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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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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Index terms

1. What is vitamin E?
Vitamin E comprises a group of eight biologically active tocopherols, among which d-alpha-tocopherol has the highest antioxidant activity per mg of tocopherol (1.49 international unit [IU]/mg). The IU is defined as the biological activity of 1 mg of dl-alpha-tocopheryl acetate. One mg of d-alpha-tocopherol equivalent equals the activity of 1 mg of d-alpha-tocopherol. Vitamin E is one of several antioxidants that preterm infants can use as scavengers of free radicals, thereby potentially limiting processes which can lead to chronic lung disease and retinopathy of prematurity (Thibeault 2000) and other long-term complications (Brigelius-Flohé2002). In addition, alpha-tocopherol inhibits inflammation by modulating cellular signaling and by regulating transcription, and stimulates immunity; a metabolite of gamma-tocopherol has been proposed as a natriuretic factor (Brigelius-Flohé2002) .

2. Do preterm infants need vitamin E, and what is their requirement of this vitamin?
The content of alpha-tocopherol in the body of the fetus remains at 3-7 mg/kg throughout gestation (Bell 1981). In preterm infants, lack of vitamin E intake or fat malabsorption results in edema, thrombocytosis and hemolytic anemia and could eventually result in spinocerebellar degeneration. Signs of this deficiency are enhanced by iron supplementation (due to its oxidant activity) and by high concentration in milk formula of linoleic acid and other polyunsaturated fatty acids (PUFA), which are subject to oxidation (Hassan 1966; Oski 1967; Ritchie 1968; Williams 1975). The clinical assessment of vitamin E deficiency remains a challenge in preterm infants, because serum tocopherol levels may not reflect tissue levels and depend on serum lipid levels (Greer 2000). A tocopherol/total lipid ratio of greater than 0.8 mg/g has been recommended as an indication of vitamin E sufficiency (Johnson 1998).

The amount of vitamin E in colostrum and preterm milk is approximately two to three times that in mature milk (Gross 1993). Formulas for preterm infants should contain at least one IU of vitamin E per gram of linoleic acid, 0.6 mg of d-alpha-tocopherol equivalent per g of PUFA (Bell 1981) and 0.7 IU per 100 kcal in order to prevent vitamin E deficiency (Gross 1993; Committee N 1985). With these doses, hemolytic anemia of vitamin E deficiency has been virtually eliminated except in rare cases of prolonged total parenteral nutrition with lipid emulsion and inadequate supplemental vitamin E or in cases of fat malabsorption due to cholestatic liver disease or to cystic fibrosis (Bell 1987). The American Academy of Pediatrics Committee on Nutrition has recommended daily supplementation of 5-25 IU of vitamin E in preterm infants to ensure enough accretion (Committee N 1985); however, such supplementation might not be necessary (Gross 1985).

The optimal amount of parenteral vitamin E in preterm infants is uncertain, although the maximum recommended dose for any neonate is 7 IU per day (5 ml of M.V.I. Pediatric®, Astra Pharmaceuticals, L.P., Wayne, PA). The manufacturer's recommendation is 1.5 ml/day for infants weighing less than 1 kg, 3.25 ml/day for those weighing 1 to 3 kg, and 5 ml/day for infants and children weighing 3 kg or more and up to 11 years of age. The American Academy of Pediatrics has recommended a standard dose for all preterm infants: 40% of a vial of M.V.I. Pediatric® (Committee N 1998). Using a fixed dose per day (regardless of exact weight), serum alpha-tocopherol levels at one week of life are inversely related with birth weight (Amorde-Spalding 1992; Phillips 1987), and some infants develop serum levels greater than 3.5 mg/dl (Amorde-Spalding 1992; DeVito 1986; MacDonald 1987, Phillips 1987). The American Society for Clinical Nutrition recommends a parenteral dose of vitamin E of 2.8 IU/kg/day for preterm infants and 7 IU/day in full-term infants (Greene 1988). This dose is met by standard intravenous vitamin solutions (Gross 1993; Greer 2000): a dose of 2.8 IU/kg/day is provided by 1 ml of a vial of M.V.I. Pediatric® Solution for infants with a weight of 500 g and by 2 ml for a weight of 1000 g. Schwalbe has recommended a dose of d,l-alpha-tocopheryl acetate of 4.5 mg/kg/day (4.5 IU/kg/day) for very low birth weight infants based on serum levels during the first 2 weeks of life after a five-day infusion (Schwalbe 1992). In preterm infants with birth weight 820-2000 g, vitamin E at an average dose of 3 IU/kg/day administered intravenously by continuous infusion in multivitamins for 3-4 weeks generally yields plasma levels within the normal range (1-3 mg/dl) (Gutcher 1985; Baeckert 1988).

