- Email: [email protected]
Preterm birth, vascular function, and risk factors for atherosclerosis
RESEARCH LETTERS
recipients with cytomegalovirus-negative donors, mainly as a result of lower relapse incidence. From these findings and the HLA-A2 restriction of at least some of the known anticytomegalovirus T-cell responses we postulate that donorderived T cell-mediated mechanisms are involved. Although cytomegalovirus together with GVHD—the major T cellmediated complication following allogeneic BMT—is frequently observed, the exact mechanisms of any interaction between the virus and disease remain unclear. By analysing the entire study population we did not find any differences in the frequencies of either acute or chronic GVHD between patients with either cytomegalovirus positive or negative donors. But, if only HLA-A2 positive recipient-donor combinations were analysed we found a significant association between donor cytomegalovirus seropositivity and chronic GVHD, but not acute GVHD, resulting in a significantly reduced relapse incidence. Even in patients without chronic GVHD, having a cytomegalovirus-positive donor was associated with improved survival and a lower relapse incidence, which indicates GVHD-independent graft-versus-leukaemia effects. Again, these observations were strictly confined to the HLA-A2positive subgroup and were not found in HLA-A2-negative recipients, suggesting a cross-reactivity of cytomegalovirusspecific cytotoxic T cells with HLA-A2-restricted minor histocompatibility antigens, which have been identified as target antigens not only for GVHD but also for potent graftversus-leukaemia effects.5 In conclusion, the data presented, although preliminary, warrant further studies on the impact of donor cytomegalovirus serostatus on outcome after allogeneic stemcell transplantation and should prompt us to reconsider our understanding of the pathophysiological interactions between cytomegalovirus, GVHD, and graft-versus-leukaemia effects. If confirmed by others in larger and more homogeneous patient populations, donor selection criteria with regard to donor cytomegalovirus serostatus, in the setting of HLAidentical sibling bone marrow transplantation will have to be redefined. We thank Dietger Niederwieser at the Bone Marrow Transplant Unit, Innsbruck University Hospital, Innsbruck, Austria, the nursing staff, and all the collaborating physicians. 1
2
3
4
5
Meyers JD, Flournoy N, Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 1986; 153: 478–88. Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell SR. Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 1994; 83: 1971–79. Solache A, Morgan CL, Dodi AI, et al. Identification of three HLAA*0201-restricted cytotoxic T cell epitopes in the cytomegalovirus protein pp65 that are conserved between eight strains of the virus. J Immunol 1999; 163: 5512–18. Ljungman P, Griffiths P. Definitions of cytomegalovirus infection and disease. In: Michelson S, Plotkin SA eds. Multidisciplinary approach to understanding cytomegalovirus disease. Paris: Elsevier Science, 1993: 233–37. Goulmy E. Human minor histocompatibility antigens: new concepts for marrow transplantation. Immunol Rev 1997; 157: 125–40.
Bone Marrow Transplant Unit and Tumour and Immunobiology Laboratory (D Nachbaur MD, B Eibl PhD, G Gastl MD), Department of Transplant Surgery (H Bonatti MD), Department of Transfusion Medicine (W Nussbaumer MD), Department of Hygiene and Social Medicine (C Larcher MD), Innsbruck University Hospital, A-6020 Innsbruck, Austria; Tumor Registry Tirol, Innsbruck (W Oberaigner PhD); University Children’s Hospital, Innsbruck (G Kropshofer MD), Medizinische Klinik und Poliklinik, Abteilung II, Universität Tübingen, Tübingen, Germany (H Einsele MD) Correspondence to: Dr David Nachbaur (e-mail: [email protected])
THE LANCET • Vol 358 • October 6, 2001
Preterm birth, vascular function, and risk factors for atherosclerosis Atul Singhal, Mia Kattenhorn, Tim J Cole, John Deanfield, Alan Lucas Low birthweight may predispose to the development of atherosclerosis later in life. We have tested the hypothesis that low birthweight as a result of preterm birth is associated with reduced flow-mediated endothelialdependent vasodilation (FMD), which is an early stage in the development of atherosclerosis. Mean FMD in adolescents born preterm who had a low birthweight did not differ from that for controls born at term (0·225 mm vs 0·220 mm, SD 0·1 for both means, p=0·78). Our findings indicate that low birthweight attributable to prematurity does not increase the risk of vascular disease later in life.
