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Abnormal retinal vascularisation in preterm children
Abnormal retinal vascularisation in preterm children Sir—We have concerns about some points made by Ann Hellström and colleagues (Dec 5, p 1827).1 Many features of retinal vascularisation in preterm babies are unclear for both paediatric ophthalmologists and neonatologists. Although clinical indices in these infants are closely monitored in the neonatal intensivecare unit, no significant correlation has emerged thus far between retinopathy of prematurity and factors that determine the general condition of preterm babies. Previous attempts to identify systemic factors that might be used as a guide for the management of retinopathy of prematurity have been unsuccessful. So far the presence of threshold retinopathy of prematurity, as defined by the Cryotherapy for Retinopathy of Prematurity Cooperative Group,2 is the only clinically significant predictor of the benefits of cryotherapy. Since even this degree of retinopathy of prematurity shows no correlation with the general condition of preterm neonates,3 it is hazardous to suggest, as Hellström and colleagues do, that retinal abnormalities in preterm babies are an expression of anomalous vascularisation in general. The major shortcoming of this study was the investigators’ failure to distinguish between retinopathy of prematurity and other types of retinal vascular anomalies that might be seen in preterm babies. This shortcoming leads to an error in the attempt to explain a more restricted (local) event (retinopathy of prematurity anomalies) with a broader pattern (abnormal vascularisation in general). Hellström and colleagues fail to consider sequelae of retinopathy of prematurity, such as linearisation of major branches of retinal vessels caused by mild dragging of the optic disc. A preterm child with a history of cicatrical retinopathy of prematurity might thus be expected to present less vessel tortuosity than one born at term. Common findings in children who have a history of retinopathy of prematurity are retinal thinning with diffuse hypopigmentation, mild linearisation, or mild tortuosity of the major vessel branch, mottled pigmentation of the macula, peripheral linear vitreous contraction, and peripheral retinal anomalies such as degenerative abnormalities in myopia.4 After the fundus examination, the ophthalmologist can say whether the
THE LANCET • Vol 353 • March 27, 1999
child was a preterm neonate with retinopathy of prematurity or a simple preterm baby. Thus, it is difficult to believe that retinal vascular abnormalities could be so directly correlated with systemic vascular abnormalities. Furthermore, different stages of retinopathy of prematurity can result in different vascular abnormalities: mild dragging of the optic disc is, for example, quite common in disease that involves the posterior pole. We believe that many features of the pathogenesis of retinopathy of prematurity are unclear, and at least some of the retinal features of prematurity need to be explained before they can be included in a more general pattern of vascular development. *Giuseppe Minicucci, Domenico Lepore, Fernando Molle Department of Ophthalmology, Catholic University of Rome, 00168 Rome, Italy 1
Hellström A, Hard AL, Niklasson A, Svensson E, Jacobsson B. Abnormal retinal vascularisation in pretern child as a general vascular phenomenon. Lancet 1998; 352: 1827. 2 Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicentre trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol 1988; 106: 471–79. 3 Schulenberg WE, Acheson JF. Cryosurgery for acute retinopathy of prematurity: factors associated with treatment success and failure. Eye 1992; 6: 215–20. 4 Page JM, Schneeweiss S, Whyte HE, Harvey P. Ocular sequence in premature infants. Pediatrics 1993; 92: 787–90.
Authors’ reply Sir—Some of the issues raised by Giuseppe Minicucci and co-workers need clarification. We emphasise that 47 of the 50 very preterm babies were thoroughly screened for retinopathy of prematurity in the neonatal period and that only 27 proved to have this disorder. Hence, a large proportion of the children did not have any signs of retinal disease at the time of neonatal screening. At the time of our follow-up study (median age 7 years), 45 of the 50 preterm infants had evidence of retinal vascular abnormalities (expressed as increased arterial tortuosity). Fielder and colleagues1 have described the finding of an increased retinal tortuosity among children who were preterm babies without any signs of retinopathy of prematurity. Baum2 has also shown that the increased retinal arterial tortuosity in babies remains throughout a long-term followup. It should be noted that the figure legends in our original research letter were incorrect (see correction p 1104).