3. What is the rationale for vitamin E supplementation in preterm infants; what is the bioavailability; what is the potential indirect and direct toxicity of vitamin E supplements; and is there a safe dose?
Supplementing very low birth weight infants with vitamin E as an antioxidant agent has been proposed for preventing or limiting retinopathy of prematurity, intracranial hemorrhage, and chronic lung disease. Nevertheless, tissue levels reached by pharmacologic doses of vitamin E are several fold higher than those required to produce maximum antioxidant effect (Roberts 1987).

At steady state, umbilical cord blood serum, plasma or erythrocyte levels of tocopherol are related to, but less than half maternal levels and increase progressively during pregnancy (Navarro 1984; Cachia 1995; Jain 1996; Johnson 1998; Chan 1999; Baydas 2002; Bolisetty 2002). One study has shown that the administration of 300-600 mg of vitamin E to the mother during preterm labor may reduce the risk of neonatal intracranial hemorrhage diagnosed at non traumatic spinal tap or autopsy (1/45 in the treated group versus 6/45 in controls, RR 0.17, CI 0.02,1.33; RD -0.11, CI -0.22) (Minkowski 1949). Nevertheless, two other studies have shown that fetal cord plasma levels of tocopherol fail to increase after three days of maternal supplementation (Léger 1998) and within nine days of maternal supplementation only increase up to values lower than half those required to reduce hemolysis (Cruz 1983). Approximately 30% of the mothers have levels consistent with vitamin E deficiency (Cachia 1995), and a daily maternal intake of 400 IU of vitamin E has been estimated to prevent or correct such deficiency (Woods 2001). In a cohort of 1231 gravid women, maternal plasma concentrations of alpha-tocopherol in early pregnancy and at 28 weeks were positively associated with fetal growth (Scholl 2006).

Most but not all studies support the observation that enteral absorption of vitamin E in preterm infants is sufficient to rapidly achieve adequate blood levels of tocopherol (Bell 1987). Neonatal serum tocopherol levels increase progressively when fed human colostrum, which is rich in vitamin E (Gross 1993; Moran 1983; Ostrea 1986), or formula, which now routinely contains vitamin E. In preterm infants, enteral absorption of vitamin E from water-soluble preparations is better than from lipid-soluble preparations (Gross 1974; Jansson 1984). Intramuscular absorption of alpha-tocopheryl acetate prepared in solution in olive oil, available in several European countries, is six times lower than that of vitamin E in colloidal solution, available in England and North America (Bonati 1991). When vitamin E is provided as alpha-tocopheryl acetate, bioavailability of free vitamin E (tocopherol) requires hydrolysis, which is mediated by an enzyme (esterase). This hydrolysis is a limiting step in case of parenteral administration (Newmark 1975; Pedraz 1989) but not in case of enteral administration (Bell 1979 [see Zipursky 1987]), because of abundance of pancreatic and jejunal mucosal esterase activity (Mathias 1981). These observations explain why even a small dose of 5 mg of dl-alpha-tocopheryl acetate provided enterally has proven to be more efficient than larger intramuscular doses (30 mg) in treating scleredema (Gerlóczy 1949).

