Low birthweight and renal disease in Australian aborigines

RESEARCH LETTERS

transducers, their difference in autoimmune disease induction has been attributed to their low sequence homology potentially affecting the type I interferon receptor response when binding occurs.4 Our report, however, shows that LE can be induced by interferon beta. We have contacted the manufacturer of interferon beta-1a (Avonex, Biogen, Massachusetts, USA) and were informed of two post-marketing reports of possible but unconfirmed LE. Moreover, the manufacturer of interferon beta-1b (Betaseron, Berlex Laboratories, California, USA) informed us of six cases of “lupus erythematosus syndrome” reported directly to them. However, they were not aware whether LE was confirmed in any of these cases. Physicians should be aware of the potential association between LE and interferon beta. 1 2

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Vial T, Descotes J. Immune-mediated side-effects of cytokines in humans. Toxicology 1995; 105: 31–57. Graninger WB, Hassfeld W, Pesau BB, et al. Induction of systemic lupus erythematosus by interferon-gamma in a patient with rheumatoid arthritis. J Rheumatol 1991; 18: 1621–22. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon Beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39: 285–94. Colosimo C, Pozzilli C, Frontomi M, et al. No increase of serum autoantibodies during therapy with recombinant human interferon␤1a in relapsing-remitting multiple sclerosis. Acta Neurol Scand 1997; 96: 372–74. Linden D. Severe Raynaud’s phenomenon associated with interferon␤ treatment for multiple sclerosis. Lancet 1998; 352: 878–79.

Department of Dermatology, johns Hopkins Medical institutions, Baltimore, MD 21205, USA (H C Nousari; e-mail [email protected])

Low birthweight and renal disease in Australian aborigines W E Hoy, M Rees, E Kile, J D Mathews, D A McCredie, D J Pugsley, Zhiqiang Wang

Barker has proposed that low birthweight predisposes to type 2 diabetes, hypertension, dyslipidaemia, and cardiovascular disease in adult life.1 An epidemic of these diseases, as well as renal failure, has developed among Aborigines in Australia’s Northern Territory, against a background of persistent low birthweights and progressive weight gain in adult life. We investigated whether low birthweight predisposes to renal disease in one community in which renal failure incidence has reached 2700 per million and is doubling every 4 years.2 We screened volunteers in this community for renal disease with the urinary albumin/creatinine ratio (ACR, g/mole) as the marker;3 1153 (78%) of people aged 5 years or older participated. We assessed correlations of various factors with ACR, including birthweights.3 Birthweights had been documented sporadically after 1958, and systematically since the late 1960s, and were available for 80% of people aged 38 years or younger at screening (320 children, and 298 adults). Mean birthweight was 2·8 (SD 0·5) kg, and 27·6% were low birthweights (<2·5 kg). More females than males had low birthweights (24·2 vs 32·0%, p=0·029). Gestational age had not been estimated for most people, but currently at least 70% of underweight Aboriginal newborns have intrauterine growth retardation.4 We analysed data from the entire child and adult cohorts, and also compared them with matched low and normal birthweight pairs, to eliminate confounding related to age and sex differences. Same-sex low and normal birthweight pairs were matched within 1 year of age, and then by proximity of date of screening, but without knowledge of ACR. Albuminuria was pervasive, and increased dramatically with age, and all renal failure arose in people with progressive overt

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Characteristics*

Low birthweight

Normal birthweight

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Children (72 matched pairs) Age (years) Birthweight (kg) Current weight (kg) Weight for age (Z score) Height (cm) Height for age (Z score) Systolic blood pressure (mm Hg)† Diastolic blood pressure (mm Hg) Geometric mean ACR (g/mole) ACR ⭓1·1

12·3 (2·9) 2·17 (0·31) 35·9 (12·3) ⫺1·25 (0·99) 145·5 (1·9) ⫺1·03 (1·12) 110 (13) 62 (11) 0·79 28%

12·3 (2·9) 3·02 (0·37) 42·0 (17·8) ⫺1·71 (1·23) 148·5 (2·0) ⫺0·74 (1·22) 114 (12) 63 (9) 0·81 24%

0·57 <0·001 0·002 0·007 0·006 0·11 0·08 0·77 0·84 0·6

Adults (97 matched pairs) Age (years) Birthweight (kg) Current weight (kg) Body-mass index (kg/m2) Height (cm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Impaired glucose tolerance Diabetes‡ Geometric mean ACR (g/mole) ACR ⭓34

27·7 (5·4) 2·23 (0·25) 59·7 (13·8) 21·7 (4·7) 165·7 (8·5) 115 (15) 71 (11) 8% 4% 3·2 16%

27·7 (5·3) 3·00 (0·32) 65·6 (15·1) 23·5 (5·1) 167 (7·1) 119 (11) 71 (12) 27% 8% 1·8 7%

0·26 <0·001 0·003 0·007 0·1 0·07 0·96 0·012 0·67 0·25 0·02

*Mean (SD) unless otherwise marked. †Blood pressures on 57 pairs aged 肁10 years. ‡Formal assessment of glucose tolerance on only 57 pairs.