We would like to clarify that very preterm children, independent of an earlier history of retinopathy of prematurity, have an increased retinal arterial tortuosity. We do not know if this is an event that has not yet been classified in retinopathy of prematurity. All but five of the 50 children had tortuous retinal arteries, four of whom underwent cryotherapy. In two of the children, cicatrical retinopathy of prematurity and mild dragging of the optic disc could explain the absence of vessel tortuosity. However, in the other two cryotreated children this explanation was not the case. Perhaps cryotherapy in these patients affected the environment and hence the substrate that induces vascular tortuosity. We have merely speculated that the observed retinal vascular abnormalities could be a general vascular event, because preterm birth has been associated with increased mortality in cardiovascular disease.3 The mechanism could be that preterm children are, during a decisive period of their postnatal life, exposed to a different environment than fetuses normally are exposed to at the corresponding stage of maturity. The change of environment may affect vascular design during an important stage of development when growth of tissues is sensitively regulated by various local influences and trophic agents. 4 The abnormal vascular architecture among children born preterm was expressed as vessel tortuosity. The tortuosity may be an important marker to indicate that the architecture of systemic microvascular networks in general has become decisively affected. An increased vessel tortuosity implies vessel elongation. According to Poiseuille’s law, an 8–10% vascular length increase, which we reported, reduces flow to the same extent. Thus, the observed abnormalities may cause changes in blood flow. We have now initiated studies of the relation between preterm birth and general vascular morphology. As yet, we can only speculate that the abnormal retinal vascular pattern of very preterm babies has a wider vascular implication. *Ann Hellström, Anna-Lena Hård, Aimon Niklasson, Elisabeth Svensson, B o Jac obsson Departments of Clinical Neurosciences; Mathematical Statistics, Chalmers University of Technology; and *Department of Paediatric Radiology, Sahlgrenska University Hospital/East, S-41685 Göteborg, Sweden ( e-mail: [email protected]) 1
2
Fielder AR, Shaw DE, Robinson J, Ng YK. Natural history of retinopathy of prematurity: a prospective study. Eye 1992; 6: 233–42. Baum JD. Retinal artery tortuosity in expremature infants—18-year follow-up on
1099
3
4
eyes of premature infants. Arch Dis Child 1971; 46: 247–52. 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. 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.
Iron-deficiency anaemia in premenopausal women Sir—Richard Farrell and J Thomas LaMont’s1 19/26 Dec commentary is timely and generally helpful. However, Bini and colleagues’2 study, which was the stimulus for the commentary, was remarkable for the fact that not one woman with coeliac disease was identified among the 177 patients that they screened for this condition by routine duodenal biopsy. Our experience in the UK is very different. We have evidence from three separate sources that coeliac disease is common in premenopausal women with anaemia, and should be routinely looked for, at least in the UK. Over the past 8 years, 102 new patients with coeliac disease have been diagnosed in the Gastroenterology Department at Frenchay Hospital, Bristol, which serves a population of about 240 000. Of these patients, 70 had anaemia as a presenting feature, and 37 of these were premenopausal women. 34 of the 70 patients had iron deficiency as their only presenting feature, 11 had mixed deficiencies of iron with folic acid, vitamin B12, or both, and 25 had anaemia (mostly pure iron deficiency) in association with diarrhoea, weight loss, or other features suggestive of coeliac disease, such as a positive family history. Of the 34 patients with iron deficiency as their only presenting feature, 19 were premenopausal women, four were postmenopausal women, and 11 were men. Thus, about half of all our patients with coeliac disease who present with anaemia are premenopausal women, half of whom have nothing other than iron deficiency to suggest that they have the disease. Among 72 premenopausal women referred to our department for investigation of iron-deficiency anaemia between January, 1996, and December, 1998, nine were found to have coeliac disease on routine endoscopic biopsy of the second part of the duodenum, a rate in this selected population of one in eight. We have also screened for coeliac disease in a less selected group of
1100
