{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T23:13:14Z","timestamp":1774566794520,"version":"3.50.1"},"reference-count":30,"publisher":"BMJ","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arch Dis Child Fetal Neonatal Ed"],"published-print":{"date-parts":[[1996,3]]},"abstract":"<jats:p>AIMS: To examine the effectiveness of prophylactic intravenous indomethacin in reducing the mortality and morbidity associated with patent ductus arteriosus and intraventricular haemorrhage in infants weighing less than 1750 g at birth. METHODS: A literature search from 1980 onwards was made of three databases: Medline; Embase; and the Oxford Database of Perinatal Trials. Using strict criteria applied to randomised controlled trials only, two observers independently selected 14 studies for inclusion in the review. The methodological quality of each study was assessed independently by two observers using explicit criteria. Data on relevant outcome measures were extracted on two separate occasions. Where appropriate, the results of individual trials were combined using meta-analysis techniques to provide a pooled estimate of effect. RESULTS: There is a trend towards reduced neonatal mortality in infants receiving prophylactic indomethacin, pooled estimate of risk difference -0.025 (95% confidence interval (CI) -0.061, 0.010). The incidence of symptomatic patent ductus arteriosus is significantly reduced in treated infants, pooled estimate of risk difference -0.217 (95% CI -0.275, -0.160), but there is no evidence that treatment affects respiratory outcomes. Prophylactic indomethacin significantly reduces the incidence of grades 3 and 4 intraventricular haemorrhage in treated infants, pooled estimate of risk difference -0.039 (95% CI -0.066, -0.011). However, there is no sound evidence assessing the long term effect of prophylaxis on neurodevelopmental outcome. Although there is a trend in treated infants towards an increased incidence of necrotising enterocolitis, pooled estimate of risk difference 0.015 (95% CI -0.002, 0.033), and some evidence that treatment may transiently impair renal function, there is no evidence that haemostasis is disturbed. CONCLUSION: Prophylactic treatment with indomethacin has several immediate benefits. However, more data are needed on the incidence of possible adverse effects and neurodevelopmental outcomes before routine use of this therapy can be recommended.<\/jats:p>","DOI":"10.1136\/fn.74.2.f81","type":"journal-article","created":{"date-parts":[[2008,10,31]],"date-time":"2008-10-31T17:55:51Z","timestamp":1225475751000},"page":"F81-F87","source":"Crossref","is-referenced-by-count":46,"title":["Prophylactic indomethacin: systematic review and meta-analysis."],"prefix":"10.1136","volume":"74","author":[{"given":"P. W.","family":"Fowlie","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[1996,3,1]]},"reference":[{"key":"ref_1","article-title":"affecting the treatment group in the 24 hours immediately following treatment. This difference is no longer apparent in the subsequent 24 hour period. In 1988, Ment reported no clinically important renal abnormalities but provides no data.3' Bada33 provided data that show significant changes in plasma creatinine and sodium concentrations, osmolalities, and urine output, but comments that these differences were not abnormal - that is, not clinically important","unstructured":"-0-083 (-0-129, -0 038) 12 affecting the treatment group in the 24 hours immediately following treatment. This difference is no longer apparent in the subsequent 24 hour period. In 1988, Ment reported no clinically important renal abnormalities but provides no data.3' Bada33 provided data that show significant changes in plasma creatinine and sodium concentrations, osmolalities, and urine output, but comments that these differences were not abnormal - that is, not clinically important."