Lancet 2001; 358: 1159–60
In previous studies, low birthweight has proved to be associated with cardiovascular risk factors.1–3 However, the cardiovascular risk for individuals who had a low birthweight because they were born prematurely—compared with that in people of low birthweight for gestational age (intrauterine growth This retardation, IUGR)—is controversial.1–3 distinction has important biological and medical implications. Irving and colleagues2 showed that babies born preterm were at greater cardiovascular risk than those born at term, and preterm babies with birthweight appropriate for gestational age were at similar cardiovascular risk to those with IUGR. This study, however, did not have statistical power to detect even large differences between groups. Therefore, we have prospectively investigated the hypothesis that low birthweight as a result of preterm birth is associated with later endothelial dysfunction, which is an early stage in the pathogenesis of atherosclerosis.4 Individuals were recruited between 1982 and 1985 from five UK centres (Norwich, Cambridge, Sheffield, Ipswich, and King’s Lynn) and were from an original cohort of 926 (gestation, mean 31·0 weeks, SD 2·8; birthweight, 1·4 kg, 0·3) who had taken part in an investigation of the effects of early nutrition on cardiovascular disease (CVD) in later life.5 Participants had no major congenital abnormalities. The first 216 who agreed to participate, who were a representative subset of the original cohort, were reviewed at age 13–16 years.5 Controls (n=61) were recruited from schools in the five communities, and were all consenting adolescents of the same age as the study participants who were born at term and above the 10th centile for birthweight for gestational age. All participants and controls were non-smokers, were clinically well at the time of the study, and did not have any chronic disease or disability. Endothelial function of the brachial artery was measured by high-resolution ultrasonography4 after participants had rested supine for 10 min. Scans were done in a temperature-controlled darkened room, between 0900 h and 1100 h, by one observer who did not know the individual’s birthweight or gestational age. The brachial artery was imaged in longitudinal section, 5–10 cm above the elbow, with a 7-MHz linear array transducer and an Acuson 128XP/10 system (Acuson, Mountview, USA). The transducer was then fixed by a stereotactic clamp and fine
1159
For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
Controls (n=61)* Age (years) Sex, male (%)‡ Birthweight (kg) Gestation (weeks) BMI (kg/m2) Blood pressure Diastolic (mm Hg) Systolic (mm Hg) Fasting plasma Glucose (mmol/L) Loge insulin (pmol/L) Total cholesterol (mmol/L) HDL cholesterol (mmol/L) Endothelial function FMD (mm; mean, SD)¶ Arterial diameter (mm) Reactive hyperaemia (%)
14·7 (0·8) 29 (48) 3·5 (0·6) 40·0 (1·2) 21·6 (4·1)
All preterm (n=216)*
Preterm with appropriate birthweight for gestational age (n=144)*
15·0 (0·9)† 97 (45) 1·4 (0·3)§ 31·0 (2·7)§ 21·2 (3·7)
15·0 (0·9) 66 (46) 1·4 (0·3) 30·0 (2·2) 21·0 (3·4)
Preterm with IUGR (n=72)* 15·0 (0·9) 31 (43) 1·3 (0·3) 33·0 (2·4)§ 21·6 (4·2)
64·2 (8·2) 115·8 (8·9)
63·7 (7·4) 115·8 (8·4)
63·9 (7·5) 115·5 (7·9)
63·2 (7·2) 116·2 (9·1)
4·8 (0·4) 3·9 (0·6) 3·9 (0·8) 1·2 (0·3)
4·7 (0·5) 3·8 (0·6) 4·0 (0·7) 1·2 (0·3)
4·7 (0·6) 3·8 (0·5) 4·0 (0·8) 1·2 (0·2)
4·7 (0·5) 3·8 (0·5) 4·0 (0·6) 1·2 (0·3)
0·220 (0·10) 3·7 (0·6) 683 (362)
0·225 (0·10)㛳 3·5 (0.5)†† 682 (314)
0·237 (0·11) 3·5 (0·5) 670 (340)
0·206 (0·11)** 3·5 (0·5) 690 (301)
Data are mean (SD) unless otherwise indicated. IUGR=intrauterine growth retardation; BMI=body-mass index; FMD=flow-mediated dilation. *Some loss of n for some variables; †p=0·046; ‡Analysis by 2; §p<0·0001; ¶Adjusted for resting arterial diameter; 㛳p=0·78; **p=0·044; ††p=0·01.