patients; symptom-free blood donors drawn from the general population. All volunteer blood donors in the catchment area of the National Blood Authority Laboratories at Southmead Hospital, Bristol, which covers a population of about 10 000 000 in the south west of the UK, are screened for anaemia according to National Blood Authority standard practice. Over 4 months, donors with anaemia were tested for the presence of IgA antiendomysial antibodies. 408 women were anaemic and were tested in this way, and 28 (26 premenopausal) were positive for IgA antiendomysial antibodies. 22 of these women agreed to have endoscopic small-bowel biopsies, and all but one had the typical histological changes of coeliac disease. These findings and those from other recent studies3 suggest that, at least in the UK, the frequency of coeliac disease in premenopausal women with anaemia varies from about one in 16 in symptom-free individuals up to about one in eight in those referred for gastroenterological investigation. The reason for the large discrepancy between the apparent rate of coeliac disease in iron-deficient premenopausal women in the USA and that in the UK is not clear, particularly since the New York population studied by Bini included many women of European family background, in whom a broadly similar incidence of coeliac disease might be expected. Farrell and LaMont should not have cited the report by Rockey and colleagues4 as showing that routine duodenal biopsy was rarely helpful in the investigation of iron deficiency. It was certainly not helpful in that series, but this was because the investigators did not do duodenal biopsies in any of their patients, an omission which was criticised subsequently.5 D J Unsworth, F J Lock, *R F Harvey *Department of General Medicine, Frenchay Hospital, Bristol BS16 1LE, UK; and National Blood Authority Laboratories, Southmead Hospital, Bristol 1
Farrell RJ, LaMont JT. Rational approach to iron-deficiency anaemia in premenopausal women. Lancet 1998; 352: 1953–54. 2 Bini EJ, Micale PL, Weinshel EH. Evaluation of the gastrointestinal tract in premenopausal women with iron-deficiency anaemia. Am J Med 1998; 105: 281–86. 3 Hin H, Bird G, Fisher P, Mahy N, Jewell D. Coeliac disease in primary care: case finding study. BMJ 1999; 318: 164–67. 4 Rockey DC, Cello JP. Evaluation of the gastrointestinal tract in patients with irondeficiency anaemia. N Engl J Med 1993; 329: 1691–95. 5 Sanderson JD, Pereira SP, Hussaini SH. Evaluation of the gastrointestinal tract in patients with iron-deficiency anaemia. N Engl J Med 1994; 330: 1239.
Is there an inapparent dengue explosion? Sir—José Rigau-Perez and colleagues,1 inflation of global annual morbidity data and case fatality rates for dengue could have serious unintended consequences. In their introductory paragraphs, the investigators estimate 50–100 million dengue cases annually. A number of this magnitude was first suggested in 1988.2 It is becoming increasingly clear, however, that most dengue infections are inapparent. Although dengue fever is reported in only a few countries, comprehensive data for dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) have been reported to regional offices of WHO for more than 30 years. Summaries have been published from time to time.3 For many western and other countries, these data include cases of dengue fever, but global totals seldom exceed 500 000 annually. Most of the estimated 50–100 million dengue infections occur in children, and when studied carefully, are largely silent. In their summary, the investigators state that “case fatality rates in patients with dengue shock syndrome can be as high as 44%.” This value is taken from a fairly small hospital-based treatment study (the case fatality rate reported in the original text was 38%) in which the most severely ill patients were recruited to allow an evaluation of a putative life saving therapeutic regimen.4 Nowhere are reliable national statistics available for incidence of DSS. As a result, DSS case fatality rates are not well known. Case fatality rates for DHF and DSS are available.3 For 12 Asian countries, cumulative DHF-DSS case fatality rates vary between 0·5% and 3·5%. Physicians need reliable data on prognosis of DHF and DSS to plan treatment regimens, allocate scarce resources and counsel families. In the Americas, Cuban physicians, confronted for the first time with DHF and DSS, took justifiable pride in achieving a case fatality rate of 1·5% among 10 000 cases admitted in the 1981 epidemic.5 This rate is the benchmark, and not 44%. Scott B Halstead Office of Naval Research, Arlington, VA 22217, USA 1
Rigau-Perez JG, Clark GG, Gubler DJ, Reiter P, Sanders EJ, Vorndam AV. Dengue and dengue haemorrhagic fever. Lancet 1998; 352: 971–77. 2 Halstead SB. Pathogenesis of dengue: challenges to molecular biology. Science 1988; 239: 476–81. 3 Halstead SB. Epidemiology of dengue and dengue hemorrhagic fever. In: Gubler DJ, Kuno G, eds. Dengue and dengue hemorrhagic fever. Wallingford, UK: CAB International, 1997: 23–44.
