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Vitamin E supplementation for prevention of morbidity and mortality in preterm infants

  1. Luc P Brion1,*,
  2. Edward F Bell2,
  3. Talkad S Raghuveer3

Editorial Group: Cochrane Neonatal Group

Published Online: 20 OCT 2003

Assessed as up-to-date: 30 MAR 2007

DOI: 10.1002/14651858.CD003665


How to Cite

Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD003665. DOI: 10.1002/14651858.CD003665.

Author Information

  1. 1

    University of Texas Southwestern at Dallas, Division of Neonatal-Perinatal Medicine, Dallas, Texas, USA

  2. 2

    University of Iowa, Department of Pediatrics, Iowa City, Iowa, USA

  3. 3

    University of Kansas Medical Center, Pediatrics, Kansas City, USA

*Luc P Brion, Division of Neonatal-Perinatal Medicine, University of Texas Southwestern at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas, 75390-9063, USA. Luc.Brion@UTSouthwestern.edu.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 20 OCT 2003

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Characteristics of included studies [ordered by study ID]
Bonati 1991

MethodsDesign: multi-center randomized trial. Method of randomization: random allocation of the first baby; alternating medication in subsequent infants.
Blinding of intervention: no. Complete follow-up: no; data reported on the 44 infants who completed the 3-day schedule of vitamin E. Blinding of outcome: no.


ParticipantsTotal number of patients entered into the study: 50. Data reported in 22 patients in each group. Entry criteria: liveborn, gestational age equal or less than 32 weeks, no malformations, born in participating centers over 3 months, admitted to a neonatal intensive care within 2 hours of birth


InterventionsTreatment: 20 mg/kg dl-alpha-tocopheryl acetate given intramuscularly as aqueous colloidal solution (Ephynal, Hoffmann-La Roche, Basel, Switzerland). Control: 20 mg/kg vitamin E given intramuscularly as alpha-tocopherol in an olive solution (Evion Forte, Bracco, Milano) on three consecutive days, starting within 8 hours of life.


OutcomesMortality, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, patent ductus arteriosus, phototherapy, exchange transfusion


NotesPlasma tocopherol level: treatment group: 3.60±1.12 mg/dl; control group: 0.31±0.20 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Chiswick 1982

MethodsDesign: Randomized trial. Method of randomization: not described.
Blinding of intervention: no. Complete follow-up: yes.
Blinding of outcome: no.


ParticipantsTotal number of patients entered into the study: 35. Treatment group: 14; control group: 21. Entry criteria: preterm infants without major congenital malformations


InterventionsTreatment: dl-alpha-tocopheryl acetate (Ephynal, Hoffmann-La Roche) 20 mg/kg given intramuscularly daily for 4 doses commencing within 24 hours after birth. Control: no injection


OutcomesMortality, intraventricular hemorrhage


NotesPlasma tocopherol level: treatment group 4.84±2.37 mg/dl; control group 0.58±0.29 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Chiswick 1983

MethodsDesign: Randomized trial. Method of randomization: not provided.
Blinding of intervention: not mentioned. Complete follow-up: yes.
Blinding of outcome: not mentioned.


ParticipantsTotal number of patients entered into the study: 44. Treatment group: n=21, control group: n=23. Entry criteria: gestational age less than 37 weeks and birth weight less than 1751 g.


InterventionsTreatment: dl-alpha-tocopheryl acetate (Ephynal, Hoffmann-La Roche) 20 mg/kg given intramuscularly at 12, 36 and 60 hours of life. Control: no injection


OutcomesMortality, germinal matrix/intraventricular hemorrhage, intraventricular hemorrhage


NotesPlasma tocopherol level: treatment group 3.69±1.41 mg/dl; control group 0.42±0.38 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Cruz 1983

MethodsDesign: Randomized trial (groups I and II). Method of randomization: not provided.
Blinding of intervention: no, Complete follow-up: yes.
Blinding of outcome: no.


ParticipantsTotal number of patients entered into the study: 53 mothers and 55 infants. Groups I and II: 27 and 28, respectively (randomized); group III: 40 (not randomized). Entry criteria: (1) mothers admitted with threatened premature delivery at 26-34 weeks of gestation, (2) infant's birth weight less than 2,300 g


InterventionsGroup I: mother given vitamin E orally 900 mg for three days, followed by 100 mg daily until delivery. Infant given intramuscular vitamin E 25 mg/kg on days 1,2,4 and 8. Group II: mother given vitamin E orally as in group I, infant given no vitamin E injection. Group III (not randomized): neither mother nor infant received vitamin E supplementation.


OutcomesRetrolental fibroplasia, bronchopulmonary dysplasia


NotesOral multivitamin drops started on day five of life, this provided two mg of vitamin E daily.
Plasma tocopherol level on day 9: treatment group 4.14±1.08 mg/dl, control group 0.91±0.46 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Ehrenkranz 1982

MethodsDesign: randomized double-blind trial.
Method of randomization: not provided.
Blinding of intervention: yes. Complete follow-up: yes, except for intraventricular hemorrhage. Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 100. Treatment group: 47, control group: 53. Entry criteria: respiratory distress syndrome, informed consent.


InterventionsTreatment: 20 mg/kg vitamin E Injectable (Hoffmann-LaRoche) intramuscularly upon admission to the study (first day of life) and 24, 48, and 168 hours later, and then twice weekly as long as the infant remained in oxygen and could not tolerate feedings and vitamin supplements. Control: placebo.


OutcomesMortality, bronchopulmonary dysplasia, patent ductus arteriosus, patent ductus arteriosus requiring therapy, intraventricular hemorrhage, retrolental fibroplasia


NotesAll infants received initially an intravenous protein solution containing vitamin E 2.5 U/L. Enteral feeding provided 16 U/L (formula) or 3 U/L (human milk). Patients tolerating feeds regularly were given oral vitamin E supplementation (Aquasol E, USV Pharmaceutical Corp.) at a dose of 50 IU/day if weight was < 1000 g and 25 IU/day if weight was > 1000 g.
Plasma tocopherol level: treatment group 3.89±1.31 mg/dl, control group 0.78±0.37 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Ferlin 1998

MethodsDesign: randomized trial. Method of randomization: not provided.
Blinding of intervention: yes. Complete follow-up: unclear (by design, only patients with regular follow-up visits were included). Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 40. Group I: 10, II: 10; III: 10; IV: 10. Entry criteria: birth weight less than or equal to 1600 g and gestational age less than or equal to 35 weeks, informed consent, stable clinical course, no blood transfusion, regular follow-up visits after discharge, absence of interfering events that would require discontinuation of medications.


InterventionsFour groups: I: placebo started on the 15th day of life, iron starting at 2 months of age; II: 4 mg/kg/day iron started on the 15th day of life; III: 4 mg/kg/day iron and 25 IU/day alpha-tocopherol (Roche) orally started on the 15th day of life; IV: 25 IU/day vitamin E started on the 15th day of life.


OutcomesHemoglobin


NotesAll infants received 1.5 IU vitamin E/day and 0.1 mg iron (in multivitamin preparation) starting on the 7th day of life. Iron supplementation started at 2 months of age in patients who not yet supplemented.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Finer 1982

MethodsDesign: randomized trial.
Method of randomization: sealed envelopes, stratification by birth weight and by severity of respiratory distress (requirement for oxygen and endotracheal intubation). Blinding of intervention: no. Complete follow-up: no. Most data are available only for the 99 infants who completed the trial. Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 126. Treatment group: 62, control group: 64. Entry criteria: birth weight between 750 and 1500 g, appropriate for gestational age, informed consent.


InterventionsTreatment: 25 mg vitamin E, two doses, administered intramuscularly respectively within 12 hours of birth and 12 hours afterwards; then 20 mg intramuscularly daily for 14 days, then 20 mg intramuscularly every 3 days for 5 doses; then either 100 U daily orally or (if feeds not tolerated) 20 mg intramuscularly every 3 days. Control: no vitamin E.


OutcomesBronchopulmonary dysplasia, patent ductus arteriosus, retrolental fibroplasia among infants survived/examined, blindness from retrolental fibroplasia, necrotizing enterocolitis


NotesOsmolality of the oral preparation, used as a 1:1 dilution: 2,025 mOsm/kg.
Plasma tocopherol level: treatment group 4.21±3.35 mg/dl, control group 0.71±0.67 mg/dl.
Outcome variables available among infants surviving/examined: retrolental fibroplasia, blindness from retrolental fibroplasia


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Fischer 1987

MethodsDesign: randomized double-blind trial.
Method of randomization: not provided.
Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 28. Treatment group: 17, control group: 11. Entry criteria: birth weight less than 1,500 g, normal size for gestational age, informed consent . entered during the first 24 hours of life


InterventionsTreatment: oral administration of d-alpha-tocopherol polyethylene glycol-1000-succinate, 50 mg/day for three doses. Control: placebo.


OutcomesBilirubin, hemoglobin


NotesSeveral infants randomized to treatment group received only 25 mg/day.
Plasma tocopherol level: treatment group 1.85±0.76 mg/dl, control group 0.76±0.49 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Fish 1990

MethodsDesign: randomized double-blind trial.
Method of randomization: by the pharmacy, stratified by birth weight.
Blinding of intervention: no. Complete follow-up: no: two infants were excluded because of initially inapparent structural anomalies. Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 149, of which two were excluded after entry. Treatment group: 73, control group: 74. Entry criteria: birth weight equal to or less than 1000 g, postnatal age equal to or less than 24 hours, informed consent. Exclusion criteria: extremely poor condition on admission, major congenital abnormalities.


InterventionsTreatment: dl-alpha-tocopherol (Ephynal, Hoffmann-La Roche) intramuscularly in four doses at 15,10,10 and 10 mg/kg on days 1,2,4, and 6 of life, respectively. Doses of dl-alpha-tocopherol 10 mg/kg were administered intramuscularly every 3 days if the attending neonatologist felt that the infant could not tolerate oral vitamin E (see Notes) after 7 days of life. Control: placebo.


OutcomesMortality, intracranial hemorrhage, necrotizing enterocolitis, sepsis, patent ductus arteriosus, local reaction at injection site


NotesPlasma tocopherol levels were not blinded to the clinicians. All neonates received oral dl-alpha-tocopheryl acetate (Aquasol E) 100 mg/kg/day beginning at admission; dose adjusted after day 7 to maintain total vitamin E serum level 0.5-3.5 mg/dl.
Plasma tocopherol level during first week: treatment group
4.24±1.59 mg/dl, control 1.95±1.04 mg/dl; after first week: treatment group 2.70±0.09 mg/dl, control group 2.39±0.09 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Graeber 1977

MethodsDesign: randomized trial. Method of randomization: not provided. Blinding of intervention: no. Complete follow-up: yes. Blinding of outcome: no.


ParticipantsTotal number of patients entered into the study: 35. Groups I: 5, II: 5, III: 5, IV: 5, V: 5, VI: 10. Entry criteria: birth weight less than 1,500 g, gestational age less than 34 weeks. Exclusion criteria: ABO or Rh isoimmunization, hemoglobin value less than 13 g/dl at seven days of age, transfusion of whole blood or plasma at any age, transfusion of red blood cells after one week of age.


InterventionsTreatment: (1) intramuscular dl-alpha-tocopheryl acetate in a water-dispersible vehicle (Roche) with total dose divided in four aliquots (days 1,2,7 and 8); (2) Intramuscular iron: iron-dextran complex (Imferon): 25 mg/day on days 7,14,21, and 28; control: no injection. Control: no injection.
Six groups (by dose of vitamin E and dose of iron) in the original trial: Group I: total dose of vitamin E: 100 mg/kg, no iron; group II: vitamin E 125 mg/kg, no iron; group III: vitamin E 150 mg/kg, no iron; group IV: vitamin E 125 mg/kg and iron 100 mg; group V: no vitamin E, iron 100 mg; group VI: neither vitamin E, nor iron.


OutcomesBronchopulmonary dysplasia, retrolental fibroplasia


NotesPlasma tocopherol level: treatment group 1.78±0.60 mg/dl, control group 0.53±0.34 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Gross 1977

MethodsDesign: randomized trial. Method of randomization: not provided. Blinding of intervention: no. Complete follow-up: yes. Blinding of outcome: no.


ParticipantsTotal number of patients entered into the study: 20. Treatment group: 10, control group: 10. Entry criteria: birth weight less than 2,500 g, gestational age less than 36 weeks, well, breathing room air, hemoglobin concentration greater than 13 g/dl on the third day of life. Exclusion criterion: Rh or ABO isoimmunization.


InterventionsTreatment: total dose of 125 mg/kg tocopheryl acetate (Roche) administered intramuscularly in 8 divided doses, an injection in each thigh, on days 4,5,6 and 7 of life. Control: no injection.


OutcomesHemoglobin


Notes


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Gross 1979

MethodsDesign: randomized trial. Method of randomization: not provided. Randomization stratified by weight (1000-1500 g and 1501-2000 g). Blinding of intervention: no. Complete follow-up: yes. Blinding of outcome: no.


ParticipantsTotal number of patients entered into the study: 40; treatment group: 20, control group: 20. Entry criteria: birth weight between 1000 and 2000 g, appropriate for gestational age. Exclusion criteria: hemoglobin concentration less than 13 g/dl, Rh or ABO isoimmunization.


InterventionsTreatment: total dose of 50 mg/kg dl-alpha-tocopheryl acetate (Roche) administered intramuscularly in 6 divided doses, an injection in each thigh on days 1,2, and 3 of life. Control: no injection.


OutcomesSerum bilirubin


NotesPlasma tocopherol level: treatment group 3.00±1.00 mg/dl, control group 0.50±0.30 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Hittner 1981

MethodsDesign: randomized double-blind trial. Method of randomization: random-number table. Randomization stratified by weight. Blinding of intervention: yes. Complete follow-up: no: information on 49 patients is incomplete. Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 150. One patient with necrotizing enterocolitis was excluded (no information on treatment allocation). Treatment group: 75, control group: 74. Entry criteria: birth weight less than or equal to 1,500 g, requiring oxygen for respiratory distress, admitted to the unit within the first 24 hours of life, informed consent. Exclusion criteria: necrotizing enterocolitis preventing oral administration of vitamin E (n=1); exclusion from all other outcomes: death before four weeks (n=48).


InterventionsTreatment: dl alpha-tocopherol 100 mg/kg/day orally, provided as water-dispersible liquid containing dl alpha-tocopherol 50 mg/ml in propylene glycol-polysorbate 80. Control (placebo): dl alpha-tocopherol 5 mg/kg/day orally, provided as 2.5 mg/ml in propylene glycol-polysorbate 80. Treatment and placebo were started on the first 24 hours of life and continued throughout the hospital stay.