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/S0022-3476(79)80454-0","article-title":"Increased risk of bronchopulmonary dysplasia in infants with patent ductus arteriosus","volume":"95","author":"Brown, E.R.","year":"1979","unstructured":"Brown ER. Increased risk of bronchopulmonary dysplasia in infants with patent ductus arteriosus. J Pediatr 1979; 95: 865.","journal-title":"J Pediatr"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1056\/NEJM197209072871001","article-title":"Patent ductus arteriosus in premature infants: incidence and relation to pulmonary disease and management","volume":"287","author":"Kitterman, J.A.; LH, Jr., Edmunds; Gregory, G.A.; Heymann, M.A.; Tooley, W.H.; Rudolph, A.M.","year":"1972","unstructured":"Kitterman JA, Edmunds LH Jr., Gregory GA, Heymann MA, Tooley WH, Rudolph AM. Patent ductus arteriosus in premature infants: incidence and relation to pulmonary disease and management. N Eng J Med 1972; 287: 473.","journal-title":"N Eng J Med"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1056\/NEJM197609022951004","article-title":"Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis","volume":"295","author":"Heymann, M.A.; Rudolph, A.M.; Silverman, N.H.","year":"1976","unstructured":"Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. NEnglJMed 1976; 295: 530-3.","journal-title":"NEnglJMed"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1542\/peds.69.6.778","article-title":"Abnormal cerebral haemodynamics in preterm infants with patent ductus arteriosus","volume":"69","author":"Lipman, B.; Server, G.A.; Brazy, J.E.","year":"1982","unstructured":"Lipman B, Server GA, Brazy JE. Abnormal cerebral haemodynamics in preterm infants with patent ductus arteriosus. Pediatrics 1982; 69: 778-81.","journal-title":"Pediatrics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"857","DOI":"10.3171\/jns.1983.58.6.0857","article-title":"Beagle puppy model of intraventricular haemorrhage: effect of indomethacin on cerebral blood flow","volume":"58","author":"Ment, L.A.; Stewart, W.B.; Duncan, C.C.; Scott, D.T.; Lambrecht, R.","year":"1983","unstructured":"Ment LA, Stewart WB, Duncan CC, Scott DT, Lambrecht R. Beagle puppy model of intraventricular haemorrhage: effect of indomethacin on cerebral blood flow. J Neurosurgery 1983; 58: 857-62.","journal-title":"J Neurosurgery"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1161\/01.STR.23.8.1132","article-title":"Indomethacin promotes germinal matrix maturation in the newborn beagle puppy","volume":"23","author":"Ment, L.A.; Stewart, W.B.; Ardito, T.A.; Huang, E.; Madri, J.A.","year":"1992","unstructured":"Ment LA, Stewart WB, Ardito TA, Huang E, Madri JA. Indomethacin promotes germinal matrix maturation in the newborn beagle puppy. Stroke 1992; 23: 1132-7.","journal-title":"Stroke"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1016\/0140-6736(90)93030-S","article-title":"Effects of indomethacin on cerebral haemodynamics in very preterm infants","volume":"335","author":"Edwards, A.D.; Wyatt, J.S.; Richardson, C.; Potter, A.; Cope, M.; Delpy, D.T.","year":"1990","unstructured":"Edwards AD, Wyatt JS, Richardson C, Potter A, Cope M, Delpy DT, et al. Effects of indomethacin on cerebral haemodynamics in very preterm infants. Lancet 1990; 335: 1491-5.","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1136\/adc.65.10_Spec_No.1067","article-title":"Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin","volume":"65","author":"Coombs, R.C.; Morgan, M.E.I.; Durbin, G.M.; Booth, I.W.; McNeish, A.S.","year":"1990","unstructured":"Coombs RC, Morgan MEI, Durbin GM, Booth IW, McNeish AS. Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin. Arch Dis Child 1990; 65: 1067-71.","journal-title":"Arch Dis Child"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/S0022-3476(79)80775-1","article-title":"Indomethacin and renal function in premature infants with persistent patent ductus arteriosus","volume":"95","author":"Cifuentes, R.F.; Olley, P.M.; Balfe, J.W.; Radde, I.C.; Soldin, S.J.","year":"1979","unstructured":"Cifuentes RF, Olley PM, Balfe JW, Radde IC, Soldin SJ. Indomethacin and renal function in premature infants with persistent patent ductus arteriosus. J Pediatr 1979; 95: 583-7.","journal-title":"J Pediatr"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1002\/j.1552-4604.1978.tb02446.x","article-title":"Indomethacin disposition and indomethacin-induced platelet dysfunction in premature infants","volume":"18","author":"Friedman, Z.; Whitman, V.; Maisels, M.J.; WJr, Berman; Marks, K.H.; Vessell, E.S.","year":"1978","unstructured":"Friedman Z, Whitman V, Maisels MJ, Berman WJr, Marks KH, Vessell ES. Indomethacin disposition and indomethacin-induced platelet dysfunction in premature infants. 