Correspondence
Vitamin A Supplementation for Extremely-Low-Birth-Weight Infants
N Engl J Med 1999; 341:1697-1698November 25, 1999
- Article
To the Editor:
The study by Tyson et al. (June 24 issue),1 while impressive in design and numbers of infants studied, does not really answer the question of whether vitamin A supplementation reduces the risk of chronic lung disease in premature infants. The main drawback of this study, as well as those published previously,2 is the definition of chronic lung disease. The best predictor of chronic lung disease is a chest x-ray film,3 whereas the authors' definition of chronic lung disease, the need for oxygen at 36 weeks' postmenstrual age, has a positive predictive value of only 63 percent.4
Although the authors found that fewer infants given vitamin A had chronic lung disease at 36 weeks (by their definition) than was the case in the control group, we question whether the difference is enough to convince a clinician to give 12 intramuscular injections to extremely-low-birth-weight infants, especially when all other measures of chronic lung disease in this study were not different in the two groups. Their argument in favor of vitamin A supplementation would be greatly strengthened by additional follow-up data.
4 ReferencesYoram A. Bental, M.D.
Avi Rotschild, M.D.
Carmel Medical Center, Haifa 34362, IsraelPeter A. Cooper, F.C.P.(S.A.)
University of the Witwatersrand, Johannesburg 2193, South Africa1
Tyson JE ,Wright LL ,Oh W , et al. Vitamin A supplementation for extremely-low-birth-weight infants. N Engl J Med 1999;340:1962-1968
Full Text | Web of Science | Medline2
Darlow B, Graham PJ. Vitamin A supplementation in very low birth-weight infants. In: Sinclair JC, Bracken MB, Soll RF, Horbar JD, eds. Neonatal module of the Cochrane database of systematic reviews: Cochrane Collaboration: issue 4. London: BMJ Publishing, 1998 (software).
3
Palta M ,Sadek M ,Barnet JH , et al. Evaluation of criteria for chronic lung disease in surviving very low birth weight infants. J Pediatr 1998;132:57-63
CrossRef | Web of Science | Medline4
Shennan AT ,Dunn MS ,Ohlsson A ,Lennox K ,Hoskins EM . Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527-532
Web of Science | Medline
To the Editor:
In considering the implications of the study by Tyson et al., one has to consider whether the degree of vitamin A deficiency in the infants studied was due to maternal deficiency of this vitamin or to metabolic defects in the processing of the vitamin and its products in the infants. Clarification of this point would help to determine the importance of preventing vitamin A deficiency in pregnant women.
The possibility of maternal vitamin A deficiency may well have been increased by a report on the hazards of excessive vitamin A intake in pregnant women.1 This report may also be contributing to the risk of vitamin D deficiency, because these two vitamins occur together in many foods, including fish oils, liver, and liver pâté, which expectant mothers in the United Kingdom are advised to eat. Vitamin D deficiency increases the risks of certain infections and of low birth weight and alters immune responses.2,3 Can the authors, therefore, provide information on maternal serum concentrations of retinol and its esters or 25-hydroxyvitamin D? This information would be of value in the continuing debate on the best dietary advice to offer pregnant women.
3 ReferencesBarbara J. Boucher, M.D.
Royal London Hospital, London E11BB, United Kingdom1
Rothman KJ ,Moore LL ,Singer MR ,Nguyen U-SDT ,Mannino S ,Milunsky A . Teratogenicity of high vitamin A intake. N Engl J Med 1995;333:1369-1373
Full Text | Web of Science | Medline2
Douglas AS ,Strachan DP ,Maxwell JD . Seasonality of tuberculosis: the reverse of other respiratory diseases in the UK. Thorax 1996;51:944-946
CrossRef | Web of Science | Medline3
Maxwell JD ,Ang L ,Brooke OG ,Brown JR . Vitamin D supplements enhance weight gain and nutritional status in pregnant Asians. Br J Obstet Gynaecol 1981;88:987-991
CrossRef | Medline
Author/Editor Response
Dr. Tyson replies:
To the Editor: The best method of diagnosing chronic lung disease in infants is unclear.1 Bental et al. are critical of the diagnostic criterion used in our study (the administration of oxygen at 36 weeks' postmenstrual age) and assert that radiologic findings are a better predictor of later outcome. However, the study cited to support this assertion had several limitations. Outcome was not determined for 48 percent of the infants studied. Radiographs were not evaluated at a consistent postnatal or postmenstrual age and were not obtained for all infants. All radiographs obtained between 25 and 35 postnatal days were scored by a neonatologist and a radiologist, and the mean value was calculated for each infant. This method of evaluation is not commonly or easily used. The radiographic findings were not much better (more sensitive but less specific) for predicting outcome than was the use of supplemental oxygen at 36 weeks' postmenstrual age.
We considered obtaining radiographs of all infants at 36 weeks. However, we wished to avoid unnecessary exposure to radiation, expense, variability in interpretations by different radiologists, and the logistical problems of obtaining readings by a single radiologist. Finally, radiographs could be misleading if the administration of vitamin A altered the radiographic findings without changing the clinical course of chronic lung disease. For all these reasons, we — like other investigators1,2 — did not pursue radiologic findings. The need for oxygen at 36 weeks, which we used as a marker of chronic lung disease, has been found to be predictive of later pulmonary and developmental morbidity.2,3
Bental et al. also question whether the reduction in the risk of chronic lung disease in our study justifies the intramuscular administration of supplemental vitamin A to extremely-low-birth-weight infants. The vitamin A intake of these infants is limited by prolonged feeding intolerance, poor enteral absorption of vitamin A, and unreliable intravenous delivery in crystalloid solutions. In contrast, intramuscular supplementation with vitamin A was found in our multicenter trial and in a meta-analysis of all prior trials4 to reduce chronic lung disease as well as biochemical signs of vitamin A deficiency safely.
Although the effect on chronic lung disease is not dramatic, the evidence available supports the clinical use of the regimen we tested. Whether the benefits would be increased by the use of higher doses or by the administration of vitamin A in intravenous fat emulsions remains to be assessed.
Dr. Boucher raises interesting questions. However, our study was not designed to assess vitamin intake in pregnancy, and we did not measure serum retinol, retinyl esters, or 25-hydroxyvitamin D in the mothers.
4 ReferencesJon Tyson, M.D., M.P.H.
University of Texas–Houston Medical School, Houston, TX 770301
Ballard RA ,Banks BA . Definition of bronchopulmonary dysplasia. Pediatrics 1999;103:533-534
CrossRef | Web of Science | Medline2
Gregoire MC ,Lefebvre F ,Glorieux J . Health and developmental outcomes at 18 months in very preterm infants with bronchopulmonary dysplasia. Pediatrics 1998;101:856-860
CrossRef | Web of Science | Medline3
Shennan AT ,Dunn MS ,Ohlsson A ,Lennox K ,Hoskins EM . Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527-532
Web of Science | Medline4
Darlow B, Graham PJ. Vitamin A supplementation in very low birth-weight infants. In: Sinclair JC, Bracken MB, Soll RF, Horbar JD, eds. Neonatal module of the Cochrane database of systematic reviews: Cochrane Collaboration: issue 4. London: BMJ Publishing, 1998 (software).
