But that is what advertisements do for baby food (smiling babies), antidepressants (sad then happy people), and cigarettes and beverages (very happy people socialising), the images suggesting an effect that may be exaggerated or is not necessarily intrinsic to the product. Glucosamine is available as a “nutritional supplement” from health-food stores and via the internet. There are few, if any, meaningful statements about efficacy or any need for caution. It is as if anything “natural” or “organic” cannot be bad. Criticisms of the marketing apart, the scientific questions are: ● Is glucosamine effective and safe in the treatment of osteoarthritis? ● How might it work? ● When, if ever, should it be used? ● How do different preparations compare one with another and with existing therapies? Glucosamine is important in the metabolism of all glycoproteins, including those in cartilage, where one of
THE LANCET • Vol 354 • July 31, 1999
its major roles is in the formation of the glycosaminoglycan chains in aggrecan and other proteoglycans. Aggrecan gives cartilage its hydrophilicity, providing a swelling pressure that is restrained by the tensile forces of collagen fibres. This balance gives cartilage the deformable resilience so necessary for its function. In cartilage affected by osteoarthritis, at least until the disorder is advanced,1 the metabolism is increased, with increased synthesis of collagen, aggrecan, and other structural proteins.1–3 Catabolism is also increased, with elaboration of catalytic cytokines and proteases.4 Chrondrocytes in culture media supplemented with glucosamine do elaborate more aggrecan.5 Thus, if additional aggrecan synthesis is necessary, glucosamine might be beneficial in osteoarthritis, and might slow down disease progression. Whether glucosamine does work this way or by some other method, such as by scavenging free radicals6 or by effects on synthesis of other substances, is unknown. Glucosamine also has a very important role in glucose metabolism; it increases insulin resistance. The mechanism here is complex and not fully understood but could lead to effects ranging from alteration of receptor binding to glycosylation of intracellular proteins.7–9 An analogue of glucosamine, streptozotocin, causes islet-cell death.9 Glucosamine increases glucose resistance in normal and in experimentally diabetic animals.8 Intravenous glucosamine in doses as low as 0·1 mg.kg–1 min–1 results in a 50% reduction in the rate of glucose uptake in skeletal muscle.10 For a 70 kg man this would be an influx of 7 mg/min, a level possibly achieved in vivo with oral doses of 500 mg (calculated from data in ref 11). Patients with osteoarthritis tend to be elderly and obese, and thus prone to type 2 diabetes. A subtle worsening of insulin resistance, even one that might not be seen in a short-term trial with no or only a few mildly diabetic patients, might well have harmful consequences in the long term. Double-blind, placebo-controlled randomised trials show that glucosamine is mildly effective for relieving the pain of osteoarthritis.6,12,13 The trials lasted 4–6 weeks. There were few adverse events. One trial compared glucosamine with half the maximum dose of ibuprofen. Glucosamine showed less efficacy at 1 week and the same efficacy at 4 weeks, interpreted as meaning that glucosamine is a “slow-acting drug” for osteoarthritis, and that it will continue to act long after 4 weeks. These trials clearly do not meet the requirements of the Osteoarthritis Research Society for slow-acting drugs,14 which recommends trials of 3–12 months for such products, nor did they impress the editors of the Medical Letter.15 Recently, all trials for glucosamine and chondroitin for treating osteoarthritis have been subjected to a meta-analysis.16 The quality assessment for these studies ranged from 8–36, where 33 or less is poor and 34–45 is moderate. The conclusion was that, although these treatments also show effects, there is insufficient information about trial design to allow a definitive evaluation. No treatment for osteoarthritis has been proved to affect structural changes in the joint or the rate of progression. Treatments are for symptomatic relief, and since osteoarthritis is a chronic disease lasting 10–30 years, longer-term studies of efficacy and safety are needed. Such studies have not been done for glucosamine, nor for many other treatments for this 353
disorder, except as postmarketing surveys. Furthermore, glucosamine is marketed as a nutritional supplement, and the testing of “nutritional substances” required by most regulatory agencies is minimal. There is also little quality control, and products from various suppliers may differ widely in content of both presumed active product and excipients. The main problem with glucosamine is that its longterm efficacy and safety are unknown. Study of these effects would require large numbers of patients followed up for a very long time, and would be expensive. On June 8, 1998, the US National Institutes of Health in the USA issued a Request for Proposals to study the efficacy and safety of glucosamine and glycosaminoglycans in osteoarthritis. It will be a long time before any of the studies that are funded will be completed. Till then, what should patients be advised? Many of them will probably take glucosamine whatever they are told. Perhaps all, but especially those who are overweight or have diabetes, should be urged caution and have their attention drawn to the short duration of the studies. Mark E Adams Department of Rheumatic Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada 1 Mankin HJ, Lippiello L. Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. J Bone Joint Surg [Am] 1970; 52: 424–34. 2 Adams ME, Dourado GS, Matyas JR, Huang D. mRNA expression of biglycan, decorin, and fibromodulin in experimental osteoarthritis. Osteoarthritis Cartilage 1994; 45 (abstr). 