THE LANCET • Vol 353 • March 27, 1999
THE LANCET • Vol 353 • March 27, 1999
child was a preterm neonate with retinopathy of prematurity or a simple preterm baby. Thus, it is difficult to believe that retinal vascular abnormalities could be so directly correlated with systemic vascular abnormalities. Furthermore, different stages of retinopathy of prematurity can result in different vascular abnormalities: mild dragging of the optic disc is, for example, quite common in disease that involves the posterior pole. We believe that many features of the pathogenesis of retinopathy of prematurity are unclear, and at least some of the retinal features of prematurity need to be explained before they can be included in a more general pattern of vascular development. *Giuseppe Minicucci, Domenico Lepore, Fernando Molle Department of Ophthalmology, Catholic University of Rome, 00168 Rome, Italy 1
Hellström A, Hard AL, Niklasson A, Svensson E, Jacobsson B. Abnormal retinal vascularisation in pretern child as a general vascular phenomenon. Lancet 1998; 352: 1827. 2 Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicentre trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol 1988; 106: 471–79. 3 Schulenberg WE, Acheson JF. Cryosurgery for acute retinopathy of prematurity: factors associated with treatment success and failure. Eye 1992; 6: 215–20. 4 Page JM, Schneeweiss S, Whyte HE, Harvey P. Ocular sequence in premature infants. Pediatrics 1993; 92: 787–90.
Authors’ reply Sir—Some of the issues raised by Giuseppe Minicucci and co-workers need clarification. We emphasise that 47 of the 50 very preterm babies were thoroughly screened for retinopathy of prematurity in the neonatal period and that only 27 proved to have this disorder. Hence, a large proportion of the children did not have any signs of retinal disease at the time of neonatal screening. At the time of our follow-up study (median age 7 years), 45 of the 50 preterm infants had evidence of retinal vascular abnormalities (expressed as increased arterial tortuosity). Fielder and colleagues1 have described the finding of an increased retinal tortuosity among children who were preterm babies without any signs of retinopathy of prematurity. Baum2 has also shown that the increased retinal arterial tortuosity in babies remains throughout a long-term followup. It should be noted that the figure legends in our original research letter were incorrect (see correction p 1104).