Characteristics of matched pairs by birthweight

albuminuria (ACR ⭓34 g/mole). ACR correlated positively with the presence of scabies, a history of poststreptococcal glomerulonephritis, increasing adult weight, blood pressure and glucose, cholesterol, and triglyceride concentrations, and heavy drinking, and inversely with birthweight. Low birthweight children were lighter, shorter, and had lower systolic blood pressure than normal birthweight children, but had higher rates of suspiciously raised ACR (⭓1·1; 29 vs 21%, p=0·224). Low birthweight adults were generally shorter, lighter, had lower systolic blood pressure, and less impaired glucose tolerance and diabetes than normal birthweight adults, but had higher rates of overt albuminuria (17·9 vs 10·2%, p=0·07). The matched-pair data (table) confirm these observations, with significantly higher rates of overt albuminuria in low birthweight adults. The association of low birthweight with ACR of 1·1 or more in children was not significant, after accounting for age, sex, weight, and blood pressure (odds ratio 1·3 [95% CI 0·7–2·7]). Among adults, after accounting for the same variables, the odds ratio for ACR of 34 or greater associated with low birthweight was 2·6 (1·2–5·9), and in adult matched pairs was 4·0 (1·3–19·4). Low birthweight therefore predisposes to renal disease in this high-risk environment. The association is, however, understated because of the high early mortality of low birthweight people and because we were not able to include patients with renal failure in the screen. The data predict further amplification of ACR as age and weight increase. Renal disease might be linked to low birthweight through impaired nephrogenesis due to intrauterine malnutrition.5 The association was not explained by higher rates of impaired glucose tolerance, type 2 diabetes, or higher blood pressures in low birthweight people. The epidemic of chronic disease in Aborigines is probably due partly to the great fall in infant mortality since the 1960s and better hospital management of sick babies. Therefore, many low birthweight people are reaching adulthood and are at high risk of renal and other chronic diseases. Slow improvement in birthweights provides grounds for optimism, but weight control in adolescents and adults, better living conditions, and changes in health behaviours are also critical. We thank the Tiwi people who participated in this study; their community councils, their land Council and their Health Board for interest, collaboration, and support; Aboriginal Health Workers, Darren Fernando, Colleen Kantilla, Jerome Kerinauia, and Nellie Punguati; and staff at the Menzies School of Health Research and the Royal Darwin Hospital.

THE LANCET • Vol 352 • December 5, 1998

RESEARCH LETTERS This study was supported by the National Health and Medical Research Council of Australia, the Stanley Tipiloura fund and a grant from the Tiwi Land Council.

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Barker DJP, Martyn CN. The maternal and infant origins of cardiovascular disease. J Epidemiol Community Health 1992; 46: 8–11. Hoy WE. Renal disease in Australian Aborigines. Med J Aust 1996; 165: 309–12. Hoy WE, Mathews JD, McCredie DA, et al. The multidimensional nature of renal disease rates and associations of albuminuria in an Australian Aboriginal community. Kidney Int 1998; 54: 1296–304. Sayers SM. Low birth weight in Aboriginal babies. Aust NZ J Obstet Gynaecol 1997; 37: 131–32. Brenner BM, Mackenzie HS. Nephron mass as a risk factor for progression of renal disease. Kidney Int 1997; 52 (suppl 63): S124–27.