3 Matyas JR, Adams ME, Huang D, Sandell LJ. Discoordinate gene expression of aggrecan and type II collagen in experimental osteoarthritis. Arthritis Rheum 1995; 38: 420–25. 4 Malemud CJ, Hering TM. Regulation of chrondrocytes in osteoarthrosis. In: Adolphe M, ed. Biological regulation of the chondrocytes. Boca Raton, Florida: CRC Press, 1992: 295–319. 5 Bassleer C, Rovati L, Franchimont P. Stimulation of proteoglycan production by glucosamine sulfate in chrondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage 1998; 6: 427–34. 6 Müller-Fabbender H, Bach GL, Haase W, Rovati LC, Setnikar I. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage 1994; 2: 61–69. 7 Roos MD, Han IO, Paterson AJ, Kudlow JE. Role of glucosamine synthesis in the stimulation of TGF-a gene transcription by glucose and EGF. Am J Physiol Cell Physiol 1996; 270: C803–11. 8 McClain DA, Crook ED. Hexosamines and insulin resistance. Diabetes 1996; 45: 1003–09. 9 Poos MD, Xie W, Kaihong S, et al. Streptozotocin, an analog of Nacetylglucosamine, blocks the removal of O-GlcNAc from intracellular proteins. Proc Assoc Am Phys 1998; 110: 422–32. 10 Baron AD, Zhu J, Weldon H, Mainnu L, Garvy WT. Glucosamine induces insulin resistance in vivo by affecting GLUC4 translocation in skeletal muscle. J Clin Invest 1995; 96: 2792–801. 11 Setnikar I, Giacchetti C, Zanolo G. Pharmacokinetics of glucosamine in the dog and in man. Arzneimittelforsgung 1986; 36: 729–35. 12 Reichelt A, Förster KK, Fischer M, Rovati LC, Setnikar I. Efficacy and safety of intramuscular glucosamine sulfate in osteoarthritis of the knee: a randomised, placebo-controlled, double-blind study. Arzneimittelforsgung 1994; 44: 75–80. 13 Noack W, Fischer M, Förster KK, Rovati LC, Setnikar I. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage 1994; 2: 51–59. 14 Altman R, Brandt K, Hochberg M, Moskowitz R. Design and conduct of clinical trials in patients with osteoarthritis: recommendation from a task force of the Osteoarthritis Research Society. Osteoarthritis Cartilage 1996; 4: 217–43. 15 Quackwatch. Glucosamine for arthritis. (http://www.quackwatch.com /01QuackeryRelatedTopics/DSH/glucosamine.html; accessed on July 26, 1999. 16 McAlindon TE, Guilin J, Felson DT. Glucosamine (GL) and chondroitin (CH) treatment for osteoarthritis (OA) of the knee or hip: a meta-analysis and quality of assessment of clinical trials. Arthritis Rheum 1998; S198 (abstr).
354
Survival after being born too soon, but at what cost? The survival rate of very preterm infants has been increasing steadily in recent decades.1,2 Although the remarkable advances in medical care and technology that have permitted this secular trend are commendable, there are undercurrents of concern about the quality of life for such children in later life.3 Many have learning difficulties or behavioural problems when they get to school, and up to half require additional help or facilities.4,5 Yet there has been no consensus among published studies, even those of high-risk groups of extremely low birthweight infants (<1000 g) (eg, ref 6). This situation may reflect variation in study design rather than real differences in reproductive casualty. Nevertheless, it is important to establish benchmarks for the success of neonatal intensive care in representative samples. Many studies of intellectual abilities, educational success, and behavioural adjustment of individuals born much too soon or too small have included too few individuals or have lacked control groups. The generalisability of their findings is thus open to question. Methods used to assess cognitive and adaptive functioning at school age have been variable in thoroughness.7,8 To address deficiencies in previous research D Wolke and colleagues9 undertook the ambitious Bavarian Longitudinal Study of preterm infants. They have recently published data on outcome at school entry.9 This impressive body of work combines both a prospective survey of a large number of at-risk infants, together with innovative assessments of their developmental attainments. The survey results add to the sum of knowledge on the long-term consequences of preterm birth, although they do not provide a startling contrast to the consensus of previous work. 70 600 babies were enrolled in Bavaria over a 14 month period in 1985/86. Cases were defined as those having a gestation of less than 32 weeks (and 78% had birthweight under 1500 g). 75% (264) of all eligible births were assessed between the ages of 5 months and 6 years 3 months. There were 264 full-term controls, born in the same area over the same period. The team employed a wide variety of outcome measures, such as intelligence (based on Kaufman-ABC test10), receptive and expressive language, speech articulation, and prereading and number skills. The Kaufman-ABC test yields mental-processing subscales that are arguably more predictive of educational success than are conventional IQ measures, although this point is controversial. The psychological tests were standardised against a large random sample of the German population. The Kaufman-ABC test draws a distinction between “sequential” mental processing (eg, repeating numbers spoken by an examiner) and “simultaneous” mental processing (eg, recalling the spatial locations of stimuli). The former is thought to be important for skills such as reading, the latter for problem solving. At follow-up the proportion of infants born preterm who had significant problems with sequential information processing (12·1%) was more than ten times greater than that of controls. The proportion with simultaneous information processing problems (34·8%) was 30 times greater. Language problems were also much commoner among the preterm group. They had a poorer quality of speech, and poorer grammatical constructions in expressive
THE LANCET • Vol 354 • July 31, 1999