Patient characteristics, cardiovascular risk factors, and endothelial function
position adjustments were made with micrometre screws. A pneumatic cuff was inflated around the forearm to 300 mm Hg for 5 min; after inflation, the cuff was rapidly deflated causing a large increase in blood flow (reactive hyperaemia). The resting and posthyperaemic blood flow velocities in the centre of the brachial artery were measured by pulsed doppler. Enddiastolic B-mode images for measurement of arterial diameter were taken every 3 s (for 1 min at rest, 5 min cuff inflation, and 3 min after cuff deflation) and digitally stored in sequence. Flow-mediated endothelialdependent vasodilation (FMD) was expressed as the maximum change between prehyperaemic and posthyperaemic brachial artery diameter adjusted for prehyperaemic diameter.4 Blood pressure was measured twice in the left arm with an automated device (Accutorrsat, Datascope Corp, New Jersey, USA) and appropriate cuff size. A blood sample was taken after an overnight fast, and concentrations of glucose, insulin, total cholesterol, HDL cholesterol, and LDL cholesterol were measured by standard laboratory techniques. Participants born preterm were compared with controls by Student’s t test. We used multiple regression analysis to test for between-group differences in FMD. In a secondary analysis within the preterm population, people with IUGR were compared with those with birthweight appropriate for gestational age. IUGR was calculated with reference data for preterm infants as birthweight for gestation less than the 10th centile for expected birthweight. FMD (or other cardiovascular risk factors) did not differ between participants born preterm and controls (table), nor did this difference change after adjustment for age and sex (p=0·95). In the secondary analysis within the preterm group, FMD, but not other cardiovascular risk factors, was significantly lower in participants born with IUGR than in those with birthweight appropriate for gestational age, and this difference remained significant after adjustment for age and sex (p=0·048). In our study, which was powered to detect a 0·5 SD difference in FMD between groups, low birthweight as a result of preterm birth was not associated with endothelial dysfunction, a key early stage in the atherosclerotic process. In a secondary
1160
analysis, people who had been preterm babies with IUGR had a lower FMD than those with birthweight appropriate for gestational age, which is consistent with the results of studies that show an association between IUGR and endothelial dysfunction,4 atherosclerosis, and CVD1 in adults born at full term. The absence of an association between IUGR and high blood pressure in our study was consistent with work showing a smaller association during adolescence than at other ages. We and other investigators have shown that FMD is a robust clinical measure with a clear relation to the vascular biology of atherosclerosis. FMD indicates bioavailability of nitric oxide and shows a dose–response relation with classic cardiovascular risk factors. Furthermore, endothelial dysfunction of the brachial artery is closely related to dysfunction in the coronary vessels, and is responsive to interventions known to reduce atherogenesis and atherosclerotic mortality. Therefore, reassuringly for the 6% of infants born preterm, our observations do not lend support to the hypothesis that babies born early are at a high risk of CVD later in life,2 solely on the account of their prematurity. 1
2
3 4
5
Leon DA, Lithell HO, Vagero D, et al. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915–29. BMJ 1998; 317: 241–45. Irving RJ, Belton NR, Elton RA, Walker BR. Adult cardiovascular risk factors in premature babies. Lancet 2000; 355: 2135–36. Whincup PH, Cook DG. Adult cardiovascular risk factors in premature babies. Lancet 2000; 356: 938. Leeson CP, Whincup PH, Cook DG, et al. Flow-mediated dilation in 9- to 11-year-old children: the influence of intrauterine and childhood factors. Circulation 1997; 96: 2233–38. Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials. Lancet 2001; 357: 413–19.