Vitamin E toxicity may be related to the dose, chemical form, route of administration, or (in the case of parenteral forms) speed of administration, or to some combination of these factors (Bell 1987; Hale 1995). Risks associated with vitamin E excess in adult humans (Bell 1989) include (1) impaired resistance to infection resulting from decreased leukocyte function, and (2) increased bleeding resulting from a decrease in vitamin-K-dependent factors in vitamin-K deficient individuals (Corrigan 1979) and inhibition of platelet prostaglandin synthesis and of platelet aggregation (Stuart 1979). Reports of toxicity of enteral vitamin E are rare in infants. Enteral intake of vitamin E up to 25 mg/kg/day rarely yields serum levels greater than 3.5 mg/dl (81 micromol/L), i.e., the levels associated with an increased incidence of sepsis and necrotizing enterocolitis (Bell 1989). The safe upper limit of vitamin E in infant formulas was estimated to be 10 mg d-alpha-tocopherol equivalent per 100 kcal or 15 IU/100 kcal, which would provide half the amount of enteral vitamin E (25 mg/kg/day) that appears to be safe and well tolerated (Bell 1989). This dose also corresponds to the highest concentration of vitamin E in colostrum (˜60 mg/dl). Johnson has recently proposed to classify serum tocopherol levels as physiologic (1-3.5 mg/dl), proposed for prophylaxis and treatment of early retinopathy of prematurity, and pharmacologic (4-5 mg/dl), proposed for treating severe retinopathy of prematurity (Johnson 1995). Increased necrotizing enterocolitis has been observed in patients with serum concentration of vitamin E greater than 3.5 mg/dl while receiving a total (intravenous vitamins, intravenous lipid solution, formula and oral vitamin supplementation 0-25 mg/kg/day) vitamin E dose less than 25 mg/kg/day (Friedman 1988).

Fifty-eight infants at a single institution received pharmacologic doses (25-50 IU/kg/day intravenously) of a new preparation of vitamin E (E-Ferol®, O'Neal, Jones and Feldman, Maryland Heights, MO), which contained dl-alpha-tocopheryl acetate solubilized at 25 IU/ml with 9% polysorbate 80 and 1% polysorbate 20. Among these 58 infants, eight developed pulmonary deterioration, liver failure (hepatomegaly, ascites, and in some cases cholestatic jaundice and hypoproteinemia), thrombocytopenia, and renal failure, and five died (Lorch 1985). Review of autopsy-derived tissue from 20 infants showed vascular hepatotoxicity characterized by progressive intralobular cholestasis, inflammation of hepatic venules, and extensive sinusoidal veno-occlusion by fibrosis (Bove 1985). Two subsequent retrospective reports described E-Ferol®-related events (Martone 1986; Arrowsmith 1989). A total of 38 deaths were attributed to E-Ferol®, which was removed from the market. It remains unclear whether the toxicity of E-Ferol® resulted from the vitamin E itself, its preparation as tocopheryl acetate (which could not be hydrolyzed when given intravenously), the polysorbates present in the product, or an undetermined contaminant (Balistreri 1986; Bell 1987). Parenteral vitamin E administration (either dl-alpha-tocopheryl acetate, or free dl-alpha tocopherol in ethanol) caused dose-related toxicity in kittens, including hepatosplenomegaly and mortality (Phelps 1987b). Toxicologic studies (see Arrowsmith 1989; Balistreri 1986; Alade 1986) suggested that the effects of E-Ferol® could be at least in part reproduced by high doses of polysorbates 20 and 80. However tissue accumulation of vitamin E and tissue changes after E-Ferol® administration depended on the dose, route and duration of administration, with toxicity associated with rapid intravenous administration (Hale 1995).