Menzies School of Health Research, Darwin, PO Box 41096, Casuarina, NT 0811, Australia (W Hoy; E-mail [email protected])

Abnormal retinal vascularisation in preterm children as a general vascular phenomenon Ann Hellström, Anna-Lena Hård, Aimon Niklasson, Elisabeth Svensson, Bo Jacobsson

Preterm babies are at increased risk of perinatal vascular disease, manifested, for example, by cerebral haemorrhage and retinopathy of prematurity (ROP). Preterm babies are also at risk of developing vascular disease later in life, seen as raised systolic blood pressure1 and death from coronary heart disease.2 Low birthweight has been associated with cardiovascular disease.3 The pathogenesis of these relations is unknown. There is a hypothesis that undernutrition before birth leads to persisting changes in several metabolic and physiological variables and that these changes increase the rate of vascular disease among children with low birthweight.3 We investigated a possible influence of preterm birth on the blood-vessel morphology by assessment of retinal vasculature in a population-based study of 50 children born at less than 29 weeks’ gestation. The median gestational age at birth was 28 weeks (range 24–28), birthweight 1055 g (450–1520), and age at assessment ranged from 4·1 years to 9·3 years. We chose the retinal vasculature because it is the only vascular bed that enables detailed, non-invasive morphometrical assessment. All children had an eye examination, including ocular fundus photography. Only correctly focused photographs (n=43) were accepted for digital image analysis; the remaining seven children were investigated by ophthalmoscopy. For each child we measured the retinal vessels by tracing each vessel manually and calculated the tortuosity index (path length of vessel divided by linear distance from vessel origin to a reference circle 3 mm from the centre of the optic disc).4 Preterm babies had significantly higher tortuosity indexes for retinal arteries than full-term children (p<0·0001, figure).4 Four of the five children who had a tortuosity index less than the median of the reference group had been treated with cryotherapy for ROP. The abnormal arterial retinal vascularisation was independent of the presence and degree of ROP, even when the cryotherapy infants were excluded (r=0·18, p=0·3). The seven children who were analysed by ophthalmoscopy were classified as having tortuous retinal vessels. Preterm birth interrupts the normal intrauterine development, after which multiple environmental factors influence the further development of these babies. Preterm babies have to adapt from an intrauterine partial oxygen tension of 40–45 mm Hg to an extrauterine tension of 100 mm Hg before they are prepared for extrauterine life. The development of the vasculature is regulated by genetic and biochemical control, such as by vascular endothelial growth factor (VEGF), and tissue oxygen regulates VEGF.5 An

THE LANCET • Vol 352 • December 5, 1998

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Tortuosity index for arteries

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Age (years) Abnormal retinal vascularisation in boy aged 7 years, born at 27 weeks’ gestation (A), normal vascularisation in healthy boy aged 6 years, born at full term (B), and morphometrical data for 43 children born preterm (C) Shaded area is 5th to 95th centile range, dotted line is median for healthy children.

altered environment can therefore influence inhibitory and stimulatory mechanisms, which may affect the architecture of the vessels. The abnormal vascular pattern develops at age 2–3 months, which suggests a role for the postnatal vascular environment. Retinal vascular abnormalities may be part of a more general abnormal vascular development pattern. The relation between such vascular changes and cardiovascular disease needs further exploration. We thank Björn Folkow, Department of Physiology, and Bengt Hagberg, Department of Pediatrics, Sahlgrenska University Hospital, for valuable discussions. This work was supported by grants from The Knut and Alice Wallenberg Foundation, Albert and Martina Lundgrens foundation and The Göteborg Medical Society. 1

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Siewert-Delle A, Ljungman S. The impact of birthweight and gestational age on blood pressure in adult life: a population-based study on 49-year-old men. Am J Hematol 1998; 11: 946–53. Martyn CN, Barker DJP, Osmond C. Mothers’ pelvic size, fetal growth, and death from stroke and coronary heart disease in men in the UK. Lancet 1996; 348: 1264–68. Barker DJP, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet 1993; 341: 938–41. Hellström A, Svensson E. Optic disc size and retinal vessel characteristics in healthy children. Acta Ophthalmol 1998; 76: 260–67. Pierce EA, Foley ED, Smith LE. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol 1996; 114: 1219–28.

Department of Clinical Neurosciences, Section of Ophthalomolgy and International Pediatric Growth Research Centre, Department of Mathematical Statistics, Chalmers University of Technology; Department of Pediatric Radiology, Sahlgrenska University Hospital/East, Göteborg, Sweden (A Hellström; e-mail [email protected])

Trimethoprim and fasting plasma homocysteine Yvo M Smulders, Angelique M E de Man, Coen D A Stehouwer, Ed H Slaats

Trimethoprim is commonly prescribed, often in combination with sulphamethoxazole (co-trimoxazole). Trimethoprim inhibits dihydrofolate-reductase (DHFR), which converts dihydrofolate to biologically active tetrahydrofolate. Although

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