7 Clin Pharmacol 1978; 18: 272-9.","journal-title":"7 Clin Pharmacol"},{"key":"ref_12","first-page":"555","article-title":"Indomethacin associated sepsis in the very low birth weight infant","volume":"142","author":"Herson, V.C.; Krause, P.J.; Eisenfeld, L.I.; Pontius, L.; Maderazo, E.G.","year":"1988","unstructured":"Herson VC, Krause PJ, Eisenfeld LI, Pontius L, Maderazo EG. Indomethacin associated sepsis in the very low birth weight infant. AmJfDis Child 1988; 142: 555-8.","journal-title":"AmJfDis Child"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"485","DOI":"10.7326\/0003-4819-106-3-485","article-title":"The medical review article: state of the science","volume":"106","author":"Mulrow, C.D.","year":"1987","unstructured":"Mulrow CD. The medical review article: state of the science. Ann Intern Med 1987; 106: 485-8.","journal-title":"Ann Intern Med"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/0197-2456(94)00031-W","article-title":"Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists","volume":"16","author":"Moher, D.; Jadad, A.R.; Nichol, G.; Penam, M.; Tugwell, P.; Walsh, S.","year":"1995","unstructured":"Moher D, Jadad AR, Nichol G, Penam M, Tugwell P, Walsh S. Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. Controlled Clinical Trials 1995; 16: 62-73.","journal-title":"Controlled Clinical Trials"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1001\/jama.1995.03520290060030","article-title":"Empirical evidence of bias; dimensions of methodologic quality associated with estimates of treatment effect in controlled clinical trials","volume":"273","author":"Schultz, K.F.; Chalmers, I.; Hayes, R.J.; Altman, D.G.","year":"1995","unstructured":"Schultz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias; dimensions of methodologic quality associated with estimates of treatment effect in controlled clinical trials. JAMA 1995; 273: 408-12.","journal-title":"JAMA"},{"key":"ref_16","first-page":"353","article-title":"Indomethacin reduces relative risks of severe intraventricular haemorrhage","volume":"25","author":"Bada, H.S.; Green, R.S.; Pourcyrous, M.; Leffler, C.W.; Korones, S.B.; Arheart, K.","year":"1989","unstructured":"Bada HS, Green RS, Pourcyrous M, Leffler CW, Korones SB, Arheart K. Indomethacin reduces relative risks of severe intraventricular haemorrhage. PedRes 1989; 25: 353A.","journal-title":"PedRes"},{"issue":"427","key":"ref_17","first-page":"17","article-title":"Prophylactic indomethacin for prevention of intraventricular haemorrhage: neurodevelopmental follow-up","volume":"22","author":"Bandstra, E.S.; Bauer, C.R.; Duenas, M.L.; Chao, H.; Montalvo, B.M.; Bancalari, E.","year":"1987","unstructured":"Bandstra ES, Bauer CR, Duenas ML, Chao H, Montalvo BM, Bancalari E. Prophylactic indomethacin for prevention of intraventricular haemorrhage: neurodevelopmental follow-up. Ann Neurol 1987; 22: 427A. 17 Pourcyrous M, Bada HS, Green RS, Korones SB. Safety of indomethacin use for newborn infants. Ped Res 1988; 23: 422A.","journal-title":"Ann Neurol; Safety of indomethacin use for newborn infants"},{"issue":"345","key":"ref_18","article-title":"Prophylactic indomethacin and intraventricular haemorrhage in the premature","volume":"18","author":"Setzer, E.S.; Morse, B.M.; Goldberg, R.N.; Smith, M.; Bancalari, E.","year":"1984","unstructured":"Setzer ES, Morse BM, Goldberg RN, Smith M, Bancalari E. Prophylactic indomethacin and intraventricular haemorrhage in the premature. Ped Res 1984; 18: 345A. 19 Setzer ES, Torres-Arraut E, Gomez-del-Rio M, Young ML, Pacheco I, Ferrer PL, et al. Cardiopulmonary effects of