We would like to clarify that very preterm children, independent of an earlier history of retinopathy of prematurity, have an increased retinal arterial tortuosity. We do not know if this is an event that has not yet been classified in retinopathy of prematurity. All but five of the 50 children had tortuous retinal arteries, four of whom underwent cryotherapy. In two of the children, cicatrical retinopathy of prematurity and mild dragging of the optic disc could explain the absence of vessel tortuosity. However, in the other two cryotreated children this explanation was not the case. Perhaps cryotherapy in these patients affected the environment and hence the substrate that induces vascular tortuosity. We have merely speculated that the observed retinal vascular abnormalities could be a general vascular event, because preterm birth has been associated with increased mortality in cardiovascular disease.3 The mechanism could be that preterm children are, during a decisive period of their postnatal life, exposed to a different environment than fetuses normally are exposed to at the corresponding stage of maturity. The change of environment may affect vascular design during an important stage of development when growth of tissues is sensitively regulated by various local influences and trophic agents. 4 The abnormal vascular architecture among children born preterm was expressed as vessel tortuosity. The tortuosity may be an important marker to indicate that the architecture of systemic microvascular networks in general has become decisively affected. An increased vessel tortuosity implies vessel elongation. According to Poiseuille’s law, an 8–10% vascular length increase, which we reported, reduces flow to the same extent. Thus, the observed abnormalities may cause changes in blood flow. We have now initiated studies of the relation between preterm birth and general vascular morphology. As yet, we can only speculate that the abnormal retinal vascular pattern of very preterm babies has a wider vascular implication. *Ann Hellström, Anna-Lena Hård, Aimon Niklasson, Elisabeth Svensson, B o Jac obsson Departments of Clinical Neurosciences; Mathematical Statistics, Chalmers University of Technology; and *Department of Paediatric Radiology, Sahlgrenska University Hospital/East, S-41685 Göteborg, Sweden ( e-mail: [email protected]) 1
2
Fielder AR, Shaw DE, Robinson J, Ng YK. Natural history of retinopathy of prematurity: a prospective study. Eye 1992; 6: 233–42. Baum JD. Retinal artery tortuosity in expremature infants—18-year follow-up on
1099
3
4
eyes of premature infants. Arch Dis Child 1971; 46: 247–52. 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. 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.
Iron-deficiency anaemia in premenopausal women Sir—Richard Farrell and J Thomas LaMont’s1 19/26 Dec commentary is timely and generally helpful. However, Bini and colleagues’2 study, which was the stimulus for the commentary, was remarkable for the fact that not one woman with coeliac disease was identified among the 177 patients that they screened for this condition by routine duodenal biopsy. Our experience in the UK is very different. We have evidence from three separate sources that coeliac disease is common in premenopausal women with anaemia, and should be routinely looked for, at least in the UK. Over the past 8 years, 102 new patients with coeliac disease have been diagnosed in the Gastroenterology Department at Frenchay Hospital, Bristol, which serves a population of about 240 000. Of these patients, 70 had anaemia as a presenting feature, and 37 of these were premenopausal women. 34 of the 70 patients had iron deficiency as their only presenting feature, 11 had mixed deficiencies of iron with folic acid, vitamin B12, or both, and 25 had anaemia (mostly pure iron deficiency) in association with diarrhoea, weight loss, or other features suggestive of coeliac disease, such as a positive family history. Of the 34 patients with iron deficiency as their only presenting feature, 19 were premenopausal women, four were postmenopausal women, and 11 were men. Thus, about half of all our patients with coeliac disease who present with anaemia are premenopausal women, half of whom have nothing other than iron deficiency to suggest that they have the disease. Among 72 premenopausal women referred to our department for investigation of iron-deficiency anaemia between January, 1996, and December, 1998, nine were found to have coeliac disease on routine endoscopic biopsy of the second part of the duodenum, a rate in this selected population of one in eight. We have also screened for coeliac disease in a less selected group of
1100