OutcomesMortality. Outcomes among patients surviving four weeks: bronchopulmonary dysplasia, patent ductus arteriosus, sepsis, periventricular- intraventricular hemorrhage, retrolental fibroplasia


NotesOsmolality of the oral preparation: 3000 mOsm/kg.
Plasma tocopherol level: treatment group
1.21±0.79 mg/dl, control group 0.62±0.40 mg/dl.
Outcome variables available only among patients surviving at least four weeks and without necrotizing enterocolitis: bronchopulmonary dysplasia, patent ductus arteriosus, sepsis, periventricular-intraventricular hemorrhage and retrolental fibroplasia.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Hittner 1984

MethodsDesign: double-masked randomized trial. Method of randomization: random-number table. Randomization stratified by weight. Blinding of intervention: yes. Complete follow-up: no: information incomplete in 33 infants not surviving ten weeks (primary reference) or in 34 outpatients (secondary reference). Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 168. Treatment group: 79, control group: 89. Entry criteria: birth weight equal to or less than 1,500 g, oxygen requirement for respiratory distress, admission within 24 hours, informed consent. Exclusion criteria from all other outcomes: death before 10 weeks ( n=33).


InterventionsTreatment: dl-alpha-tocopherol, 55 mg/ml (Ephynal, Hoffman-La Roche, preparation containing benzyl alcohol, propylene glycol, ethyl alcohol, Emulphor E1-620, and buffering salts), given intramuscularly at doses of 15, 10, 10, and 10 mg/kg on days 1,2,4 and 6 of life. Control: placebo injections.


OutcomesMortality. Outcomes available either among patients surviving ten weeks or among inpatients: bronchopulmonary dysplasia, patent ductus arteriosus, sepsis, periventricular-intraventricular hemorrhage, retrolental fibroplasia, necrotizing enterocolitis, number of transfusions and amount of blood transfused


NotesVitamin E 100 mg/kg/day given orally to all infants starting within the first 24 hours of life. This was provided as an emulsion of dl-alpha-tocopheryl acetate in gelatin, silicon dioxide, polysorbate 80, and medium chain triglycerides, osmolality 150 mOsm/kg.
Plasma tocopherol level: treatment group 3.29±1.58 mg/dl, control group 1.42±1.12 mg/dl.
Outcome variables available among those surviving ten weeks: bronchopulmonary dysplasia, patent ductus arteriosus, sepsis, periventricular-intraventricular hemorrhage, retrolental fibroplasia, necrotizing enterocolitis, number of transfusions and amount of blood transfused


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Jansson 1978

MethodsDesign: randomized trial. Method of randomization: not provided. Randomization stratified by weight (1000-1999 and 2000-2499 g). Blinding of intervention: no. Complete follow-up: yes. Blinding of outcome: no.


ParticipantsTotal number of patients entered into the study: 57. Group I: 24, group II: 17, group III: 16. Entry criteria: birth weight less than 2500 g. Exclusion criteria: hemoglobin concentration below 15 g/dl or greater than 26 g/dl in the first 24 hours, hyperbilirubinemia, blood transfusion.


InterventionsGroup I (control): ferrous succinate starting at 3 weeks of age (elemental iron 2-3 mg/kg/day); group II: dl-alpha-tocopheryl acetate (E-vitamin, AB ACO, dispersible in lipid solutions) 15 mg/day started at 10 days and ferrous succinate started at 3 weeks; group III: tocopheryl acetate 15 mg/day started at 10 days and ferrous succinate started at 10 weeks.


OutcomesHemoglobin, reticulocyte count, platelet count


NotesFrom 10 days of age, all infants received 1.5 mg/day of tocopheryl acetate orally.
Plasma tocopherol level: treatment group 1.22±0.20 mg/dl, control group 0.80±0.28 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Johnson 1989

MethodsDesign: randomized, double-blind controlled trial. Method of randomization: not provided. Randomization stratified by hospital and by birth weight. Blinding of intervention: yes. Complete follow-up: no; complete data available in only 755 of 914 enrolled. Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 914. Treatment group: 454, control group: 460. Entry criteria: (1) birth weight equal to or less than 2000 g or (2) gestational age equal to or less than 36 weeks and oxygen treatment required; informed consent, admission within 5 days of age. Sixty-eight percent of the infants were enrolled by calendar age one day.


InterventionsTreatment: (1) infants receiving intravenous feeding: 15 mg/kg vitamin E intramuscularly and 15 mg/kg intravenously at study admission, followed by 15 mg/kg intravenously the next day; (2) infants receiving oral feedings: 15 mg/kg vitamin E intramuscularly and 100 mg/kg/day divided in aliquots in the feeds. Subsequent dosage adjusted to maintain serum vitamin E level of 5 mg/dl. Control: placebo both for oral and parenteral preparations, with dosage adjustments to mimic those in the control group. Study medication was replaced by vitamin E in patients who had developed severe ROP.


OutcomesRetinopathy of prematurity and serum bilirubin. Among infants with birth weight less than or equal to 1500 g: mortality, bronchopulmonary dysplasia (diagnosed radiographically), sepsis, intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis


NotesVitamin E was provided as free dl-alpha-tocopherol 50 mg/ml (55 IU/ml) emulsified for parenteral administration with Emulfor 620. This is one of the two studies in which vitamin E was administered intravenously.
Plasma tocopherol level: treatment group 5.10±1.90 mg/dl, control group 0.82±0.36 mg/dl.
Examination for the presence of retinopathy of prematurity was done in 755 patients. Outcome variables available among the 545 infants with birth weight less than or equal to 1500 g: mortality, bronchopulmonary dysplasia (diagnosed radiographically), patent ductus arteriosus, patent ductus arteriosus requiring treatment, sepsis after study entry, intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis. Outcome variables available in subsets of the population included sepsis after study entry among very low birth weight infants treated for more than one week, bilirubin (excluding hemolytic anemia, polycythemia, and prior transfusion, and amount of blood transfusion (subset of very low birth weight infants).


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Melhorn 1971

MethodsDesign: randomized controlled trial. Method of randomization: not provided. Randomization stratified by weight and gestational age. Complete follow-up: no: data are provided on only 186 patients. Blinding of outcome: no


ParticipantsTotal number of patients entered into the study: 234, including some full-term infants. Group I: 45, II: 47, III: 44, IV: 50. Entry criteria: admission to the premature nursery unit. Exclusion criteria: either small or large for gestational age, hemoglobin concentration < 14 g/dl in the first 24 hours of life, blood group incompatibility, hemoglobinopathy, red blood cell enzyme deficiency, infection, defects requiring surgical intervention.


InterventionsGroup I: no supplement (control). Group II: vitamin E: alpha tocopheryl acetate 25 units/day orally from the eighth to the forty-second day of life. Group III: iron from the fifteenth to forty-second day of life: 10 mg/day if weight < 1500 g, 15 mg/day if weight 1501-2000 g, 20 mg/day if weight > 2001 g. Group IV: iron and vitamin E.


OutcomesHemoglobin, reticulocyte count


NotesPlasma tocopherol level: treatment group 0.5-1.0 mg/dl, control group 0.2-0.8 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Pathak 2003

MethodsDesign: randomized double-blind trial. Method of randomization: sealed envelopes in the pharmacy. Blinding of the intervention: no. Complete follow-up: yes.
Blinding of outcome: yes


ParticipantsTotal number of patients entered into the study: 30. Treatment group: 15, control group: 15. Entry criteria: gestational age less than or equal to 32 weeks, birth weight less than or equal to 1250 grams, clinically stable (less than 7.5 ml/week phlebotomy, oxygen requirement less than or equal to 35%, intermittent mandatory ventilation less than or equal to 25 breaths per minute, mean airway pressure less than or equal to 8 cm of water). Exclusion criteria: disease involving any major organ system, life-threatening congenital malformations or sepsis, isoimmunization with clinically apparent hemolytic anemia, hemolytic disorder, intraventricular hemorrhage grade III or greater.


InterventionsTreatment: vitamin E 50 IU/day enterally. Controls: placebo


OutcomesMortality, patent ductus arteriosus requiring treatment, sepsis, necrotizing enterocolitis, hemoglobin concentration, reticulocyte count, transfusions, total volume transfused


NotesAll infants received erythropoietin 100 units/kg/day five days a week for eight weeks or until discharge, whichever came first. Infants fed intravenously received a multivitamin preparation (MVI Pediatric) containing 1.4 mg alpha-tocopherol acetate/ml at dose of 1.5 ml/day and 3.25 ml/day to infants weighing < 1 kg and > 1 kg, respectively. All infants fed enterally at least 40 ml/kg/day received oral iron 6 mg/kg/day and 1 ml of a multivitamin preparation containing 5 U/ml vitamin E. Plasma tocopherol level: treatment group 2.86±1.26 mg/dl, control group 1.66±1.25 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Phelps 1987a

MethodsDesign: randomized double-blind trial. Method of randomization: sealed envelopes stratified by study center, sex, and birth weight, opened at the pharmacy (center 1) or drug control center (center 2). Numbers balanced by groups of eight. Multiple births randomized separately so that one of each pair received placebo and one tocopherol. Blinding of intervention: yes. Follow-up was complete for several neonatal outcomes. However retinal examinations were not obtained in 55 infants, including nine infants lost to follow-up and 46 who had died. Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 287. Treatment group: 140, control group: 147. Entry criteria included birth weight less than 1.5 kg or gestational age less than 33 weeks, less than 24 hours of age, free from recognized congenital anomalies of the eyes or congenital anomalies incompatible with survival, and informed consent. Exclusion criteria included major congenital anomalies and Rhesus hemolytic disease.


InterventionsTreatment: intravenous dose provided within 24 hours of birth and repeated on day 2 (and sometimes day 3): 20 mg/kg of nonesterified dl-alpha-tocopherol in alcohol or its vehicle (10% ethyl alcohol, 10% propylene glycol, 10% Emulphor, 1% benzyl alcohol, and buffering salts). Doses adjusted to achieve plasma vitamin E levels of 3-3.5 mg/dl: supplemental intramuscular injection given to infants with plasma levels lower than 2.5 mg/dl despite oral doses exceeding 200 mg/kg/day. Control: placebo.


OutcomesMortality, sepsis, late-onset sepsis, periventricular-intraventricular hemorrhage, necrotizing enterocolitis.
Among survivors: retinopathy of prematurity, retinal hemorrhage


NotesAll infants fed intravenously received 1.2 mg/kg/day of tocopherol acetate in standard multivitamin supplements.
In infants in whim severe ROP had developed, the study medication was replaced with vitamin E. Median plasma tocopherol level in the treatment group: 3-3.5 mg/dl (1-2 weeks of age); 2-2.5 mg/dl (3 weeks - second month). Outcome variable available among surviving infants: retinopathy of prematurity.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Rudolph 1989

MethodsDesign: randomized controlled trial. Method of randomization: not provided. Blinding of intervention: no. Complete follow-up: yes.
Blinding of outcome: yes (cardiologist).


ParticipantsTotal number of patients entered into the study: 29. Treatment group: 13, control group: 16. Entry criteria: preterm infant, birth weight 750-1500 g, intensive care.


InterventionsTreatment: dl-alpha-tocopherol (Hoffman-La Roche) intramuscularly at a dose of 25 mg/kg within 12 hours of birth. Repeated injections 24 hours later, and at 4, 5, 10, 20 and 30 days of age. Total cumulative dose: 175 mg/kg. Control: no vitamin E supplementation.


OutcomesMortality, patent ductus arteriosus, severe retinopathy of prematurity, necrotizing enterocolitis


NotesAll infants fed intravenously received 2.5 IU vitamin E per liter of parenteral solution.
Plasma tocopherol level: treatment group 1.62±0.91 mg/dl, control group 0.41±0.21


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Rönnholm 1989

MethodsDesign: randomized controlled trial. Method of randomization: not provided. Blinding of intervention: no. Complete follow-up: no; incomplete information on three patients who died. Blinding of outcome: no.


ParticipantsTotal number of patients entered into the study: 54. Treatment group: 23; control group: 31. Entry criteria: birth weight less than or equal to 1520 g.


InterventionsTreatment: intramuscular dU-rac-alpha-tocopheryl acetate 20 mg/kg/day (Ephynal, Hoffmann-La Roche) during the first three days of life. Controls: No injection.


OutcomesBronchopulmonary dysplasia, intraventricular hemorrhage, retrolental fibroplasia, necrotizing enterocolitis


NotesPatients were randomly supplemented with human milk protein, medium-chain triglycerides, both or neither. All patients received oral administration of water soluble vitamin E dl-alpha-tocopherol polyethyleneglycol 1000-succinate (part of a multivitamin preparation, Ekavitol, Orion Corp Ltd) in increasing doses of 1.6 mg/day on day 3 to 10 mg/day at age 2-12 weeks.
Plasma tocopherol level in the treatment group: 1.50±0.21 mg/dl.
Outcome variables among the 51 survivors: bronchopulmonary dysplasia, intraventricular hemorrhage, retrolental fibroplasia, and necrotizing enterocolitis.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Saldanha 1982

MethodsDesign: randomized controlled trial. Method of randomization: drawing of a card from a randomized deck. Blinding of intervention: no. Complete follow-up: no; incomplete data provided on babies who died before 10 days of age. Blinding of outcome: no.


ParticipantsTotal number of patients entered into the study: 44. Treatment group: 21, control group: 23. Entry criteria: gestational age less than 37 weeks, hyaline membrane disease, oxygen requirement at least 60% in first 24 hours or 80% thereafter, informed consent. Exclusion criteria: cyanotic heart disease, multiple malformations, known infectious disease.


InterventionsTreatment: 25 mg of dl-alpha-tocopherol (Hoffman-La Roche) intramuscularly upon entry into the study and daily thereafter until vitamin E serum level rose above 2-4 mgl/dl or until no longer oxygen requirement. Mean age at entry into the study 24±5 hours. Control: no injection. Mean age at entry into the study 18±3 hours


OutcomesOutcomes among patients surviving ten days or more: bronchopulmonary dysplasia, patent ductus arteriosus


NotesPlasma tocopherol level: treatment group 3.87±3.94 mg/dl, control group 0.94±1.06 mg/dl.
Outcome variables among patients surviving ten days or more included: bronchopulmonary dysplasia and patent ductus arteriosus


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Schiller 1980

MethodsDesign: randomized controlled trial. Method of randomization: not provided. Blinding of intervention: no. Complete follow-up: unclear. Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 29. Treatment group: 16, control group: 13.
Entry criteria: preterm infant, birth weight < 1750 g.


InterventionsTreatment: dl-alpha-tocopherol intramuscularly (175 mg/kg over a 30-day period). Control: no injection.


OutcomesPatent ductus arteriosus


NotesAbstract only.
Plasma tocopherol level: treatment group 1.70±1.22 mg/dl, control group 0.50±0.57 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Sinha 1987

MethodsDesign: Randomized trial. Method of randomization: sealed envelope.
Blinding of intervention: no. Complete follow-up: no; three infants with lethal major malformations were excluded and only partial information is provided in eighteen patients with periventricular-intraventricular hemorrhage at entry. Blinding of outcome: unclear


ParticipantsTotal number of patients entered into the study: 231. No data are provided among three infants with lethal congenital malformations. Among the 228 with information provided, 115 were in the treatment group and 113 in the control group. Entry criteria: Gestational age equal or less than 32 weeks, admitted from January 1984 to September 1985. Exclusion criteria: none described before randomization.