MRC Childhood Nutrition Research Centre (A Singhal MRCP, M Kattenhorn BSc, A Lucas FRCP), Department of Vascular Physiology (M Kattenhorn BSc, J Deanfield FRCP), and Department of Paediatric Epidemiology and Biostatistics (T J Cole PhD) Institute of Child Health, Guilford Street, London WC1N 1EH, UK Correspondence to: Dr A Singhal (e-mail: [email protected])
THE LANCET • Vol 358 • October 6, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
recipients with cytomegalovirus-negative donors, mainly as a result of lower relapse incidence. From these findings and the HLA-A2 restriction of at least some of the known anticytomegalovirus T-cell responses we postulate that donorderived T cell-mediated mechanisms are involved. Although cytomegalovirus together with GVHD—the major T cellmediated complication following allogeneic BMT—is frequently observed, the exact mechanisms of any interaction between the virus and disease remain unclear. By analysing the entire study population we did not find any differences in the frequencies of either acute or chronic GVHD between patients with either cytomegalovirus positive or negative donors. But, if only HLA-A2 positive recipient-donor combinations were analysed we found a significant association between donor cytomegalovirus seropositivity and chronic GVHD, but not acute GVHD, resulting in a significantly reduced relapse incidence. Even in patients without chronic GVHD, having a cytomegalovirus-positive donor was associated with improved survival and a lower relapse incidence, which indicates GVHD-independent graft-versus-leukaemia effects. Again, these observations were strictly confined to the HLA-A2positive subgroup and were not found in HLA-A2-negative recipients, suggesting a cross-reactivity of cytomegalovirusspecific cytotoxic T cells with HLA-A2-restricted minor histocompatibility antigens, which have been identified as target antigens not only for GVHD but also for potent graftversus-leukaemia effects.5 In conclusion, the data presented, although preliminary, warrant further studies on the impact of donor cytomegalovirus serostatus on outcome after allogeneic stemcell transplantation and should prompt us to reconsider our understanding of the pathophysiological interactions between cytomegalovirus, GVHD, and graft-versus-leukaemia effects. If confirmed by others in larger and more homogeneous patient populations, donor selection criteria with regard to donor cytomegalovirus serostatus, in the setting of HLAidentical sibling bone marrow transplantation will have to be redefined. We thank Dietger Niederwieser at the Bone Marrow Transplant Unit, Innsbruck University Hospital, Innsbruck, Austria, the nursing staff, and all the collaborating physicians. 1
2
3
4
5
Meyers JD, Flournoy N, Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 1986; 153: 478–88. Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell SR. Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 1994; 83: 1971–79. Solache A, Morgan CL, Dodi AI, et al. Identification of three HLAA*0201-restricted cytotoxic T cell epitopes in the cytomegalovirus protein pp65 that are conserved between eight strains of the virus. J Immunol 1999; 163: 5512–18. Ljungman P, Griffiths P. Definitions of cytomegalovirus infection and disease. In: Michelson S, Plotkin SA eds. Multidisciplinary approach to understanding cytomegalovirus disease. Paris: Elsevier Science, 1993: 233–37. Goulmy E. Human minor histocompatibility antigens: new concepts for marrow transplantation. Immunol Rev 1997; 157: 125–40.
Bone Marrow Transplant Unit and Tumour and Immunobiology Laboratory (D Nachbaur MD, B Eibl PhD, G Gastl MD), Department of Transplant Surgery (H Bonatti MD), Department of Transfusion Medicine (W Nussbaumer MD), Department of Hygiene and Social Medicine (C Larcher MD), Innsbruck University Hospital, A-6020 Innsbruck, Austria; Tumor Registry Tirol, Innsbruck (W Oberaigner PhD); University Children’s Hospital, Innsbruck (G Kropshofer MD), Medizinische Klinik und Poliklinik, Abteilung II, Universität Tübingen, Tübingen, Germany (H Einsele MD) Correspondence to: Dr David Nachbaur (e-mail: [email protected])
THE LANCET • Vol 358 • October 6, 2001
Preterm birth, vascular function, and risk factors for atherosclerosis Atul Singhal, Mia Kattenhorn, Tim J Cole, John Deanfield, Alan Lucas Low birthweight may predispose to the development of atherosclerosis later in life. We have tested the hypothesis that low birthweight as a result of preterm birth is associated with reduced flow-mediated endothelialdependent vasodilation (FMD), which is an early stage in the development of atherosclerosis. Mean FMD in adolescents born preterm who had a low birthweight did not differ from that for controls born at term (0·225 mm vs 0·220 mm, SD 0·1 for both means, p=0·78). Our findings indicate that low birthweight attributable to prematurity does not increase the risk of vascular disease later in life.