patients; symptom-free blood donors drawn from the general population. All volunteer blood donors in the catchment area of the National Blood Authority Laboratories at Southmead Hospital, Bristol, which covers a population of about 10 000 000 in the south west of the UK, are screened for anaemia according to National Blood Authority standard practice. Over 4 months, donors with anaemia were tested for the presence of IgA antiendomysial antibodies. 408 women were anaemic and were tested in this way, and 28 (26 premenopausal) were positive for IgA antiendomysial antibodies. 22 of these women agreed to have endoscopic small-bowel biopsies, and all but one had the typical histological changes of coeliac disease. These findings and those from other recent studies3 suggest that, at least in the UK, the frequency of coeliac disease in premenopausal women with anaemia varies from about one in 16 in symptom-free individuals up to about one in eight in those referred for gastroenterological investigation. The reason for the large discrepancy between the apparent rate of coeliac disease in iron-deficient premenopausal women in the USA and that in the UK is not clear, particularly since the New York population studied by Bini included many women of European family background, in whom a broadly similar incidence of coeliac disease might be expected. Farrell and LaMont should not have cited the report by Rockey and colleagues4 as showing that routine duodenal biopsy was rarely helpful in the investigation of iron deficiency. It was certainly not helpful in that series, but this was because the investigators did not do duodenal biopsies in any of their patients, an omission which was criticised subsequently.5 D J Unsworth, F J Lock, *R F Harvey *Department of General Medicine, Frenchay Hospital, Bristol BS16 1LE, UK; and National Blood Authority Laboratories, Southmead Hospital, Bristol 1
Farrell RJ, LaMont JT. Rational approach to iron-deficiency anaemia in premenopausal women. Lancet 1998; 352: 1953–54. 2 Bini EJ, Micale PL, Weinshel EH. Evaluation of the gastrointestinal tract in premenopausal women with iron-deficiency anaemia. Am J Med 1998; 105: 281–86. 3 Hin H, Bird G, Fisher P, Mahy N, Jewell D. Coeliac disease in primary care: case finding study. BMJ 1999; 318: 164–67. 4 Rockey DC, Cello JP. Evaluation of the gastrointestinal tract in patients with irondeficiency anaemia. N Engl J Med 1993; 329: 1691–95. 5 Sanderson JD, Pereira SP, Hussaini SH. Evaluation of the gastrointestinal tract in patients with iron-deficiency anaemia. N Engl J Med 1994; 330: 1239.
Is there an inapparent dengue explosion? Sir—José Rigau-Perez and colleagues,1 inflation of global annual morbidity data and case fatality rates for dengue could have serious unintended consequences. In their introductory paragraphs, the investigators estimate 50–100 million dengue cases annually. A number of this magnitude was first suggested in 1988.2 It is becoming increasingly clear, however, that most dengue infections are inapparent. Although dengue fever is reported in only a few countries, comprehensive data for dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) have been reported to regional offices of WHO for more than 30 years. Summaries have been published from time to time.3 For many western and other countries, these data include cases of dengue fever, but global totals seldom exceed 500 000 annually. Most of the estimated 50–100 million dengue infections occur in children, and when studied carefully, are largely silent. In their summary, the investigators state that “case fatality rates in patients with dengue shock syndrome can be as high as 44%.” This value is taken from a fairly small hospital-based treatment study (the case fatality rate reported in the original text was 38%) in which the most severely ill patients were recruited to allow an evaluation of a putative life saving therapeutic regimen.4 Nowhere are reliable national statistics available for incidence of DSS. As a result, DSS case fatality rates are not well known. Case fatality rates for DHF and DSS are available.3 For 12 Asian countries, cumulative DHF-DSS case fatality rates vary between 0·5% and 3·5%. Physicians need reliable data on prognosis of DHF and DSS to plan treatment regimens, allocate scarce resources and counsel families. In the Americas, Cuban physicians, confronted for the first time with DHF and DSS, took justifiable pride in achieving a case fatality rate of 1·5% among 10 000 cases admitted in the 1981 epidemic.5 This rate is the benchmark, and not 44%. Scott B Halstead Office of Naval Research, Arlington, VA 22217, USA 1
Rigau-Perez JG, Clark GG, Gubler DJ, Reiter P, Sanders EJ, Vorndam AV. Dengue and dengue haemorrhagic fever. Lancet 1998; 352: 971–77. 2 Halstead SB. Pathogenesis of dengue: challenges to molecular biology. Science 1988; 239: 476–81. 3 Halstead SB. Epidemiology of dengue and dengue hemorrhagic fever. In: Gubler DJ, Kuno G, eds. Dengue and dengue hemorrhagic fever. Wallingford, UK: CAB International, 1997: 23–44.
THE LANCET • Vol 353 • March 27, 1999