InterventionsTreatment: alpha-tocopheryl acetate (Ephynal) 20 mg/kg given intramuscularly daily for three doses commencing within two hours after randomization (first day of life). Controls: no injection


OutcomesMortality, periventricular-intraventricular hemorrhage, worsening of the intracranial hemorrhage, inflammation at site of injection


NotesMothers of some infants were part of another randomized trial. They were allocated either to vitamin E 400 mg every 4-6 hours or to placebo capsules during preterm labor.
Plasma tocopherol level: treatment group 2.99±1.00 mg/dl, control group 0.42±0.14 mg/dl. Outcome variables are available only after eliminating patients with lethal malformations. Outcome variable available only in the 210 patients with negative initial scan: complete information about the grade of the intracranial hemorrhage


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Smith 1985

MethodsDesign: Randomized double-blind trial. Method of randomization: not provided. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 30. Treatment group: 17, control group: 13. Entry criteria: gestational age 30-36 weeks, birth weight 970-2610 g, healthy, lack of pulmonary disease or oxygen requirement, no ABO or Rh isoimmunization, no other sources of bilirubin production, such as hematoma or bruising. Exclusion criteria: infection.


InterventionsTreatment: dl-alpha-tocopheryl polyethylene glycol-succinate (Mead Johnson) 50 mg/day orally once a day for 3 consecutive days, starting before 24 hours of life. Control: placebo.


OutcomesBilirubin, hemoglobin


NotesPlasma tocopherol level: treatment group 2.11±0.79 mg/dl, control group 1.71±1.40 mg/dl


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Zipursky 1987

MethodsDesign: Randomized double-blind trial. Method of randomization: computer-generated randomization in the pharmacy, stratified by severity of illness. Blinding of intervention: yes. Complete follow-up: no: chronic lung disease information in 266; eye examination in 225 infants; hematologic data in 90 treated patients and 88 controls . Blinding of outcome: yes.


ParticipantsTotal number of patients entered into the study: 269. Treatment group: 135, control group: 134. Entry criteria: birth weight < 1500 g, expected survival greater than 48 hours, informed consent. Exclusion criteria: major congenital anomalies, Rhesus hemolytic disease. Age at entry into the trial: 2.7±3 days in treatment group and 2.9±2 days in control group.


InterventionsTreatment: 25 IU tocopherol provided by gavage as 16 mg dl-alpha-tocopherol (Hoffman-La Roche) started day one, daily for six weeks. Control: placebo: drug vehicle (Tween 80).


OutcomesMortality in NICU, bronchopulmonary dysplasia, retinopathy of prematurity, hemoglobin, reticulocyte count, platelet count, coagulation tests


NotesPlasma tocopherol level at six weeks: treatment group 2.88±2.02 mg/dl, control group 0.86±0.50 mg/dl.
Outcome variables available only in subsets: hemoglobin concentration, reticulocyte count, platelet count, and coagulation tests


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Barness 1968Quasi-randomized trial assessing the effect of adding a small amount of vitamin E (11.5 mg per quart) to the formula on plasma tocopherol level, hemoglobin concentration and reticulocyte count measured in very low birth weight infants.

Chadd 1970Randomized double blind placebo controlled trial of vitamin E for treatment of anemia of prematurity. Variability of hemoglobin is not provided.

Chirico 1983None of the outcomes selected for this systematic review was analyzed. Outcome variables in this study included various in vitro indices of white cell function.

Conway 1986None of the outcomes selected for this systematic review could be analyzed using standard (parametric) meta-analysis, because the authors only provided medians and ranges, without means and standard deviations or percentages.
Nevertheless, this double-blind randomized trial showed that adding either five or fifteen mg of vitamin E daily for ten weeks did not affect hemoglobin concentration, reticulocyte count of platelet count in preterm infants with a birth weight < 1760 g. All infants received at least the minimum of vitamin E recommended, i.e., a vitamin E: PUFA ratio at least equal to 0.6. No infant received iron supplementation. No infant developed clinical or hematological sign of vitamin E deficiency.

Curran 1979Quasi-randomized trial assessing the effect of three intramuscular injections of 50 mg/kg of Vitamin E Injectable (Roche) on days zero (< six hours of life), one and two of life on retinopathy of prematurity in very low birth weight infants.

Dyggve 1963Quasi-randomized trial assessing the effect of one intramuscular injection of 100 mg of al-alpha-tocopherol in aqueous colloidal solution (Ephynal, Hoffman-La Roche) just after birth on hemolysis in preterm infants. Entry criteria were prematurity and birth weight equal or less than 2,500 g.

Ehrenkranz 1978Quasi-randomized trial assessing the effect of daily intramuscular injections of 20 mg/kg of vitamin E Injectable (Hoffmann-LaRoche), starting upon admission to the study and continued as long as inspiratory oxygen concentration was greater than 40%. Entry criteria included respiratory distress syndrome, inspiratory oxygen concentration greater than 40% and continuous distending pressure required to maintain arterial oxygen tension greater than 50 mm Hg.

Fermanian 1976None of the outcomes selected for this systematic review could be analyzed using meta-analysis because standard deviation or standard error is not provided. This is a double-blind randomized trial assessing the effect of daily oral supplementation of 10 mg dl alpha-tocopheryl acetate (Ephynal, Roche) from the eighth day of life until nineteen weeks of life on hematologic parameters in preterm infants with a birth weight equal or less than 2500 g. Controls received placebo (lactose). Both vitamin E and placebo were dissolved in the milk. Infants were fed banked breast milk until reaching a weight of 1800 g (vitamin E content 9 mg/100 ml) and then formula (no measurable vitamin E). Iron was not provided. Among 74 infants entered into the study, 37 were randomized to treatment and 37 to control. Outcome measurements included hemoglobin concentration, hematocrit and reticulocyte count at seven weeks of life.

Finer 1983This study included three groups: a historical control group (1978-81), and two vitamin E groups (1982). The early vitamin E group was given vitamin E orally before 12 hours of age by design, while late administration of vitamin E (after 40 hours) in the late vitamin E group was usually the result of an oversight.

Gerlóczy 1949This study compares several consecutive cohorts.

Goldbloom 1963No variability provided for the outcome variable, hemoglobin, at the end of the study. This is a quasi randomized trial comparing the effect of oral supplementation of vitamin E on hemoglobin concentration in healthy preterm infants. The trial had three arms, receiving, respectively, a vitamin E-free formula, a formula containing 3 mg/L of alpha tocopherol, and a formula supplemented to a total content of 8 mg per liter. The total number of enrolled patients was 44, including 14, 14 and 16 patients, respectively. Mean birth weights were, respectively, 1808±349 g, 1902±282 g, and 1732±242 g. Mean hemoglobin values were similar in all three arms at the end of the study.

González-Corbella 98This study was done in full-term infants. None of the outcomes selected for this systematic review was analyzed.

Gross 1974Variability of the outcome variable (hemoglobin) is not provided. This study included a quasi-randomized trial and a randomized trial, both comparing the effects of water-soluble and fat-soluble vitamin E in preterm infants on hemoglobin concentration, vitamin E levels and erythrocyte phospholipids.

Gutcher 1985None of the outcomes selected for this systematic review was analyzed. Outcome variables in this study included vitamin E level and percent peroxide-induced hemolysis.

Hashim 1968This study compares breast milk, cotton seed formula and evaporated milk. The difference in vitamin E content (18 mg/quart in the two formulas and 12 mg/quart in breast milk) is only one of several major differences in milk composition. The authors do not provide the variability in hemoglobin and reticulocyte counts.

Hassan 1966Quasi-randomized trial comparing two formulae and assessing the effects of vitamin E supplementation. Entry criteria were birth weight 940-2150 g, absence of congenital defects, and uncomplicated neonatal course.

Hervei 1983Quasi-randomized trial assessing the effect of daily intramuscular injections of dl-alpha-tocopheryl acetate (Ephynal, Hoffmann-La Roche) 50 mg/kg/day from the first day of life until two weeks of age on blindness secondary to retrolental fibroplasia in preterm infants with birth weight equal or less than 1500 g.

Hittner 1983This study compares two consecutive cohorts.

Huston 1982Randomized allocation to either total parenteral nutrition with Intralip or total parenteral nutrition without Intralipid. Vitamin E was a co-intervention.

Jansson 1984None of the outcomes selected for this systematic review was analyzed. The outcome variable in this study was serum vitamin E level.

Johnson 1974Quasi-randomized trial assessing the effect of intramuscular administration of vitamin E on retrolental fibroplasia in preterm infants. Entry criteria included birth weight less than 2001 g regardless of oxygen need or birth weight over 2001 g with gestational age less than 36 weeks if oxygen required for over 24 hours, and informed consent.

Johnson 1982These studies compare either (1) non simultaneous cohorts assigned, respectively, to vitamin E or no treatment or (2) combined data from two different protocols run in 1972-74 and 1974-76, respectively. These studies are also reported in Ann NY Acad Sci 1982 (see Johnson 1974 in included studies).

Johnson 1995This study compared a group of patients with threshold retinopathy of prematurity treated with cryotherapy and vitamin E (1985-91) in one hospital with a non simultaneous group of patients treated with cryotherapy and no vitamin E in a multicenter trial (CRYO-ROP, 1986-7).

Kinsey 1951This study compares several consecutive cohorts.

Levene 1979Quasi randomized trial assessing hemoglobin and reticulocyte count. No data provided.

Lo 1973Quasi randomized trial comparing three methods of treating hemolysis in preterm infants: vitamin E at the first sign of hemolyis, vitamin E within 2-4 weeks after developing hemolytic anemia, and no treatment. Averages and standard deviations of hemoglobin and reticulocyte count are provided
only for the first group.

MacDonald 1987This study describes two consecutive cohorts assigned, respectively, to MVI-Concentrate and 50 mg/week of intramuscular vitamin E, and to MVI-Pediatric 65% of a vial per day.

McWhirter 1974No variability is provided for the outcome variable, i.e., hemoglobin.

Nishida 1986None of the outcomes selected for this systematic review was analyzed. The outcome variables in this study were vitamin E levels in various eye compartments.

Oski 1967Quasi-randomized trial assessing the effect of enteral vitamin E, beginning on the third day of life on hematologic parameters in preterm infants.

Owens 1949Quasi-randomized trial assessing the effect of enteral vitamin E on retrolental fibroplasia in infants with a birth weight less than or equal to 1360 grams.

Panos 1968Comparison of the outcome variable (hemoglobin) among groups is not possible because either standard deviation is not provided, or not all individual data are provided.

Sartain 1967No data are provided in the published abstract.

Schwalbe 1992None of the outcomes selected for this systematic review was analyzed. The outcome variable in this study was serum free alpha-tocopherol level.

Stone 2003No preterm infants were enrolled and none of the outcomes selected for this systematic review were analyzed.

Zöberlein 1982This study included both full-term and preterm infants.

 
Comparison 1. Vitamin E versus placebo or no vitamin E

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality until discharge12Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 All infants in all studies
122028Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.83, 1.14]

    1.2 Birth weight > 1000 grams
197Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.34, 2.62]

    1.3 Enteral
3445Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.63, 1.35]

    1.4 Enteral hypertonic formulation, at pharmacologic doses
1149Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.62, 1.46]

    1.5 Parenteral with or without enteral
91583Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.83, 1.17]

    1.6 Parenteral with hypertonic enteral formulation at pharmacologic dose
51247Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.82, 1.20]

    1.7 Intravenous (with or without other routes of administration)
2832Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.82, 1.32]

    1.8 Excluding intravenous vitamin E administration
101196Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.75, 1.14]

    1.9 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
5575Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.60, 1.34]

    1.10 Total dose of vitamin E in the treatment group > 30 IU/kg/day
61396Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.83, 1.17]

    1.11 Serum tocopherol level in the treatment group <= 3.5 mg/dl
71157Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.75, 1.19]

    1.12 Serum tocopherol level in the treatment group >3.5 mg/dl
5871Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.80, 1.24]

    1.13 Onset of vitamin E supplementation in the treatment group within 48 hours of life
111998Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.83, 1.14]

    1.14 Onset of treatment after 48 hours of life
130Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    1.15 Duration of treatment <= 1 week (7 days)
4475Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.56, 1.18]

    1.16 Duration of treatment > 1 week
71008Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.82, 1.28]

    1.17 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
91613Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.82, 1.19]

    1.18 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
3415Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.68, 1.24]

    1.19 Iron supplementation > 2 mg/kg/day in both groups
130Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    1.20 Iron supplementation > 2 mg/kg/day in neither group
1266Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.40, 1.85]

    1.21 PUFA >= 400 mg/100 ml milk
1266Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.40, 1.85]

 2 Mortality until discharge among very low birth weight infants8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 All infants in all studies
71334Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.80, 1.16]

    2.2 Birth weight <= 1500 grams
61187Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.75, 1.15]

    2.3 Birth weight > 1000 grams
2496Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.74, 1.67]

    2.4 Birth weight <= 1000 grams
4449Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.77, 1.17]

    2.5 Enteral
3445Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.63, 1.35]

    2.6 Enteral hypertonic formulation, at pharmacologic doses
1149Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.62, 1.46]

    2.7 Parenteral with or without enteral
4889Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.79, 1.21]

    2.8 Parenteral with hypertonic enteral formulation at pharmacologic dose
1168Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.38, 1.24]

    2.9 Intravenous (with or without other routes of administration)
1545Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.75, 1.34]

    2.10 Excluding intravenous vitamin E supplementation
6789Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.73, 1.19]

    2.11 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2268Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.40, 1.85]

    2.12 Total dose of vitamin E in the treatment group > 30 IU/kg/day
41009Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.80, 1.18]

    2.13 Serum tocopherol level in the treatment group <= 3.5 mg/dl
5642Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.63, 1.17]

    2.14 Serum tocopherol level in the treatment group >3.5 mg/dl
2692Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.82, 1.31]

    2.15 Onset of vitamin E supplementation in the treatment group within 48 hours of life
61304Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.80, 1.16]

    2.16 Onset of treatment after 48 hours of life
130Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    2.17 Duration of treatment <= 1 week (7 days)
1168Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.38, 1.24]

    2.18 Duration of treatment > 1 week
61166Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.83, 1.23]

    2.19 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
51019Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.78, 1.23]

    2.20 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
2315Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.67, 1.29]

    2.21 Iron supplementation > 2 mg/kg/day in both groups
130Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    2.22 Iron supplementation > 2 mg/kg/day in neither group
1266Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.40, 1.85]

    2.23 PUFA >= 400 mg/100 ml milk
1266Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.40, 1.85]

 3 Bronchopulmonary dysplasia7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 All infants in all studies
61127Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.73, 1.14]

    3.2 Enteral
1266Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.50, 1.38]

    3.3 Parenteral with or without enteral
6912Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.75, 1.23]

    3.4 Parenteral with hypertonic enteral formulation at pharmacologic dose
3771Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.73, 1.20]