Lancet 2001; 358: 1159–60
In previous studies, low birthweight has proved to be associated with cardiovascular risk factors.1–3 However, the cardiovascular risk for individuals who had a low birthweight because they were born prematurely—compared with that in people of low birthweight for gestational age (intrauterine growth This retardation, IUGR)—is controversial.1–3 distinction has important biological and medical implications. Irving and colleagues2 showed that babies born preterm were at greater cardiovascular risk than those born at term, and preterm babies with birthweight appropriate for gestational age were at similar cardiovascular risk to those with IUGR. This study, however, did not have statistical power to detect even large differences between groups. Therefore, we have prospectively investigated the hypothesis that low birthweight as a result of preterm birth is associated with later endothelial dysfunction, which is an early stage in the pathogenesis of atherosclerosis.4 Individuals were recruited between 1982 and 1985 from five UK centres (Norwich, Cambridge, Sheffield, Ipswich, and King’s Lynn) and were from an original cohort of 926 (gestation, mean 31·0 weeks, SD 2·8; birthweight, 1·4 kg, 0·3) who had taken part in an investigation of the effects of early nutrition on cardiovascular disease (CVD) in later life.5 Participants had no major congenital abnormalities. The first 216 who agreed to participate, who were a representative subset of the original cohort, were reviewed at age 13–16 years.5 Controls (n=61) were recruited from schools in the five communities, and were all consenting adolescents of the same age as the study participants who were born at term and above the 10th centile for birthweight for gestational age. All participants and controls were non-smokers, were clinically well at the time of the study, and did not have any chronic disease or disability. Endothelial function of the brachial artery was measured by high-resolution ultrasonography4 after participants had rested supine for 10 min. Scans were done in a temperature-controlled darkened room, between 0900 h and 1100 h, by one observer who did not know the individual’s birthweight or gestational age. The brachial artery was imaged in longitudinal section, 5–10 cm above the elbow, with a 7-MHz linear array transducer and an Acuson 128XP/10 system (Acuson, Mountview, USA). The transducer was then fixed by a stereotactic clamp and fine
1159
For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
Controls (n=61)* Age (years) Sex, male (%)‡ Birthweight (kg) Gestation (weeks) BMI (kg/m2) Blood pressure Diastolic (mm Hg) Systolic (mm Hg) Fasting plasma Glucose (mmol/L) Loge insulin (pmol/L) Total cholesterol (mmol/L) HDL cholesterol (mmol/L) Endothelial function FMD (mm; mean, SD)¶ Arterial diameter (mm) Reactive hyperaemia (%)
14·7 (0·8) 29 (48) 3·5 (0·6) 40·0 (1·2) 21·6 (4·1)
All preterm (n=216)*
Preterm with appropriate birthweight for gestational age (n=144)*
15·0 (0·9)† 97 (45) 1·4 (0·3)§ 31·0 (2·7)§ 21·2 (3·7)
15·0 (0·9) 66 (46) 1·4 (0·3) 30·0 (2·2) 21·0 (3·4)
Preterm with IUGR (n=72)* 15·0 (0·9) 31 (43) 1·3 (0·3) 33·0 (2·4)§ 21·6 (4·2)
64·2 (8·2) 115·8 (8·9)
63·7 (7·4) 115·8 (8·4)
63·9 (7·5) 115·5 (7·9)
63·2 (7·2) 116·2 (9·1)
4·8 (0·4) 3·9 (0·6) 3·9 (0·8) 1·2 (0·3)
4·7 (0·5) 3·8 (0·6) 4·0 (0·7) 1·2 (0·3)
4·7 (0·6) 3·8 (0·5) 4·0 (0·8) 1·2 (0·2)
4·7 (0·5) 3·8 (0·5) 4·0 (0·6) 1·2 (0·3)
0·220 (0·10) 3·7 (0·6) 683 (362)
0·225 (0·10)㛳 3·5 (0.5)†† 682 (314)
0·237 (0·11) 3·5 (0·5) 670 (340)
0·206 (0·11)** 3·5 (0·5) 690 (301)
Data are mean (SD) unless otherwise indicated. IUGR=intrauterine growth retardation; BMI=body-mass index; FMD=flow-mediated dilation. *Some loss of n for some variables; †p=0·046; ‡Analysis by 2; §p<0·0001; ¶Adjusted for resting arterial diameter; 㛳p=0·78; **p=0·044; ††p=0·01.