prophylactic indomethacin in the very low birth weight infant. Ped Res 1984; 18: 346A. 20 Rothman KJ. In: Modern epidemiology. Boston: Little Brown, 1986.","journal-title":"Ped Res; Cardiopulmonary effects of prophylactic indomethacin in the very low birth weight infant"},{"key":"ref_19","first-page":"13","article-title":"Statistical methods for analysis of effects of treatment in overviews of randomised trials","volume-title":"Effective care of the newborn infant","author":"Bracken, M.B.","year":"1992","unstructured":"Bracken MB. Statistical methods for analysis of effects of treatment in overviews of randomised trials. In: Sinclair JC, Bracken MB, eds. Effective care of the newborn infant. New York: Oxford University Press, 1992: 13-20."},{"issue":"346","key":"ref_20","first-page":"801","article-title":"Severity of platelet dysfunction induced by prophylactic indomethacin in the premature","volume":"18","author":"Setzer, E.S.; Smith, M.; Goulding, P.J.; Bandstra, T.E.","year":"1984","unstructured":"Setzer ES, Smith M, Goulding PJ, Bandstra TE. Severity of platelet dysfunction induced by prophylactic indomethacin in the premature. Ped Res 1984; 18: 346A. 23 Mahoney L, Caldwell RL, Girod DA, Hurwitz RA, Jansen RD, Lemons JA, et al. Indomethacin therapy on the first day of life in infants with very low birth weight. J Pediatr 1985; 106: 801-5.","journal-title":"Ped Res; Indomethacin therapy on the first day of life in infants with very low birth weight"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/S0022-3476(85)80197-9","article-title":"Randomized indomethacin trial for prevention of intraventricular haemorrhage in very low birth weight infants","volume":"107","author":"Ment, L.R.; Duncan, C.C.; Ehrenkranz, R.A.; Kleinman, C.S.; Pitt, B.R.; Taylor, K.J.","year":"1985","unstructured":"Ment LR, Duncan CC, Ehrenkranz RA, Kleinman CS, Pitt BR, Taylor KJ, et al. Randomized indomethacin trial for prevention of intraventricular haemorrhage in very low birth weight infants. J Pediatr 1985; 107: 937-43.","journal-title":"J Pediatr"},{"key":"ref_22","first-page":"894","article-title":"Prophylactic indomethacin (I) for the prevention of patent ductus arteriosus (PDA). Ped Res 1985; 19: 358A. 26 Vincer","volume":"76","author":"Puckett, C.G.; Cox, M.A.; Haskins, K.S.; Fisher, D.J.","year":"1985","unstructured":"Puckett CG, Cox MA, Haskins KS, Fisher DJ. Prophylactic indomethacin (I) for the prevention of patent ductus arteriosus (PDA). Ped Res 1985; 19: 358A. 26 Vincer V, Allen A, Evans J, Nwaesei C, Stinson D, Rees E, et al. Early intravenous indomethacin prolongs respiratory support in very low birth weight infants. Acta Paediatr Scand 1985; 76: 894-7.","journal-title":"Acta Paediatr Scand; intravenous indomethacin prolongs respiratory support in very low birth weight infants"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1136\/adc.61.3.233","article-title":"Early administration of indomethacin to preterm infants","volume":"61","author":"Rennie, J.M.; Doyle, J.; Cooke, R.W.I.","year":"1986","unstructured":"Rennie JM, Doyle J, Cooke RWI. Early administration of indomethacin to preterm infants. Arch Dis Child 1986; 61: 233-8.","journal-title":"Arch Dis Child"},{"issue":"391","key":"ref_24","first-page":"749","article-title":"Prophylactic indomethacin for the prevention of intraventricular haemorrhage (IVH): neurodevelopmental follow-up","volume":"21","author":"Bandstra, E.S.; Duenas, M.L.; Rodriguez, I.; Chao, H.; Montalvo, B.M.; Bauer, C.R.","year":"1987","unstructured":"Bandstra ES, Duenas ML, Rodriguez I, Chao H, Montalvo BM, Bauer CR, et al. Prophylactic indomethacin for the prevention of intraventricular haemorrhage (IVH): neurodevelopmental follow-up. Ped Res 1987; 21: 391A. 29 Krueger E, Mellander M, Bratton D, Cotton R. Prevention of symptomatic patent ductus arteriosus with a single dose of indomethacin. Jf Pediatr 1987; 111: 749-54.","journal-title":"Ped Res; Prevention of symptomatic patent ductus arteriosus with a single dose of indomethacin"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/S0022-3476(88)80224-5","article-title":"Administration