    3.5 Intravenous (with or without other routes of administration)
1545Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.68, 1.21]

    3.6 Excluding intravenous vitamin E administration
5582Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.64, 1.31]

    3.7 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
4498Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.63, 1.38]

    3.8 Total dose of vitamin E in the treatment group > 30 IU/kg/day
3680Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.71, 1.22]

    3.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
3352Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.56, 1.50]

    3.10 Serum tocopherol level in the treatment group > 3.5 mg/dl
4826Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.73, 1.20]

    3.11 Onset of treatment within 48 hours of life
71178Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.74, 1.16]

    3.12 Duration of treatment <= 1 week
3141Risk Ratio (M-H, Fixed, 95% CI)6.04 [0.30, 119.88]

    3.13 Duration of treatment > 1 week
3492Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.64, 1.31]

    3.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
61078Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.72, 1.16]

    3.15 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1100Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.49, 2.60]

    3.16 Iron supplementation >2 mg/kg/day in both groups
110Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    3.17 Iron supplementation > 2 mg/kg/day in neither group
2291Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.50, 1.38]

    3.18 PUFA >= 400 mg/100 ml milk
1266Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.50, 1.38]

    3.19 Vitamin A supplementation in both groups >= 1500 IU/day
135Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 4 Bronchopulmonary dysplasia among very low birth weight infants4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 All infants in all studies
4972Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.71, 1.13]

    4.2 Enteral
1266Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.50, 1.38]

    4.3 Parenteral with or without enteral
3706Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.70, 1.19]

    4.4 Parenteral with hypertonic enteral formulation at pharmacologic dose
1545Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.68, 1.21]

    4.5 Intravenous (with or without other routes of administration)
1545Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.68, 1.21]

    4.6 Excluding intravenous
3427Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.59, 1.30]

    4.7 Total dose of vitamin E <= 30 IU/kg/day
2392Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.59, 1.30]

    4.8 Total dose of vitamin E > 30 IU/kg/day
2580Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.68, 1.21]

    4.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2301Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.50, 1.38]

    4.10 Serum tocopherol level in the treatment group > 3.5 mg/dl
2671Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.70, 1.19]

    4.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
4972Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.71, 1.13]

    4.12 Duration of treatment <= 1 week
135Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.13 Duration of treatment > 1 week
2392Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.59, 1.30]

    4.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
4972Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.71, 1.13]

    4.15 Iron supplementation >2 mg/kg/day in both groups
110Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.16 Iron supplementation > 2 mg/kg/day in neither group
2291Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.50, 1.38]

    4.17 PUFA >= 400 mg/100 ml mik
1266Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.50, 1.38]

    4.18 Vitamin A supplementation in both groups >= 1500 IU/day
135Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 5 Bronchopulmonary dysplasia among surviving patients4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 All infants in all studies
4322Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.84, 1.58]

    5.2 Enteral
1101Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.63, 2.21]

    5.3 Enteral hypertonic formulation at pharmacologic dose
1101Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.63, 2.21]

    5.4 Parenteral with or without enteral
3221Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.80, 1.64]

    5.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
1135Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.55, 1.76]

    5.6 Excluding intravenous vitamin E administration
4322Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.84, 1.58]

    5.7 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
286Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.91, 2.02]

    5.8 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2236Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.70, 1.64]

    5.9 Serum tocopherol level in the treatment group <=3.5 mg/dl
3287Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.75, 1.74]

    5.10 Serum tocopherol level in the treatment group >3.5 mg/dl
135Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.82, 1.71]

    5.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
4322Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.84, 1.58]

    5.12 Duration of treatment <=1 week (7 days)
2186Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.64, 1.96]

    5.13 Duration of treatment > 1 week
2136Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.81, 1.71]

    5.14 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1135Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.55, 1.76]

    5.15 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
3187Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.87, 1.83]

    5.16 Iron supplementation > 2 mg/kg/day in both groups
151Risk Ratio (M-H, Fixed, 95% CI)6.04 [0.30, 119.88]

 6 Bronchopulmonary dysplasia among surviving very low birth weight infants2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 All infants in all studies
2236Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.70, 1.64]

    6.2 Enteral
1101Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.63, 2.21]

    6.3 Enteral hypertonic formulation at pharmacologic dose
1101Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.63, 2.21]

    6.4 Parenteral with or without enteral
1135Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.55, 1.76]

    6.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
1135Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.55, 1.76]

    6.6 Excluding intravenous vitamin E administration
2236Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.70, 1.64]

    6.7 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2236Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.70, 1.64]

    6.8 Serum tocopherol level in the treatment group <=3.5 mg/dl
2236Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.70, 1.64]

    6.9 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2236Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.70, 1.64]

    6.10 Duration of treatment <=1 week (7 days)
1135Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.55, 1.76]

    6.11 Duration of treatment > 1 week
1101Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.63, 2.21]

    6.12 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1135Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.55, 1.76]

    6.13 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
1101Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.63, 2.21]

 7 Radiographic signs of bronchopulmonary dysplasia persistent at 6 weeks - 2 months3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 All infants in all studies
3364Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.67, 1.46]

    7.2 Enteral
1138Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.51, 1.72]

    7.3 Parenteral with or without enteral
2226Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.62, 1.70]

    7.4 Parenteral with hypertonic enteral formulation at pharmacologic dose
2226Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.62, 1.70]

    7.5 Excluding intravenous vitamin E administration
3364Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.67, 1.46]

    7.6 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2264Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.61, 1.47]

    7.7 Total dose of vitamin E in the treatment group > 30 IU/kg/day
1100Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.49, 2.60]

    7.8 Serum tocopherol level in the treatment group <=3.5 mg/dl
1138Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.51, 1.72]

    7.9 Serum tocopherol level in the treatment group >3.5 mg/dl
2226Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.62, 1.70]

    7.10 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3364Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.67, 1.46]

    7.11 Duration of treatment > 1 week
3364Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.67, 1.46]

    7.12 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2264Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.61, 1.47]

    7.13 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1100Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.49, 2.60]

    7.14 Iron supplementation >2 mg/kg/day in neither group
1138Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.51, 1.72]

    7.15 PUFA >= 400 mg/100 ml milk
1138Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.51, 1.72]

 8 Radiographic signs of bronchopulmonary dysplasia at 6 weeks - 2 months among very low birth weight infants2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 All infants in all studies
2264Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.61, 1.47]

    8.2 Birth weight <= 1500 grams
2264Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.61, 1.47]

    8.3 Birth weight <= 1000 grams
154Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.72, 2.17]

    8.4 Birth weight > 1000 grams
184Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.09, 2.46]

    8.5 Enteral
1138Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.51, 1.72]

    8.6 Parenteral with or without enteral
1126Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.51, 1.83]

    8.7 Parenteral with hypertonic enteral formulation at pharmacologic dose
1126Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.51, 1.83]

    8.8 Excluding intravenous vitamin E administration
2264Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.61, 1.47]

    8.9 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2264Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.61, 1.47]

    8.10 Serum tocopherol level in the treatment group <=3.5 mg/dl
1138Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.51, 1.72]

    8.11 Serum tocopherol level in the treatment group >3.5 mg/dl
1126Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.51, 1.83]

    8.12 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2264Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.61, 1.47]

    8.13 Duration of treatment > 1 week
2264Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.61, 1.47]

    8.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2264Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.61, 1.47]

    8.15 Iron supplementation >2 mg/kg/day in neither group
1138Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.51, 1.72]

    8.16 PUFA >= 400 mg/100 ml milk
1138Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.51, 1.72]

 9 Patent ductus arteriosus6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 All infants in all studies
6976Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.93, 1.23]

    9.2 Parenteral with or without enteral
6976Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.93, 1.23]

    9.3 Parenteral with hypertonic enteral formulation at pharmacologic dose
4918Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.93, 1.25]

    9.4 Intravenous (with or without other routes of administration)
1545Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.91, 1.31]

    9.5 Excluding intravenous vitamin E administration
5431Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.83, 1.28]

    9.6 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
3184Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.75, 1.38]

    9.7 Total dose of vitamin E in the treatment group > 30 IU/kg/day
3792Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.93, 1.26]

    9.8 Serum tocopherol level in the treatment group <=3.5 mg/dl
258Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.69, 1.45]

    9.9 Serum tocopherol level in the treatment group >3.5 mg/dl
4918Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.93, 1.25]

    9.10 Onset of vitamin E supplementation in the treatment group within 48 hours of life
5947Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.93, 1.24]

    9.11 Duration of treatment > 1 week
5431Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.83, 1.28]

    9.12 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
4729Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.92, 1.25]

    9.13 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
2247Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.77, 1.42]

 10 Patent ductus arteriosus among very low birth weight infants4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 All infants in all studies
4847Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.93, 1.28]

    10.2 Birth weight <= 1500 grams
3700Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.92, 1.27]

    10.3 Birth weight <= 1000 grams
1147Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.55, 2.81]

    10.4 Parenteral with or without enteral
4847Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.93, 1.28]

    10.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
1545Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.91, 1.31]

    10.6 Intravenous with our without other routes of administration
1545Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.91, 1.31]

    10.7 Excluding intravenous administration
3302Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.78, 1.54]

    10.8 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2155Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.73, 1.52]

    10.9 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2692Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.93, 1.31]

    10.10 Serum tocopherol level in the treatment group <= 3.5 mg/dl
129Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.66, 1.87]

    10.11 Serum tocopherol level in the treatment group >3.5 mg/dl
3818Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.93, 1.29]

    10.12 Onset of vitamin E supplementation in the treatment group within 48 hours of life
4847Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.93, 1.28]

    10.13 Duration of treatment > 1 week
3302Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.78, 1.54]

    10.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
3700Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.92, 1.27]

    10.15 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1147Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.55, 2.81]

 11 Patent ductus arteriosus among surviving patients (at 10 days-10 weeks)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 All infants in all studies
3271Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.70, 1.38]

    11.2 Enteral
1101Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.35, 2.28]

    11.3 Enteral hypertonic formulation at pharmacologic doses
1101Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.35, 2.28]

    11.4 Parenteral with or without enteral
2170Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.70, 1.44]

    11.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
1135Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.54, 1.31]

    11.6 Excluding intravenous administration
3271Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.70, 1.38]

    11.7 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
135Risk Ratio (M-H, Fixed, 95% CI)1.62 [0.84, 3.12]

    11.8 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2236Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.57, 1.27]

    11.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2236Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.57, 1.27]

    11.10 Serum tocopherol level in the treatment group >3.5 mg/dl
135Risk Ratio (M-H, Fixed, 95% CI)1.62 [0.84, 3.12]

    11.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3271Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.70, 1.38]

    11.12 Duration of treatment <= 1 week (7 days)
1135Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.54, 1.31]

    11.13 Duration of treatment > 1 week
2136Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.72, 2.14]

    11.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2136Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.72, 2.14]

    11.15 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1135Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.54, 1.31]

 12 Patent ductus arteriosus among surviving very low birth infants (at 10 days-10 weeks)2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 All infants in all studies
2236Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.57, 1.27]

    12.2 Birth weight <= 1500 grams
2236Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.57, 1.27]

    12.3 Enteral
1101Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.35, 2.28]

    12.4 Enteral hypertonic formulation at pharmacologic doses
1101Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.35, 2.28]

    12.5 Parenteral with or without enteral
1135Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.54, 1.31]

    12.6 Parenteral with hypertonic enteral formulation at pharmacologic dose
1135Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.54, 1.31]

    12.7 Excluding intravenous administration
2236Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.57, 1.27]

    12.8 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2236Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.57, 1.27]

    12.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2236Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.57, 1.27]

    12.10 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2236Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.57, 1.27]

    12.11 Duration of treatment <= 1 week (7 days)
1135Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.54, 1.31]

    12.12 Duration of treatment > 1 week
1101Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.35, 2.28]

    12.13 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
1101Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.35, 2.28]

    12.14 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1135Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.54, 1.31]

 13 Patent ductus arteriosus requiring treatment3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    13.1 All infants in all studies
3675Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.79, 1.31]

    13.2 Enteral
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 14.55]

    13.3 Parenteral with or without enteral
2645Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.79, 1.32]

    13.4 Parenteral with hypertonic enteral formulation at pharmacologic dose
2645Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.79, 1.32]

    13.5 Intravenous (with or without other routes of administration)
1545Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.61]

    13.6 Excluding intravenous treatment
2130Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.32, 0.97]

    13.7 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
1545Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.61]

    13.8 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2645Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.79, 1.32]

    13.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 14.55]

    13.10 Serum tocopherol level in the treatment group >3.5 mg/dl
2645Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.79, 1.32]

    13.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2645Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.79, 1.32]

    13.12 Duration of treatment > 1 week
2130Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.32, 0.97]

    13.13 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2575Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.60]

    13.14 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1100Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.31, 0.95]

    13.15 Iron supplementation > 2 mg/kg/day in both groups
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 14.55]

 14 Patent ductus arteriosus requiring treatment among very low birth weight infants2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 All infants in all studies
2575Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.60]

    14.2 Birth weight <= 1500 grams
2575Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.60]

    14.3 Enteral
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 14.55]

    14.4 Parenteral with or without enteral
1545Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.61]

    14.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
1545Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.61]

    14.6 Intravenous (with or without other routes of administration)
1545Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.61]

    14.7 Excluding intravenous treatment
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 14.55]

    14.8 Total dose of vitamin E in the treatment group > 30 IU/kg/day
1545Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.61]

    14.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 14.55]

    14.10 Serum tocopherol level in the treatment group >3.5 mg/dl
1545Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.61]

    14.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
1545Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.61]

    14.12 Onset of treatment after 48 hours of life
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 14.55]

    14.13 Duration of treatment > 1 week
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 14.55]

    14.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2575Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.60]

    14.15 Iron supplementation > 2 mg/kg/day in both groups
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 14.55]

 15 Sepsis after study entry4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    15.1 All infants in all studies
41009Risk Ratio (M-H, Fixed, 95% CI)1.52 [1.13, 2.04]

    15.2 Enteral
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.36, 2.75]

    15.3 Parenteral with or without enteral
3979Risk Ratio (M-H, Fixed, 95% CI)1.57 [1.15, 2.14]

    15.4 Parenteral with hypertonic enteral formulation at pharmacologic dose
3979Risk Ratio (M-H, Fixed, 95% CI)1.57 [1.15, 2.14]

    15.5 Intravenous
2832Risk Ratio (M-H, Fixed, 95% CI)1.54 [1.07, 2.21]

    15.6 Excluding intravenous vitamin E administration
2177Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.90, 2.46]

    15.7 Total dose of vitamin E in the treatment group > 30 IU/kg/day
3979Risk Ratio (M-H, Fixed, 95% CI)1.57 [1.15, 2.14]

    15.8 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2317Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.45, 1.77]

    15.9 Serum tocopherol level in the treatment group > 3.5 mg/dl
2692Risk Ratio (M-H, Fixed, 95% CI)1.72 [1.24, 2.40]

    15.10 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3979Risk Ratio (M-H, Fixed, 95% CI)1.57 [1.15, 2.14]

    15.11 Onset of treatment after 48 hours of life
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.36, 2.75]

    15.12 Duration of treatment > 1 week
3464Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.82, 1.96]

    15.13 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
3862Risk Ratio (M-H, Fixed, 95% CI)1.48 [1.05, 2.08]