Patient characteristics, cardiovascular risk factors, and endothelial function
position adjustments were made with micrometre screws. A pneumatic cuff was inflated around the forearm to 300 mm Hg for 5 min; after inflation, the cuff was rapidly deflated causing a large increase in blood flow (reactive hyperaemia). The resting and posthyperaemic blood flow velocities in the centre of the brachial artery were measured by pulsed doppler. Enddiastolic B-mode images for measurement of arterial diameter were taken every 3 s (for 1 min at rest, 5 min cuff inflation, and 3 min after cuff deflation) and digitally stored in sequence. Flow-mediated endothelialdependent vasodilation (FMD) was expressed as the maximum change between prehyperaemic and posthyperaemic brachial artery diameter adjusted for prehyperaemic diameter.4 Blood pressure was measured twice in the left arm with an automated device (Accutorrsat, Datascope Corp, New Jersey, USA) and appropriate cuff size. A blood sample was taken after an overnight fast, and concentrations of glucose, insulin, total cholesterol, HDL cholesterol, and LDL cholesterol were measured by standard laboratory techniques. Participants born preterm were compared with controls by Student’s t test. We used multiple regression analysis to test for between-group differences in FMD. In a secondary analysis within the preterm population, people with IUGR were compared with those with birthweight appropriate for gestational age. IUGR was calculated with reference data for preterm infants as birthweight for gestation less than the 10th centile for expected birthweight. FMD (or other cardiovascular risk factors) did not differ between participants born preterm and controls (table), nor did this difference change after adjustment for age and sex (p=0·95). In the secondary analysis within the preterm group, FMD, but not other cardiovascular risk factors, was significantly lower in participants born with IUGR than in those with birthweight appropriate for gestational age, and this difference remained significant after adjustment for age and sex (p=0·048). In our study, which was powered to detect a 0·5 SD difference in FMD between groups, low birthweight as a result of preterm birth was not associated with endothelial dysfunction, a key early stage in the atherosclerotic process. In a secondary
1160
analysis, people who had been preterm babies with IUGR had a lower FMD than those with birthweight appropriate for gestational age, which is consistent with the results of studies that show an association between IUGR and endothelial dysfunction,4 atherosclerosis, and CVD1 in adults born at full term. The absence of an association between IUGR and high blood pressure in our study was consistent with work showing a smaller association during adolescence than at other ages. We and other investigators have shown that FMD is a robust clinical measure with a clear relation to the vascular biology of atherosclerosis. FMD indicates bioavailability of nitric oxide and shows a dose–response relation with classic cardiovascular risk factors. Furthermore, endothelial dysfunction of the brachial artery is closely related to dysfunction in the coronary vessels, and is responsive to interventions known to reduce atherogenesis and atherosclerotic mortality. Therefore, reassuringly for the 6% of infants born preterm, our observations do not lend support to the hypothesis that babies born early are at a high risk of CVD later in life,2 solely on the account of their prematurity. 1
2
3 4
5
Leon DA, Lithell HO, Vagero D, et al. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915–29. BMJ 1998; 317: 241–45. Irving RJ, Belton NR, Elton RA, Walker BR. Adult cardiovascular risk factors in premature babies. Lancet 2000; 355: 2135–36. Whincup PH, Cook DG. Adult cardiovascular risk factors in premature babies. Lancet 2000; 356: 938. Leeson CP, Whincup PH, Cook DG, et al. Flow-mediated dilation in 9- to 11-year-old children: the influence of intrauterine and childhood factors. Circulation 1997; 96: 2233–38. Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials. Lancet 2001; 357: 413–19.
MRC Childhood Nutrition Research Centre (A Singhal MRCP, M Kattenhorn BSc, A Lucas FRCP), Department of Vascular Physiology (M Kattenhorn BSc, J Deanfield FRCP), and Department of Paediatric Epidemiology and Biostatistics (T J Cole PhD) Institute of Child Health, Guilford Street, London WC1N 1EH, UK Correspondence to: Dr A Singhal (e-mail: [email protected])
THE LANCET • Vol 358 • October 6, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.