of indomethacin for the prevention of periventricular haemorrhage in high-risk neonates","volume":"112","author":"Hanigan, W.C.; Kennedy, G.; Roemisch, F.; Anderson, R.; Cusack, T.; Powers, W.","year":"1988","unstructured":"Hanigan WC, Kennedy G, Roemisch F, Anderson R, Cusack T, Powers W. Administration of indomethacin for the prevention of periventricular haemorrhage in high-risk neonates. J Pediatr 1988; 112: 941-7.","journal-title":"J Pediatr"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/S0022-3476(88)80225-7","article-title":"Randomized low-dose indomethacin trial for prevention of intraventricular haemorrhage in very low birth weight neonates","volume":"112","author":"Ment, L.R.; Duncan, C.C.; Ehrenkranz, R.A.; Kleinman, C.S.; Taylor, K.J.W.; Scott, D.T.","year":"1988","unstructured":"Ment LR, Duncan CC, Ehrenkranz RA, Kleinman CS, Taylor KJW, Scott DT, et al. Randomized low-dose indomethacin trial for prevention of intraventricular haemorrhage in very low birth weight neonates. J Pediatr 1988; 112: 948-55.","journal-title":"J Pediatr"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1542\/peds.82.4.533","article-title":"Prophylactic indomethacin for prevention of intraventricular haemorrhage in premature infants","volume":"82","author":"Bandstra, E.S.; Montalvo, B.M.; Goldberg, R.N.; Pacheco, I.; Ferrer, P.L.; Flynn, J.","year":"1988","unstructured":"Bandstra ES, Montalvo BM, Goldberg RN, Pacheco I, Ferrer PL, Flynn J, et al. Prophylactic indomethacin for prevention of intraventricular haemorrhage in premature infants. Pediatrics 1988; 82: 533-42.","journal-title":"Pediatrics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/S0022-3476(89)80300-2","article-title":"Indomethacin reduces the risks of severe intraventricular haemorrhage","volume":"115","author":"Bada, H.S.; Green, R.S.; Pourcyrous, M.; Leffier, C.W.; Korones, S.B.; Magill, H.L.","year":"1989","unstructured":"Bada HS, Green RS, Pourcyrous M, Leffier CW, Korones SB, Magill HL, et al. Indomethacin reduces the risks of severe intraventricular haemorrhage. J Pediatr 1989; 115: 631-7.","journal-title":"J Pediatr"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0022-3476(05)83191-9","article-title":"Low-dose indomethacin therapy and extension of intraventricular haemorrhage: a multicentre randomized trial","volume":"124","author":"Ment, L.R.; Oh, W.; Ehrenkranz, R.A.; Phillip, A.G.S.; Vohr, B.; Allan, W.","year":"1994","unstructured":"Ment LR, Oh W, Ehrenkranz RA, Phillip AGS, Vohr B, Allan W, et al. Low-dose indomethacin therapy and extension of intraventricular haemorrhage: a multicentre randomized trial. Jf Pediatr 1994; 124: 951-5.","journal-title":"Jf Pediatr"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1542\/peds.93.4.543","article-title":"Low-dose indomethacin and prevention of intraventricular haemorrhage: a multicentre randomized trial","volume":"93","author":"Ment, L.R.; Oh, W.; Ehrenkranz, R.A.; Phillip, A.G.S.; Vohr, B.; Allan, W.","year":"1994","unstructured":"Ment LR, Oh W, Ehrenkranz RA, Phillip AGS, Vohr B, Allan W, et al. Low-dose indomethacin and prevention of intraventricular haemorrhage: a multicentre randomized trial. Pediatrics 1994; 93: 543-50.","journal-title":"Pediatrics"}],"container-title":["Archives of Disease in Childhood - Fetal and Neonatal Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/fn.74.2.F81","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T18:31:49Z","timestamp":1757097109000},"score":1,"resource":{"primary":{"URL":"https:\/\/fn.bmj.com\/lookup\/doi\/10.1136\/fn.74.2.F81"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1996,3]]},"references-count":30,"journal-issue":{"issue":"2","published-online":{"date-parts":[[1996,3,1]]},"published-print":{"date-parts":[[1996,3]]}},"alternative-id":["10.1136\/fn.74.2.F81"],"URL":"https:\/\/doi.org\/10.1136\/fn.74.2.f81","relation":{},"ISSN":["1359-2998","1468-2052"],"issn-type":[{"value":"1359-2998","type":"print"},{"value":"1468-2052","type":"electronic"}],"subject":[],"published":{"date-parts":[[1996,3]]}}}