    15.14 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1147Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.93, 2.98]

    15.15 Iron supplementation > 2mg/kg/day in both groups
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.36, 2.75]

 16 Sepsis after study entry among very low birth weight infants5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    16.1 All infants in all studies
4807Risk Ratio (M-H, Fixed, 95% CI)1.53 [1.13, 2.08]

    16.2 Birth weight <= 1500 grams
2575Risk Ratio (M-H, Fixed, 95% CI)1.65 [1.13, 2.40]

    16.3 Birth weight <= 1000 grams
2232Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.79, 2.22]

    16.4 Enteral
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.36, 2.75]

    16.5 Parental with or without enteral
3777Risk Ratio (M-H, Fixed, 95% CI)1.59 [1.15, 2.18]

   16.6 Parenteral with hypertonic enteral formulation at pharmacologic dose
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    16.7 Intravenous
2630Risk Ratio (M-H, Fixed, 95% CI)1.56 [1.07, 2.27]

    16.8 Excluding intravenous vitamin E supplementation
3326Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.86, 2.12]

    16.9 Total dose of vitamin E supplementation in the treatment group > 30 IU/kd/day
3777Risk Ratio (M-H, Fixed, 95% CI)1.59 [1.15, 2.18]

    16.10 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2115Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.33, 1.64]

    16.11 Serum tocopherol level in the treatment group > 3.5 mg/dl
2692Risk Ratio (M-H, Fixed, 95% CI)1.72 [1.24, 2.40]

    16.12 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3777Risk Ratio (M-H, Fixed, 95% CI)1.59 [1.15, 2.18]

    16.13 Onset of treatment after 48 hours of life
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.36, 2.75]

    16.14 Duration of treatment > 1 week
3262Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.79, 1.99]

    16.15 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
3660Risk Ratio (M-H, Fixed, 95% CI)1.49 [1.04, 2.13]

    16.16 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1147Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.93, 2.98]

    16.17 Iron supplementation > 2mg/kg/day in both groups
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.36, 2.75]

 17 Sepsis after study entry among very low birth weight infants treated for > 1 week4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    17.1 All infants in all studies
4726Risk Ratio (M-H, Fixed, 95% CI)1.63 [1.17, 2.26]

    17.2 Birth weight <= 1500 grams
3641Risk Ratio (M-H, Fixed, 95% CI)1.79 [1.27, 2.53]

    17.3 Birth weight <= 1000 grams
2232Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.79, 2.22]

    17.4 Enteral
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.36, 2.75]

    17.5 Parental with or without enteral
3696Risk Ratio (M-H, Fixed, 95% CI)1.70 [1.20, 2.41]

    17.6 Intravenous
2549Risk Ratio (M-H, Fixed, 95% CI)1.72 [1.11, 2.66]

    17.7 Excluding intravenous vitamin E supplementation
2177Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.90, 2.46]

    17.8 Total dose of vitamin E supplementation in the treatment group > 30 IU/kd/day
3696Risk Ratio (M-H, Fixed, 95% CI)1.70 [1.20, 2.41]

    17.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2115Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.33, 1.64]

    17.10 Serum tocopherol level in the treatment group > 3.5 mg/dl
2611Risk Ratio (M-H, Fixed, 95% CI)1.90 [1.31, 2.75]

    17.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3696Risk Ratio (M-H, Fixed, 95% CI)1.70 [1.20, 2.41]

    17.12 Onset of treatment after 48 hours of life
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.36, 2.75]

    17.13 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
3579Risk Ratio (M-H, Fixed, 95% CI)1.61 [1.08, 2.41]

    17.14 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1147Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.93, 2.98]

    17.15 Iron supplementation > 2mg/kg/day in both groups
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.36, 2.75]

 18 Sepsis among surviving very low birth weight infants2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    18.1 All infants in all studies
2284Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.48, 1.62]

    18.2 Enteral
1149Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.36, 2.67]

    18.3 Enteral hypertonic formulation, at pharmacologic doses
1149Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.36, 2.67]

    18.4 Parenteral with or without enteral
1135Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.38, 1.77]

    18.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
1135Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.38, 1.77]

    18.6 Excluding intravenous vitamin E administration
2284Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.48, 1.62]

    18.7 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2284Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.48, 1.62]

    18.8 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2284Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.48, 1.62]

    18.9 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2284Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.48, 1.62]

    18.10 Duration of treatment <= 1 week
1135Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.38, 1.77]

    18.11 Duration of treatment > 1 week
1149Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.36, 2.67]

    18.12 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
1149Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.36, 2.67]

    18.13 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1135Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.38, 1.77]

 19 Germinal matrix/intraventricular hemorrhage (grades I-IV)7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    19.1 All infants in all studies
71755Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.73, 0.99]

    19.2 Birth weight >= 1000 grams
1760Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.78, 2.14]

    19.3 Parenteral with or without enteral
71755Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.72, 0.98]

    19.4 Parenteral with hypertonic enteral formulation at pharmacologic dose
41448Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.78, 1.12]

    19.5 Intravenous (with or without other routes of administration)
21201Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.82, 1.28]

    19.6 Excluding intravenous administration
5554Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.58, 0.87]

    19.7 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
3307Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.50, 0.85]

    19.8 Total dose of vitamin E in the treatment group > 30 IU/kg/day
41448Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.78, 1.12]

    19.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2515Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.67, 1.00]

    19.10 Serum tocopherol level in the treatment group >3.5 mg/dl
51240Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.68, 1.08]

    19.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
71755Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.73, 0.99]

    19.12 Duration of treatment <= 1 week
3307Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.50, 0.85]

    19.13 Duration of treatment > 1 week
3534Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.71, 1.09]

    19.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
51508Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.73, 1.03]

    19.15 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
2247Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.55, 1.04]

 20 Germinal matrix/intraventricular hemorrhage among very low birth weight infants3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    20.1 All infants in all studies
3777Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.75, 1.18]

    20.2 Birth weight <= 1500 grams
1545Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.68, 1.46]

    20.3 Birth weight <= 1000 grams
3377Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.69, 1.11]

    20.4 Birth weight 1001-1500 grams
1393Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.69, 2.11]

    20.5 Parenteral with or without enteral
3777Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.75, 1.18]

    20.6 Parenteral with hypertonic enteral formulation at pharmacologic dose
3777Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.75, 1.18]

    20.7 Intravenous (with or without other routes of administration)
2630Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.81, 1.40]

    20.8 Excluding intravenous administration
1147Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.46, 1.04]

    20.9 Total dose of vitamin E in the treatment group > 30 IU/kg/day
3777Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.75, 1.18]

    20.10 Serum tocopherol level in the treatment group <= 3.5 mg/dl
185Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.85, 1.68]

    20.11 Serum tocopherol level in the treatment group >3.5 mg/dl
2692Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.65, 1.14]

    20.12 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3777Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.75, 1.18]

    20.13 Duration of treatment > 1 week
2232Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.69, 1.17]

    20.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2630Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.81, 1.40]

    20.15 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1147Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.46, 1.04]

 21 Germinal matrix/intraventricular hemorrhage among patients with negative initial ultrasonogram1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    21.1 All infants in all studies
1210Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.40, 0.80]

 22 Germinal matrix/intraventricular hemorrhage among survivors3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    22.1 All infants in all studies
3335Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.70, 1.60]

    22.2 Enteral
1149Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.68, 2.36]

    22.3 Enteral hypertonic formulation at pharmacologic doses
1149Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.68, 2.36]

    22.4 Parenteral with or without enteral
2186Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.52, 1.58]

    22.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
1135Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.49, 1.57]

    22.6 Excluding intravenous administration
3335Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.70, 1.60]

    22.7 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
151Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.19, 7.98]

    22.8 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2284Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.69, 1.60]

    22.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
3335Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.70, 1.60]

    22.10 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3335Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.70, 1.60]

    22.11 Duration of treatment <= 1 week
2186Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.52, 1.58]

    22.12 Duration of treatment > 1 week
1149Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.68, 2.36]

    22.13 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2200Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.70, 2.28]

    22.14 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1135Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.49, 1.57]

 23 Germinal matrix/intraventricular hemorrhage among surviving very low birth weight infants3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    23.1 All infants in all studies
2284Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.69, 1.60]

    23.2 Birth weight <= 1500 grams
2284Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.69, 1.60]

    23.3 Birth weight <= 1000 grams
149Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.40, 2.17]

    23.4 Enteral
1149Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.68, 2.36]

    23.5 Enteral hypertonic formulation at pharmacologic doses
1149Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.68, 2.36]

    23.6 Parenteral with or without enteral
1135Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.49, 1.57]

    23.7 Parenteral with hypertonic enteral formulation at pharmacologic dose
1135Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.49, 1.57]

    23.8 Excluding intravenous administration
2284Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.69, 1.60]

    23.9 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2284Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.69, 1.60]

    23.10 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2284Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.69, 1.60]

    23.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2284Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.69, 1.60]

    23.12 Duration of treatment <= 1 week
2186Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.52, 1.58]

    23.13 Duration of treatment > 1 week
1149Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.68, 2.36]

    23.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2200Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.70, 2.28]

    23.15 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1135Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.49, 1.57]

 24 Severe intraventricular hemorrhage (grade III-IV)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    24.1 All infants in all studies
3644Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.60, 1.38]

    24.2 Parenteral with or without enteral
3644Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.60, 1.38]

    24.3 Parenteral with hypertonic enteral formulation at pharmacologic dose
2434Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.67, 1.60]

    24.4 Intravenous (with or without other routes of administration)
1287Risk Ratio (M-H, Fixed, 95% CI)1.61 [0.88, 2.96]

    24.5 Excluding intravenous vitamin E supplementation
2357Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.28, 0.94]

    24.6 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
1210Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.06, 1.42]

    24.7 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2434Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.67, 1.60]

    24.8 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2497Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.70, 2.05]

    24.9 Serum tocopherol level in the treatment group > 3.5 mg/dl
1147Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.30, 1.15]

    24.10 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3644Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.60, 1.38]

    24.11 Duration of treatment <= 1 week
1210Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.06, 1.42]

    24.12 Duration of treatment > 1 week
2434Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.67, 1.60]

    24.13 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2497Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.70, 2.05]

    24.14 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1147Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.30, 1.15]

 25 Severe intraventricular hemorrhage among very low birth weight infants2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    25.1 All infants in all studies
2434Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.67, 1.60]

    25.2 Birth weight <= 1000 grams
2232Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.63, 1.78]

    25.3 Parenteral with or without enteral
2434Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.67, 1.60]

    25.4 Parenteral with hypertonic enteral formulation at pharmacologic dose
2434Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.67, 1.60]

    25.5 Intravenous (with or without other routes of administration)
1287Risk Ratio (M-H, Fixed, 95% CI)1.61 [0.88, 2.96]

    25.6 Excluding intravenous vitamin E supplementation
1147Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.30, 1.15]

    25.7 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2434Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.67, 1.60]

    25.8 Serum tocopherol level in the treatment group <= 3.5 mg/dl
1287Risk Ratio (M-H, Fixed, 95% CI)1.61 [0.88, 2.96]

    25.9 Serum tocopherol level in the treatment group > 3.5 mg/dl
1147Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.30, 1.15]

    25.10 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2434Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.67, 1.60]

    25.11 Duration of treatment > 1 week
2434Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.67, 1.60]

    25.12 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
1287Risk Ratio (M-H, Fixed, 95% CI)1.61 [0.88, 2.96]

    25.13 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1147Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.30, 1.15]

 26 Severe intraventricular hemorrhage among surviving very low birth weight infants3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    26.1 All infants in all studies
3320Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.41, 1.39]

    26.2 Birth weight <= 1500 grams
2236Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.62, 2.66]

    26.3 Birth weight <= 1000 grams
2133Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.10, 0.92]

    26.4 Enteral
1101Risk Ratio (M-H, Fixed, 95% CI)1.40 [0.62, 3.19]

    26.5 Enteral hypertonic formulation at pharmacologic dose
1101Risk Ratio (M-H, Fixed, 95% CI)1.40 [0.62, 3.19]

    26.6 Parenteral with or without enteral
2219Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.14, 1.02]

    26.7 Parenteral with hypertonic enteral formulation at pharmacologic dose
2219Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.14, 1.02]

    26.8 Excluding intravenous vitamin E supplementation
3320Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.41, 1.39]

    26.9 Total dose of vitamin E in the treatment group > 30 IU/kg/day
3320Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.41, 1.39]

    26.10 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2236Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.62, 2.66]

    26.11 Serum tocopherol level in the treatment group > 3.5 mg/dl
184Risk Ratio (M-H, Fixed, 95% CI)0.2 [0.05, 0.85]

    26.12 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3320Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.41, 1.39]

    26.13 Duration of treatment <= 1 week
1135Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.21, 4.71]

    26.14 Duration of treatment > 1 week
2185Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.37, 1.39]

    26.15 Total dose of vitamin E in the control group <= 10 mg/100 kcal
1101Risk Ratio (M-H, Fixed, 95% CI)1.40 [0.62, 3.19]

    26.16 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
2219Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.14, 1.02]

 27 Parenchymal hemorrhage (grade IV)2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    27.1 All infants in all studies
2497Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.69, 2.67]

    27.2 Parenteral with or without enteral
2497Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.69, 2.67]

    27.3 Parenteral with hypertonic enteral formulation at pharmacologic dose
1287Risk Ratio (M-H, Fixed, 95% CI)2.4 [1.02, 5.66]

    27.4 Intravenous (with or without other routes of administration)
1287Risk Ratio (M-H, Fixed, 95% CI)2.4 [1.02, 5.66]

    27.5 Excluding intravenous vitamin E administration
1210Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.06, 1.42]

    27.6 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
1210Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.06, 1.42]

    27.7 Total dose of vitamin E in the treatment group > 30 IU/kg/day
1287Risk Ratio (M-H, Fixed, 95% CI)2.4 [1.02, 5.66]

    27.8 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2497Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.69, 2.67]

    27.9 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2497Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.69, 2.67]

    27.10 Duration of treatment <= 1 week
1210Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.06, 1.42]

    27.11 Duration of treatment > 1 week
1287Risk Ratio (M-H, Fixed, 95% CI)2.4 [1.02, 5.66]

    27.12 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2497Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.69, 2.67]

 28 Parenchymal hemorrhage among very low birth weight infants1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    28.1 All infants in all studies
185Risk Ratio (M-H, Fixed, 95% CI)9.21 [1.22, 69.58]

    28.2 Birth weight <= 1000 grams
185Risk Ratio (M-H, Fixed, 95% CI)9.21 [1.22, 69.58]

 29 Parenchymal hemorrhage among patients with negative initial ultrasonogram1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    29.1 All infants in all studies
1210Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.06, 1.42]

 30 Parenchymal hemorrhage (Grade IV) among surviving very low birth weight infants2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    30.1 All infants in all studies
2236Risk Ratio (M-H, Fixed, 95% CI)1.46 [0.46, 4.66]

    30.2 Birth weight <= 1500 grams
2236Risk Ratio (M-H, Fixed, 95% CI)1.46 [0.46, 4.66]

    30.3 Birth weight <= 1000 grams
149Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.01, 6.41]

    30.4 Enteral
1101Risk Ratio (M-H, Fixed, 95% CI)2.04 [0.54, 7.71]

    30.5 Enteral hypertonic formulation at pharmacologic dose
1101Risk Ratio (M-H, Fixed, 95% CI)2.04 [0.54, 7.71]

    30.6 Parenteral with or without enteral
1135Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.92]

    30.7 Parenteral with hypertonic enteral formulation at pharmacologic dose
1135Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.92]

    30.8 Excluding intravenous vitamin E supplementation
2236Risk Ratio (M-H, Fixed, 95% CI)1.46 [0.46, 4.66]

    30.9 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2236Risk Ratio (M-H, Fixed, 95% CI)1.46 [0.46, 4.66]

    30.10 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2236Risk Ratio (M-H, Fixed, 95% CI)1.46 [0.46, 4.66]

    30.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2236Risk Ratio (M-H, Fixed, 95% CI)1.46 [0.46, 4.66]

    30.12 Duration of treatment <= 1 week
1135Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.92]

    30.13 Duration of treatment > 1 week
1101Risk Ratio (M-H, Fixed, 95% CI)2.04 [0.54, 7.71]

    30.14 Total dose of vitamin E in the control group <= 10 mg/100 kcal
1101Risk Ratio (M-H, Fixed, 95% CI)2.04 [0.54, 7.71]

    30.15 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1135Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.92]

 31 Retrolental fibroplasia/retinopathy of prematurity7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    31.1 All infants in all studies
71342Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.75, 1.09]

    31.2 Enteral
1268Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.35, 1.31]

    31.3 Parenteral with or without enteral
5973Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.75, 1.11]

    31.4 Parenteral with hypertonic enteral formulation at pharmacologic dose
3932Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.77, 1.13]

    31.5 Intravenous (with or without other routes of administration)
2832Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.75, 1.11]

    31.6 Excluding intravenous vitamin E supplementation
5510Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.50, 1.43]

    31.7 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
3374Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.35, 1.31]

    31.8 Total dose of vitamin E in the treatment group > 30 IU/kg/day
4967Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.77, 1.13]

    31.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
4641Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.59, 1.28]

    31.10 Serum tocopherol level in the treatment group > 3.5 mg/dl
3700Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.74, 1.13]

    31.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
6796Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.65, 1.32]

    31.12 Duration of treatment <= 1 week
3141Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    31.13 Duration of treatment > 1 week
3655Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.65, 1.32]

    31.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
61241Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.73, 1.07]

    31.15 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1100Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.53, 3.02]

    31.16 Iron supplementation >2 mg/kg in both groups
261Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    31.17 Iron supplementation > 2 mg/kg in neither group
2293Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.35, 1.31]

    31.18 Vitamin A supplementation in both groups >= 1500 IU/day
125Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    31.19 PUFA >= 400 mg/100 ml milk
1269Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.35, 1.32]

 32 Retrolental fibroplasia/retinopathy of prematurity among very low birth weight infants5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    32.1 All infants in all studies
5975Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.73, 1.07]

    32.2 Birth weight <= 1500 grams
4890Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.70, 1.05]

    32.3 Birth weight <= 1000 grams
185Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.60, 2.53]

    32.4 Enteral
1268Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.35, 1.31]

    32.5 Parenteral with or without enteral
4707Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.75, 1.12]

    32.6 Parenteral with hypertonic enteral formulation at pharmacologic dose
3672Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.75, 1.12]

    32.7 Intravenous (with or without other routes of administration)
2630Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.74, 1.13]

    32.8 Excluding intravenous vitamin E supplementation
3345Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.45, 1.24]

    32.9 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
1268Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.35, 1.31]

    32.10 Total dose of vitamin E in the treatment group > 30 IU/kg/day
4707Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.75, 1.12]

    32.11 Serum tocopherol level in the treatment group <= 3.5 mg/dl
3388Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.53, 1.40]

    32.12 Serum tocopherol level in the treatment group > 3.5 mg/dl
2587Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.72, 1.10]

    32.13 Onset of vitamin E supplementation in the treatment group within 48 hours of life
5975Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.73, 1.07]

    32.14 Duration of treatment <= 1 week
135Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    32.15 Duration of treatment > 1 week
3395Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.58, 1.32]

    32.16 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
4933Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.72, 1.08]

    32.17 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
142Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.42, 1.96]

    32.18 Iron supplementation >2 mg/kg in both groups
110Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    32.19 Iron supplementation > 2 mg/kg in neither group
2293Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.35, 1.31]

    32.20 Vitamin A supplementation in both groups >= 1500 IU/day
135Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    32.21 PUFA >= 400 mg/100 ml milk
1268Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.35, 1.31]

 33 Retrolental fibroplasia/retinopathy of prematurity among infants examined/survivors8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    33.1 All infants in all studies
81666Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.78, 1.03]

    33.2 Enteral
2354Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.66, 1.23]

    33.3 Enteral hypertonic formulation at pharmacologic doses
1129Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.72, 1.43]

    33.4 Parenteral with or without enteral
51261Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.77, 1.05]

    33.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
51261Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.77, 1.05]

    33.6 Intravenous (with or without other routes of administration)
2953Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.70, 1.04]

    33.7 Excluding intravenous supplementation
6713Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.79, 1.15]

    33.8 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2324Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.45, 1.22]

    33.9 Total dose of vitamin E in the treatment group > 30 IU/kg/day
51291Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.80, 1.06]

    33.10 Serum tocopherol level in the treatment group <= 3.5 mg/dl
4687Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.80, 1.15]

    33.11 Serum tocopherol level in the treatment group > 3.5 mg/dl
3928Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.69, 1.04]

    33.12 Onset of vitamin E supplementation in the treatment group within 48 hours of life
71615Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.78, 1.03]

    33.13 Duration of treatment <= 1 week
1135Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.82, 1.28]

    33.14 Duration of treatment > 1 week
61480Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.74, 1.03]

    33.15 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
51406Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.73, 1.02]

    33.16 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
2209Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.83, 1.31]

    33.17 Iron supplementation >2 mg/kg in both groups
151Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    33.18 Iron supplementation > 2 mg/kg in neither group
1225Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.36, 1.35]

    33.19 PUFA >= 400 mg/100 ml milk
1225Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.36, 1.35]

 34 Retrolental fibroplasia/retinopathy of prematurity among very low birth weight infants examined7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    34.1 All infants in all studies
71090Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.82, 1.07]

    34.2 Birth weight <= 1500 grams
61054Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.81, 1.06]

    34.3 Birth weight <= 1000 grams
384Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.81, 1.29]

    34.4 Birth weight > 1000 grams
3181Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.76, 1.42]

    34.5 Enteral
2354Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.66, 1.23]

    34.6 Enteral hypertonic formulation at pharmacologic doses
1129Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.72, 1.43]

    34.7 Parenteral with or without enteral
5736Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.82, 1.09]

    34.8 Parenteral with hypertonic enteral formulation at pharmacologic dose
5736Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.82, 1.09]

    34.9 Intravenous (with or without other routes of administration)
2460Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.77, 1.12]

    34.10 Excluding intravenous supplementation
5630Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.78, 1.13]

    34.11 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
1225Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.36, 1.35]

    34.12 Total dose of vitamin E in the treatment group > 30 IU/kg/day
6865Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.84, 1.09]

    34.13 Serum tocopherol level in the treatment group <= 3.5 mg/dl
4525Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.82, 1.18]

    34.14 Serum tocopherol level in the treatment group > 3.5 mg/dl
3565Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.74, 1.08]

    34.15 Onset of vitamin E supplementation in the treatment group within 48 hours of life
71090Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.82, 1.07]

    34.16 Duration of treatment <= 1 week
1135Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.82, 1.28]

    34.17 Duration of treatment > 1 week
5531Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.72, 1.18]

    34.18 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
5913Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.78, 1.07]

    34.19 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
2177Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.81, 1.26]

    34.20 Iron supplementation > 2 mg/kg in neither group
1225Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.36, 1.35]

    34.21 PUFA >= 400 mg/100 ml milk
1225Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.36, 1.35]

 35 Severe retrolental fibroplasia/retinopathy of prematurity (grade 3 or worse)8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    35.1 All infants in all studies
61565Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.41, 1.25]

    35.2 Enteral
129Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    35.3 Parenteral with or without enteral
51297Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.39, 1.37]

    35.4 Parenteral with hypertonic enteral formulation at pharmacologic dose
41268Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.41, 1.37]

    35.5 Intravenous (with or without other routes of administration)
21042Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.43, 1.72]

    35.6 Excluding intravenous vitamin E supplementation
4523Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.20, 1.35]

    35.7 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
3423Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.15, 1.64]

    35.8 Total dose of vitamin E in the treatment group > 30 IU/kg/day
31142Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.41, 1.52]

    35.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
3584Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.53, 2.31]

    35.10 Serum tocopherol level in the treatment group > 3.5 mg/dl
3981Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.16, 1.00]

    35.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
81882Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.40, 1.14]

    35.12 Duration of treatment > 1 week
61565Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.41, 1.25]

    35.13 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
51465Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.42, 1.35]

    35.14 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1100Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.04, 3.49]

    35.15 Iron supplementation > 2 mg/kg in neither group
1268Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.14, 2.42]

    35.16 PUFA >= 400 mg/100 ml milk
1268Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.14, 2.42]

 36 Severe retrolental fibroplasia/retinopathy of prematurity (grade >= 3) among very low birth weight infants6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    36.1 All infants in all studies
6974Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.32, 1.08]

    36.2 Birth weight <= 1500 grams
5889Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.18, 0.87]

    36.3 Birth weight <= 1000 grams
294Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.35, 2.10]

    36.4 Enteral
1268Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.14, 2.42]

    36.5 Parenteral with or without enteral
5706Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.30, 1.16]

    36.6 Parenteral with hypertonic enteral formulation at pharmacologic dose
4677Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.30, 1.16]

    36.7 Intravenous (with or without other routes of administration)
2509Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.34, 1.61]

    36.8 Excluding intravenous vitamin E supplementation
4465Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.16, 1.16]

    36.9 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
3423Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.19, 1.64]

    36.10 Total dose of vitamin E in the treatment group > 30 IU/kg/day
3551Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.29, 1.27]

    36.11 Serum tocopherol level in the treatment group <= 3.5 mg/dl
3382Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.44, 2.32]

    36.12 Serum tocopherol level in the treatment group > 3.5 mg/dl
3592Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.13, 0.87]

    36.13 Onset of vitamin E supplementation in the treatment group within 48 hours of life
6974Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.32, 1.08]

    36.14 Duration of treatment > 1 week
5550Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.36, 1.43]

    36.15 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
5932Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.35, 1.25]

    36.16 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
142Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.38]

    36.17 Iron supplementation > 2 mg/kg in neither group
1268Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.14, 2.42]

    36.18 PUFA >= 400 mg/100 ml milk
1268Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.14, 2.42]

 37 Severe retrolental fibroplasia/retinopathy of prematurity (grade 3 or worse) among patients examined7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    37.1 All infants in all studies
71587Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.40, 1.12]

    37.2 Enteral
2326Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.10, 1.13]

    37.3 Enteral hypertonic formulation at pharmacologic doses
1101Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 1.63]

    37.4 Parenteral or both parenteral and enteral
51261Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.46, 1.44]

    37.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
41162Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.47, 1.60]

    37.6 Intravenous (with or without other routes of administration)
2953Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.42, 1.66]

    37.7 Excluding intravenous vitamin E supplementation
5634Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.24, 1.13]

    37.8 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2324Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.20, 1.69]

    37.9 Total dose of vitamin E in the treatment group > 30 IU/kg/day
51263Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.39, 1.26]

    37.10 Serum tocopherol level in the treatment group <= 3.5 mg/dl
4659Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.48, 1.69]

    37.11 Serum tocopherol level in the treatment group > 3.5 mg/dl
3928Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.15, 0.98]

    37.12 Onset of vitamin E supplementation in the treatment group within 48 hours of life
71587Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.40, 1.12]

    37.13 Duration of treatment <= 1 week (7 days)
1135Risk Ratio (M-H, Fixed, 95% CI)2.96 [0.32, 27.71]

    37.14 Duration of treatment > 1 week
5697Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.39, 1.26]

    37.15 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
51378Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.36, 1.10]

    37.16 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
2209Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.25, 3.89]

    37.17 Iron supplementation > 2 mg/kg in neither group
1225Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.15, 2.52]

    37.18 PUFA >= 400 mg/100 ml milk
1225Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.15, 2.52]

 38 Severe retrolental fibroplasia/retinopathy of prematurity among very low birth weight infants examined7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    38.1 All infants in all studies
71062Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.34, 1.00]

    38.2 Birth weight <= 1500 grams
61026Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.22, 0.85]

    38.3 Birth weight <= 1000 grams
394Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.48, 2.19]

    38.4 Birth weight > 1000 grams
3181Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.02, 8.39]

    38.5 Enteral
2326Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.10, 1.13]

    38.6 Enteral hypertonic formulation at pharmacologic doses
1101Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 1.63]

    38.7 Parenteral or both parenteral and enteral
5736Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.38, 1.28]

    38.8 Parenteral with hypertonic enteral formulation at pharmacologic dose
5736Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.38, 1.28]

    38.9 Intravenous (with or without other routes of administration)
2460Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.35, 1.52]

    38.10 Excluding intravenous vitamin E supplementation
5602Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.22, 1.04]

    38.11 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2324Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.20, 1.69]

    38.12 Total dose of vitamin E in the treatment group > 30 IU/kg/day
5738Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.32, 1.09]

    38.13 Serum tocopherol level in the treatment group <= 3.5 mg/dl
4497Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.42, 1.61]

    38.14 Serum tocopherol level in the treatment group > 3.5 mg/dl
3565Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.13, 0.88]

    38.15 Onset of vitamin E supplementation in the treatment group within 48 hours of life
71062Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.34, 1.00]

    38.16 Duration of treatment <= 1 week (7 days)
1135Risk Ratio (M-H, Fixed, 95% CI)2.96 [0.32, 27.71]

    38.17 Duration of treatment > 1 week
5503Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.30, 1.07]

    38.18 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
5885Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.31, 1.00]

    38.19 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
2177Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.19, 2.88]

    38.20 Iron supplementation > 2 mg/kg in neither group
1225Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.15, 2.52]

    38.21 PUFA >= 400 mg/100 ml milk
1225Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.15, 2.52]

 39 Retinal detachment among surviving infants3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    39.1 All infants in all studies
3432Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.09]

    39.2 Enteral
1101Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    39.3 Enteral hypertonic formulation at pharmacologic doses
1101Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    39.4 Parenteral with or without enteral
2331Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.09]

    39.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
2331Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.09]

    39.6 Excluding intravenous vitamin E supplementation
3432Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.09]

    39.7 Total dose of vitamin E in the treatment group > 30 IU/kg/day
3432Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.09]

    39.8 Serum tocopherol level in the treatment group <= 3.5 mg/dl
3432Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.09]

    39.9 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3432Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.09]

    39.10 Duration of treatment <= 1 week (7 days)
1135Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    39.11 Duration of treatment > 1 week
2297Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.09]

    39.12 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2297Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.09]

    39.13 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1135Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 40 Retinal detachment among surviving very low birth weight infants3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    40.1 All infants in all studies
3321Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.07, 15.84]

    40.2 Birth weight <= 1500 grams
2236Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    40.3 Birth weight <= 1000 grams
2134Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.07, 15.84]

    40.4 Enteral
1101Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    40.5 Enteral hypertonic formulation at pharmacologic doses
1101Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    40.6 Parenteral with or without enteral
2220Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.07, 15.84]

    40.7 Parenteral with hypertonic enteral formulation at pharmacologic dose
2220Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.07, 15.84]

    40.8 Excluding intravenous vitamin E supplementation
3321Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.07, 15.84]

    40.9 Total dose of vitamin E in the treatment group > 30 IU/kg/day
3321Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.07, 15.84]

    40.10 Serum tocopherol level in the treatment group <= 3.5 mg/dl
3321Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.07, 15.84]

    40.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3321Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.07, 15.84]

    40.12 Duration of treatment <= 1 week
1135Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    40.13 Duration of treatment > 1 week
2186Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.07, 15.84]

    40.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2186Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.07, 15.84]

    40.15 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1135Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 41 Cicatricial retrolental fibroplasia, any stage, among patients examined after discharge5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    41.1 All infants in all studies
51052Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.52, 1.27]

    41.2 Enteral
1101Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.13, 1.09]

    41.3 Enteral hypertonic formulation at pharmacologic doses
1101Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.13, 1.09]

    41.4 Parenteral with or without enteral
4951Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.60, 1.62]

    41.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
4951Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.60, 1.62]

    41.6 Intravenous (with or without other routes of administration)
2778Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.55, 2.22]

    41.7 Excluding intravenous vitamin E supplementation
3274Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.37, 1.16]

    41.8 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
199Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.14, 2.01]

    41.9 Total dose of vitamin E in the treatment group > 30 IU/kg/day
4953Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.54, 1.39]

    41.10 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2297Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.25, 1.44]

    41.11 Serum tocopherol level in the treatment group > 3.5 mg/dl
3755Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.55, 1.53]

    41.12 Onset of vitamin E supplementation in the treatment group within 48 hours of life
51052Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.52, 1.27]

    41.13 Duration of treatment > 1 week
4470Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.43, 1.29]

    41.14 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
4978Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.44, 1.24]

    41.15 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
174Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.49, 2.60]

 42 Cicatricial retrolental fibroplasia, any stage, among very low birth weight infants examined after discharge5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    42.1 All infants in all studies
5858Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.48, 1.15]

    42.2 Birth weight <= 1500 grams
4824Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.45, 1.12]

    42.3 Birth weight <= 1000 grams
382Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.26, 1.19]

    42.4 Enteral
1101Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.13, 1.09]

    42.5 Enteral hypertonic formulation at pharmacologic doses
1101Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.13, 1.09]

    42.6 Parenteral with or without enteral
4757Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.55, 1.43]

    42.7 Parenteral with hypertonic enteral formulation at pharmacologic dose
4757Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.55, 1.43]

    42.8 Intravenous (with or without other routes of administration)
2616Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.51, 1.99]

    42.9 Excluding intravenous vitamin E supplementation
3242Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.33, 1.04]

    42.10 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
199Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.14, 2.01]

    42.11 Total dose of vitamin E in the treatment group > 30 IU/kg/day
4759Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.49, 1.24]

    42.12 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2135Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.22, 1.26]

    42.13 Serum tocopherol level in the treatment group > 3.5 mg/dl
3723Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.51, 1.41]

    42.14 Onset of vitamin E supplementation in the treatment group within 48 hours of life
5858Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.48, 1.15]

    42.15 Duration of treatment > 1 week
4276Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.38, 1.10]

    42.16 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
4816Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.42, 1.18]

    42.17 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
142Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.42, 1.96]

 43 Blindness from retrolental fibroplasia among very low birth weight infants examined4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    43.1 All infants in all studies
4467Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.10, 0.88]

    43.2 Birth weight <= 1500 grams
4467Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.10, 0.88]

    43.3 Birth weight <= 1000 grams
248Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 1.84]

    43.4 Enteral
2326Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.10, 1.13]

    43.5 Enteral hypertonic formulation at pharmacologic dose
1101Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 1.63]

    43.6 Parenteral with or without enteral
2141Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.86]

    43.7 Parenteral with hypertonic enteral formulation at pharmacologic dose
2141Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.86]

    43.8 Excluding intravenous vitamin E supplementation
4467Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.10, 0.88]

    43.9 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2324Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.12, 1.46]

    43.10 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2143Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 1.63]

    43.11 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2326Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.10, 1.13]

    43.12 Serum tocopherol level in the treatment group > 3.5 mg/dl
2141Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.86]

    43.13 Onset of vitamin E supplementation in the treatment group within 48 hours of life
4467Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.10, 0.88]

    43.14 Duration of treatment > 1 week
4467Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.10, 0.88]

    43.15 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
3425Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.10, 0.88]

    43.16 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
142Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    43.17 Iron supplementation > 2 mg/kg/day in neither group
1225Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.15, 2.52]

    43.18 PUFA >= 400 mg/100 ml milk
1225Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.15, 2.52]

 44 Necrotizing enterocolitis8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    44.1 All infants in all studies
81443Risk Ratio (M-H, Fixed, 95% CI)1.37 [0.96, 1.95]

    44.2 Enteral
130Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 68.26]

    44.3 Parenteral with or without enteral
71413Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.94, 1.93]

    44.4 Parenteral with hypertonic enteral formulation at pharmacologic dose
41105Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.89, 1.86]

    44.5 Intravenous (with or without other routes of supplementation)
2832Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.95, 2.19]

    44.6 Excluding intravenous vitamin E supplementation
6611Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.59, 2.35]

    44.7 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
4434Risk Ratio (M-H, Fixed, 95% CI)1.60 [0.66, 3.88]

    44.8 Total dose of vitamin E in the treatment group > 30 IU/kg/day
3979Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.88, 1.93]

    44.9 Serum tocopherol level in the treatment group <= 3.5 mg/dl
5625Risk Ratio (M-H, Fixed, 95% CI)1.58 [0.65, 3.81]

    44.10 Serum tocopherol level in the treatment group > 3.5 mg/dl
3818Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.90, 1.95]

    44.11 Onset of vitamin E supplementation in the treatment group within 48 hours of life
71413Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.94, 1.93]

    44.12 Onset of treatment after 48 hours of life
130Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 68.26]

    44.13 Duration of treatment <= 1 week
2279Risk Ratio (M-H, Fixed, 95% CI)6.88 [0.36, 131.68]

    44.14 Duration of treatment > 1 week
5619Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.53, 1.83]

    44.15 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
71296Risk Ratio (M-H, Fixed, 95% CI)1.49 [1.03, 2.16]

    44.16 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1147Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.13, 1.95]

    44.17 Iron supplementation > 2 mg/kg/day in both groups
130Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 68.26]

 45 Necrotizing enterocolitis among very low birth weight infants6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    45.1 All infants in all studies
6962Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.90, 1.87]

    45.2 Birth weight <= 1500 grams
4730Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.99, 2.22]

    45.3 Birth weight <= 1000 grams
2232Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.23, 1.62]

    45.4 Enteral
130Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 68.26]

    45.5 Parenteral with or without enteral
5932Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.88, 1.85]

    45.6 Parenteral with hypertonic enteral formulation at pharmacologic dose
4903Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.88, 1.85]

    45.7 Intravenous (with or without other routes of supplementation)
2630Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.94, 2.19]

    45.8 Excluding intravenous vitamin E supplementation
4332Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.46, 2.01]

    45.9 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2155Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.46, 3.17]

    45.10 Total dose of vitamin E in the treatment group > 30 IU/kg/day
3777Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.86, 1.92]

    45.11 Serum tocopherol level in the treatment group <= 3.5 mg/dl
3144Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.34, 3.29]

    45.12 Serum tocopherol level in the treatment group > 3.5 mg/dl
3818Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.90, 1.95]

    45.13 Onset of vitamin E supplementation in the treatment group within 48 hours of life
5932Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.88, 1.85]

    45.14 Onset of treatment after 48 hours of life
130Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 68.26]

    45.15 Duration of treatment > 1 week
5417Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.48, 1.76]

    45.16 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
5815Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.96, 2.08]

    45.17 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1147Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.13, 1.95]

    45.18 Iron supplementation > 2 mg/kg/day in both groups
130Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 68.26]

 46 Necrotizing enterocolitis among very low birth weight infants treated for > 1 week5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    46.1 All infants in all studies
5734Risk Ratio (M-H, Fixed, 95% CI)1.51 [0.99, 2.30]

    46.2 Birth weight <= 1500 grams
4649Risk Ratio (M-H, Fixed, 95% CI)1.62 [1.04, 2.51]

    46.3 Birth weight <= 1000 grams
185Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.18, 3.23]

    46.4 Enteral
130Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 68.26]

    46.5 Parenteral with or without enteral
4704Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.97, 2.28]

    46.6 Parenteral with hypertonic enteral formulation at pharmacologic dose
2549Risk Ratio (M-H, Fixed, 95% CI)1.56 [0.97, 2.51]

    46.7 Intravenous (with or without other routes of supplementation)
2549Risk Ratio (M-H, Fixed, 95% CI)1.56 [0.97, 2.51]

    46.8 Excluding intravenous vitamin E supplementation
3185Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.53, 3.32]

    46.9 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2155Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.46, 3.17]

    46.10 Total dose of vitamin E in the treatment group > 30 IU/kg/day
2549Risk Ratio (M-H, Fixed, 95% CI)1.56 [0.97, 2.51]

    46.11 Serum tocopherol level in the treatment group <= 3.5 mg/dl
3144Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.34, 3.29]

    46.12 Serum tocopherol level in the treatment group > 3.5 mg/dl
2590Risk Ratio (M-H, Fixed, 95% CI)1.60 [1.02, 2.52]

    46.13 Onset of vitamin E supplementation in the treatment group within 48 hours of life
4704Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.97, 2.28]

    46.14 Onset of treatment after 48 hours of life
130Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 68.26]

    46.15 Duration of treatment > 1 week
4270Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.53, 2.43]

    46.16 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
5734Risk Ratio (M-H, Fixed, 95% CI)1.51 [0.99, 2.30]

    46.17 Iron supplementation > 2 mg/kg/day in both groups
130Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 68.26]

 47 Necrotizing enterocolitis among survivors2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    47.1 All infants in all studies
2186Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.65]

    47.2 Birth weight <= 1500 grams
1135Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.65]

    47.3 Parenteral with or without enteral
2186Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.65]

    47.4 Parenteral with hypertonic enteral formulation at pharmacologic dose
1135Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.65]

    47.5 Excluding intravenous vitamin E supplementation
2186Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.65]

    47.6 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
151Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    47.7 Total dose of vitamin E in the treatment group > 30 IU/kg/day
1135Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.65]

    47.8 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2186Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.65]

    47.9 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2186Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.65]

    47.10 Duration of treatment <= 1 week
2186Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.65]

    47.11 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
151Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    47.12 Total dose of vitamin E in the control group > 10 mg vit E/100 kcal
1135Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.65]

    47.13 Iron supplementation > 2 mg/kg/day in both groups
151Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 48 Necrotizing enterocolitis among surviving very low birth weight infants1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    48.1 All infants in all studies
1135Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.65]

 49 Serum bilirubin concentration (mg/100 ml) on day 3-53Mean Difference (IV, Fixed, 95% CI)Subtotals only

    49.1 All infants in all studies
398Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.17, 0.57]

    49.2 Birth weight >= 1000 grams
140Mean Difference (IV, Fixed, 95% CI)-0.86 [-2.46, 0.74]

    49.3 Enteral
258Mean Difference (IV, Fixed, 95% CI)-0.07 [-1.10, 0.96]

    49.4 Parenteral with or without enteral
140Mean Difference (IV, Fixed, 95% CI)-0.86 [-2.46, 0.74]

    49.5 Excluding intravenous
398Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.17, 0.57]

    49.6 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
270Mean Difference (IV, Fixed, 95% CI)0.50 [-0.66, 1.66]

    49.7 Total dose of vitamin E in the treatment group > 30 IU/kg/day
128Mean Difference (IV, Fixed, 95% CI)Not estimable

    49.8 Serum tocopherol level in the treatment group <= 3.5 mg/dl
398Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.17, 0.57]

    49.9 Onset of vitamin E supplementation in the treatment group within 48 hours of life
398Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.17, 0.57]

    49.10 Duration of treatment <= 1 week
398Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.17, 0.57]

    49.11 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
398Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.17, 0.57]

    49.12 Iron supplementation > 2 mg/kg in neither group
270Mean Difference (IV, Fixed, 95% CI)0.50 [-0.66, 1.66]

 50 Serum bilirubin concentration in very low birth weight infants2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    50.1 All infants in all studies
248Mean Difference (IV, Fixed, 95% CI)-1.46 [-2.58, -0.33]

    50.2 Enteral
128Mean Difference (IV, Fixed, 95% CI)Not estimable

    50.3 Parenteral with or without enteral
120Mean Difference (IV, Fixed, 95% CI)-1.93 [-4.20, 0.34]

    50.4 Excluding intravenous
248Mean Difference (IV, Fixed, 95% CI)-1.46 [-2.58, -0.33]

    50.5 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
120Mean Difference (IV, Fixed, 95% CI)-1.93 [-4.20, 0.34]

    50.6 Total dose of vitamin E in the treatment group > 30 IU/kg/day
128Mean Difference (IV, Fixed, 95% CI)Not estimable

    50.7 Serum tocopherol level in the treatment group <= 3.5 mgl/gl
248Mean Difference (IV, Fixed, 95% CI)-1.46 [-2.58, -0.33]

    50.8 Onset of vitamin E supplementation in the treatment group within 48 hours of life
268Mean Difference (IV, Fixed, 95% CI)-1.13 [-2.13, -0.12]

    50.9 Duration of treatment <= 1 week
248Mean Difference (IV, Fixed, 95% CI)-1.46 [-2.58, -0.33]

    50.10 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
248Mean Difference (IV, Fixed, 95% CI)-1.46 [-2.58, -0.33]

    50.11 Iron supplementation > 2 mg/kg in neither group
120Mean Difference (IV, Fixed, 95% CI)-1.93 [-4.20, 0.34]

 51 Serum bilirubin concentration on day 3-5 in a specific group (no hemolysis, polycythemia, prior transfus1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    51.1 All infants in all studies
162Mean Difference (IV, Fixed, 95% CI)1.30 [0.20, 2.40]

 52 Hemoglobin concentration (g/100 ml)8Mean Difference (IV, Fixed, 95% CI)Subtotals only

    52.1 All infants in all studies
8416Mean Difference (IV, Fixed, 95% CI)0.46 [0.24, 0.69]

    52.2 Birth weight > 1000 grams
2162Mean Difference (IV, Fixed, 95% CI)0.49 [0.20, 0.77]

    52.3 Enteral
7396Mean Difference (IV, Fixed, 95% CI)0.48 [0.25, 0.71]

    52.4 Parenteral with or without enteral
120Mean Difference (IV, Fixed, 95% CI)-1.0 [-3.21, 1.21]

    52.5 Excluding intravenous vitamin E supplementation
8416Mean Difference (IV, Fixed, 95% CI)0.46 [0.24, 0.69]

    52.6 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
5338Mean Difference (IV, Fixed, 95% CI)0.52 [0.29, 0.76]

    52.7 Total dose of vitamin E in the treatment group >30 IU/kg/day
248Mean Difference (IV, Fixed, 95% CI)-0.77 [-1.84, 0.30]

    52.8 Serum tocopherol level in the treatment group <= 3.5 mg/dl
6356Mean Difference (IV, Fixed, 95% CI)0.47 [0.23, 0.71]

    52.9 Onset of vitamin E supplementation in the treatment group within 48 hours of life
4285Mean Difference (IV, Fixed, 95% CI)0.48 [0.21, 0.75]

    52.10 Onset of vitamin E supplementation in the treatment group after 48 hours of life
4131Mean Difference (IV, Fixed, 95% CI)0.44 [0.02, 0.85]

    52.11 Duration of treatment <= 1 week
378Mean Difference (IV, Fixed, 95% CI)-0.56 [-1.44, 0.33]

    52.12 Duration of treatment > 1 week
5338Mean Difference (IV, Fixed, 95% CI)0.54 [0.30, 0.77]

    52.13 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
8416Mean Difference (IV, Fixed, 95% CI)0.46 [0.24, 0.69]

    52.14 Iron supplementation in both groups
4161Mean Difference (IV, Fixed, 95% CI)0.57 [0.24, 0.91]

    52.15 Iron supplementation in neither group
5227Mean Difference (IV, Fixed, 95% CI)0.47 [0.16, 0.78]

    52.16 PUFA >= 400 mg/100 ml milk
190Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.02, 0.42]

 53 Hemoglobin concentration in very low birth weight infants4Mean Difference (IV, Fixed, 95% CI)Subtotals only

    53.1 All infants in all studies
4196Mean Difference (IV, Fixed, 95% CI)0.43 [0.09, 0.77]

    53.2 Enteral
4196Mean Difference (IV, Fixed, 95% CI)0.43 [0.09, 0.77]

    53.3 Excluding intravenous vitamin E supplementation
4196Mean Difference (IV, Fixed, 95% CI)0.43 [0.09, 0.77]

    53.4 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2138Mean Difference (IV, Fixed, 95% CI)0.53 [0.16, 0.90]

    53.5 Total dose of vitamin E in the treatment group >30 IU/kg/day
128Mean Difference (IV, Fixed, 95% CI)-0.70 [-1.92, 0.52]

    53.6 Serum tocopherol level in the treatment group <= 3.5 mg/dl
4196Mean Difference (IV, Fixed, 95% CI)0.43 [0.09, 0.77]

    53.7 Onset of vitamin E supplementation in the treatment group within 48 hours of life
3166Mean Difference (IV, Fixed, 95% CI)0.42 [0.07, 0.78]

    53.8 Onset of vitamin E supplementation in the treatment group after 48 hours of life
130Mean Difference (IV, Fixed, 95% CI)0.57 [-0.70, 1.84]

    53.9 Duration of treatment <= 1 week
128Mean Difference (IV, Fixed, 95% CI)-0.70 [-1.92, 0.52]

    53.10 Duration of treatment > 1 week
3168Mean Difference (IV, Fixed, 95% CI)0.53 [0.17, 0.89]

    53.11 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
4196Mean Difference (IV, Fixed, 95% CI)0.43 [0.09, 0.77]

    53.12 Iron supplementation in both groups
2100Mean Difference (IV, Fixed, 95% CI)0.67 [0.23, 1.10]

    53.13 Iron supplementation in neither group
2157Mean Difference (IV, Fixed, 95% CI)0.51 [0.17, 0.86]

    53.14 PUFA >= 400 mg/100 ml milk
190Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.02, 0.42]

 54 Reticulocyte count (%)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    54.1 All infants in all studies
2201Mean Difference (IV, Fixed, 95% CI)-1.66 [-2.24, -1.07]

    54.2 Enteral
2201Mean Difference (IV, Fixed, 95% CI)-1.66 [-2.24, -1.07]

    54.3 Excluding intravenous vitamin E supplementation
2201Mean Difference (IV, Fixed, 95% CI)-1.66 [-2.24, -1.07]

    54.4 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2201Mean Difference (IV, Fixed, 95% CI)-1.66 [-2.24, -1.07]

    54.5 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2201Mean Difference (IV, Fixed, 95% CI)-1.66 [-2.24, -1.07]

    54.6 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2201Mean Difference (IV, Fixed, 95% CI)-1.66 [-2.24, -1.07]

    54.7 Duration of treatment > 1 week
2201Mean Difference (IV, Fixed, 95% CI)-1.66 [-2.24, -1.07]

    54.8 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2201Mean Difference (IV, Fixed, 95% CI)-1.66 [-2.24, -1.07]

    54.9 Iron supplementation in both groups
170Mean Difference (IV, Fixed, 95% CI)-1.96 [-2.89, -1.03]

    54.10 Iron supplementation in neither group
2131Mean Difference (IV, Fixed, 95% CI)-1.47 [-2.22, -0.72]

    54.11 PUFA >= 400 mg/100 ml milk
164Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.50, 0.90]

 55 Reticulocyte count (%) in very low birth weight infants1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    55.1 All infants in all studies
164Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.50, 0.90]

 56 Reticulocyte count (million per liter)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    56.1 All infants in all studies
271Mean Difference (IV, Fixed, 95% CI)-34.02 [-46.19, -21.84]

    56.2 Enteral
271Mean Difference (IV, Fixed, 95% CI)-34.02 [-46.19, -21.84]

    56.3 Excluding intravenous vitamin E supplementation
271Mean Difference (IV, Fixed, 95% CI)-34.02 [-46.19, -21.84]

    56.4 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
141Mean Difference (IV, Fixed, 95% CI)-9.20 [-27.36, 8.96]

    56.5 Serum tocopherol level in the treatment group <= 3.5 mg/dl
271Mean Difference (IV, Fixed, 95% CI)-34.02 [-46.19, -21.84]

    56.6 Onset of vitamin E supplementation in the treatment group after 48 hours of life
271Mean Difference (IV, Fixed, 95% CI)-34.02 [-46.19, -21.84]

    56.7 Duration of treatment > 1 week
271Mean Difference (IV, Fixed, 95% CI)-34.02 [-46.19, -21.84]

    56.8 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
271Mean Difference (IV, Fixed, 95% CI)-34.02 [-46.19, -21.84]

    56.9 Iron supplementation in both groups
271Mean Difference (IV, Fixed, 95% CI)-34.02 [-46.19, -21.84]

 57 Reticulocyte count (million per liter) in very low birth weight infants1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    57.1 All infants in all studies
130Mean Difference (IV, Fixed, 95% CI)-54.27 [-70.67, -37.87]

 58 Number of transfusions1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    58.1 All infants in all studies
130Mean Difference (IV, Fixed, 95% CI)-0.20 [-1.17, 0.77]

 59 Number of transfusions among survivors1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    59.1 All infants in all studies
1135Mean Difference (IV, Fixed, 95% CI)1.20 [-1.42, 3.82]

 60 Amount of blood transfused (ml/kg) among very low birth weight infants2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    60.1 All infants in all studies
2454Mean Difference (IV, Fixed, 95% CI)-0.47 [-16.86, 15.92]

    60.2 Birth weight <= 1500 grams
2454Mean Difference (IV, Fixed, 95% CI)-0.47 [-16.86, 15.92]

    60.3 Enteral
130Mean Difference (IV, Fixed, 95% CI)-3.10 [-20.91, 14.71]

    60.4 Parenteral with or without enteral
1424Mean Difference (IV, Fixed, 95% CI)14.0 [-27.77, 55.77]

    60.5 Parenteral with hypertonic enteral formulation at pharmacologic dose
1424Mean Difference (IV, Fixed, 95% CI)14.0 [-27.77, 55.77]

    60.6 Intravenous vitamin E supplementation
1424Mean Difference (IV, Fixed, 95% CI)14.0 [-27.77, 55.77]

    60.7 Excluding intravenous supplementation
130Mean Difference (IV, Fixed, 95% CI)-3.10 [-20.91, 14.71]

    60.8 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
130Mean Difference (IV, Fixed, 95% CI)-3.10 [-20.91, 14.71]

    60.9 Total dose of vitamin E in the treatment group > 30 IU/kg/day
1424Mean Difference (IV, Fixed, 95% CI)14.0 [-27.77, 55.77]

    60.10 Serum tocopherol level in the treatment group <= 3.5 mg/dl
130Mean Difference (IV, Fixed, 95% CI)-3.10 [-20.91, 14.71]

    60.11 Serum tocopherol level in the treatment group > 3.5 mg/dl
1424Mean Difference (IV, Fixed, 95% CI)14.0 [-27.77, 55.77]

    60.12 Onset of vitamin E supplementation in the treatment group within 48 hours of life
1424Mean Difference (IV, Fixed, 95% CI)14.0 [-27.77, 55.77]

    60.13 Onset of vitamin E supplementation in the treatment group after 48 hours of life
130Mean Difference (IV, Fixed, 95% CI)-3.10 [-20.91, 14.71]

    60.14 Duration of treatment > 1 week
130Mean Difference (IV, Fixed, 95% CI)-3.10 [-20.91, 14.71]

    60.15 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2454Mean Difference (IV, Fixed, 95% CI)-0.47 [-16.86, 15.92]

    60.16 Iron supplementation in both groups
130Mean Difference (IV, Fixed, 95% CI)-3.10 [-20.91, 14.71]

 61 Amount of blood transfused (ml/kg) among surviving low birth weight infants1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    61.1 All infants in all studies
1135Mean Difference (IV, Fixed, 95% CI)18.10 [-17.14, 53.34]

 62 Platelet count (thousands/microliter)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    62.1 All infants in all studies
2109Mean Difference (IV, Fixed, 95% CI)-29.52 [-88.81, 29.76]

    62.2 Birth weight <= 1500 grams
168Mean Difference (IV, Fixed, 95% CI)-45.0 [-114.33, 24.33]

    62.3 Enteral
2109Mean Difference (IV, Fixed, 95% CI)-29.52 [-88.81, 29.76]

    62.4 Excluding intravenous vitamin E supplementation\
2109Mean Difference (IV, Fixed, 95% CI)-29.52 [-88.81, 29.76]

    62.5 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
2109Mean Difference (IV, Fixed, 95% CI)-29.52 [-88.81, 29.76]

    62.6 Serum tocopherol level in the treatment group <= 3.5 mg/dl
2109Mean Difference (IV, Fixed, 95% CI)-29.52 [-88.81, 29.76]

    62.7 Onset of vitamin E supplementation in the treatment group within 48 hours of life
168Mean Difference (IV, Fixed, 95% CI)-45.0 [-114.33, 24.33]

    62.8 Onset of therapy after 48 hours of life
141Mean Difference (IV, Fixed, 95% CI)12.60 [-101.78, 126.98]

    62.9 Duration of treatment > 1 week
2109Mean Difference (IV, Fixed, 95% CI)-29.52 [-88.81, 29.76]

    62.10 Total dose of vitamin E in the control group <= 10 mg vit E/100 kcal
2109Mean Difference (IV, Fixed, 95% CI)-29.52 [-88.81, 29.76]

    62.11 Iron supplementation > 2 mg/kg in both groups
141Mean Difference (IV, Fixed, 95% CI)12.60 [-101.78, 126.98]

 63 Prothrombin time (PT, seconds)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    63.1 All infants in all studies
147Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.62, 0.42]

 64 Partial thromboplastin time (PTT, seconds)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    64.1 All infants in all studies
147Mean Difference (IV, Fixed, 95% CI)-3.40 [-12.93, 6.13]

 65 Fibrinogen concentration (mg/100 ml)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    65.1 All infants in all studies
147Mean Difference (IV, Fixed, 95% CI)49.0 [-14.47, 112.47]

 66 Retinal hemorrhage among very low birth weight infants examined/surviving1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    66.1 All infants in all studies
1232Risk Ratio (M-H, Fixed, 95% CI)2.18 [0.97, 4.89]

    66.2 Birth weight <= 1000 grams
185Risk Ratio (M-H, Fixed, 95% CI)3.58 [1.28, 10.00]

 67 Reaction at site of injection2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    67.1 All infants in all studies
2357Risk Ratio (M-H, Fixed, 95% CI)4.13 [0.47, 36.68]

    67.2 Parenteral with or without enteral
2357Risk Ratio (M-H, Fixed, 95% CI)4.13 [0.47, 36.68]

    67.3 Parenteral with hypertonic enteral formulation at pharmacologic dose
1147Risk Ratio (M-H, Fixed, 95% CI)5.07 [0.25, 103.77]

    67.4 Excluding intravenous vitamin E supplementation
2357Risk Ratio (M-H, Fixed, 95% CI)4.13 [0.47, 36.68]

    67.5 Total dose of vitamin E in the treatment group <= 30 IU/kg/day
1210Risk Ratio (M-H, Fixed, 95% CI)3.17 [0.13, 77.05]

    67.6 Total dose of vitamin E in the treatment group > 30 IU/kg/day
1147Risk Ratio (M-H, Fixed, 95% CI)5.07 [0.25, 103.77]

    67.7 Serum tocopherol level in the treatment group <= 3.5 mg/dl
1210Risk Ratio (M-H, Fixed, 95% CI)3.17 [0.13, 77.05]

    67.8 Serum tocopherol level in the treatment group > 3.5 mg/dl
1147Risk Ratio (M-H, Fixed, 95% CI)5.07 [0.25, 103.77]

    67.9 Onset of vitamin E supplementation in the treatment group within 48 hours of life
2357Risk Ratio (M-H, Fixed, 95% CI)4.13 [0.47, 36.68]

    67.10 Duration of treatment <= 1 week
1210Risk Ratio (M-H, Fixed, 95% CI)3.17 [0.13, 77.05]

    67.11 Duration of treatment > 1 week
1147Risk Ratio (M-H, Fixed, 95% CI)5.07 [0.25, 103.77]

 68 Reaction at site of injection in very low birth weight infants1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    68.1 All infants in all studies
1147Risk Ratio (M-H, Fixed, 95% CI)5.07 [0.25, 103.77]

    68.2 Birth weight <= 1000 grams
1147Risk Ratio (M-H, Fixed, 95% CI)5.07 [0.25, 103.77]

 
Comparison 2. Vitamin E (aqueous colloidal) versus another form of vitamin E (olive oil)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 All infants
144Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.25, 98.52]

 2 Bronchopulmonary dysplasia1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 All infants
144Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.31, 1.80]

 3 Patent ductus arteriosus1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 All infants
144Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.19, 2.97]

 4 Sepsis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 All infants
144Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.04, 2.96]

 5 Germinal matrix-intraventricular hemorrhage1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 All infants
144Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.50, 2.61]

 6 Stage IV (intraparenchymal) intraventricular hemorrhage1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 All infants
144Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.76]

 7 Necrotizing enterocolitis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 All infants
144Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.61]

 8 Exchange transfusion1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 All infants
144Risk Ratio (M-H, Fixed, 95% CI)0.8 [0.50, 1.29]