A retrospective analysis has shown a significant association between pharmacologic oral doses of vitamin E (diluted 1:2, provided at a dose of 200 mg/day in eight aliquots) in very low birth weight infants and necrotizing enterocolitis (Finer 1984). Necrotizing enterocolitis was attributed to the high osmolality of the undiluted solution, 4050 mOsm/kg, in turn related to its high content of propylene glycol (daily dose of 200 mg tocopherol, 800 mg propylene glycol, 800 mg sorbitol, 1 g polysorbate 80 in 4 ml water). Alternatively, toxicity may have been related to direct toxicity of vitamin E or of propylene glycol. The dose of propylene glycol was almost three times as much as a well-tolerated daily dose (300 mg propylene glycol and 1 mg vitamin E in 1 ml M.V.I.-Concentrate®, Armour Pharmaceutical Co, Kankakee, IL) resulting in serum propylene glycol levels greater than 40 mg/dl in 14/30 very low birth weight infants (MacDonald 1987). The incidence of necrotizing enterocolitis decreased when this formulation was later replaced with an isotonic solution without propylene glycol.

Soft tissue calcification has been reported in two patients after intramuscular administration of vitamin E (Barak 1986).

4. Why are systematic reviews of vitamin supplementation in preterm infants and subgroup analyses needed?
Existing reviews (Ehrenkranz 1980; Bell 1981; Bell 1987; Phelps 1985; Phelps 1987; Phelps 1988; Bell 1989; Law 1990; Muller 1992; Gross 1993; Baley 1992; Bell 1992; Doyle 1992; Ehrenkranz 1992; Watts 1992; Raju 1997; Greer 2000) have assessed only some of the effects of vitamin E on mortality and morbidity in preterm infants or very low birth weight infants. The present systematic review analyzes a broader spectrum of risks and benefits of vitamin E supplementation, in preterm infants and in very low birth weight infants. Subgroup analyses are required to determine which factors affected the responses to vitamin E supplementation.

Subgroup analyses were designed to determine if the effects of vitamin E supplementation on morbidity and mortality in preterm infants depend on:
(1) Gestational age: The most immature infants body content of vitamin E at birth is lower and the risks for many of the outcome variables are higher. Birth weight could be used if gestational age is not available
(2) Vitamin E preparation and route of administration: This may affect vitamin E absorption, distribution and toxicity. The latter may result (1) from direct tissue toxicity of vitamin E and/or (2) from specific reagents, e.g., polysorbates 80 and 20 (Arrowsmith 1989; Lorch 1985), or propylene glycol, which can unduly increase osmolality, thereby increasing the risk of necrotizing enterocolitis (Finer 1984).
(3) The total daily dose of vitamin E, i.e., the sum of supplemented vitamin E and the dose contained in the formula and in parenteral nutrition in both groups, and serum tocopherol levels.
(4) Time of initiation of vitamin E supplementation: This is especially important for outcome variables which appear early (e.g., intraventricular hemorrhage) and those in which early onset of free radical-related damage and inflammation is expected (e.g., chronic lung disease)
(5) Intake of other nutritional components, which may modify the risk of production of free radicals and serum tocopherol levels (Gross 1985). These may include oxidants (e.g., iron), antioxidants (e.g., selenium, vitamin A) and oxidizable nutrients (e.g., PUFA).
(6) Selection bias: randomized trials (which prevent selection bias) only versus all controlled studies. To limit the size of this review, this subgroup analysis was eliminated (see below).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Index terms

To assess the effects of vitamin E supplementation on morbidity and mortality in preterm infants. Secondary aims included subgroup analyses designed to determine if the effect of vitamin E supplementation depends on the factors delineated above (see Background, last paragraph).

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized or quasi-randomized controlled clinical trials in which at least one of the primary or secondary outcome variables(see below) has been analyzed. After obtaining all possibly eligible trials, it became evident that many large, well-designed randomized trials were available. We therefore decided to eliminate all nine quasi-randomized trials from the analyses.

 

Types of participants

Preterm infants (gestational age less than 37 weeks). Trials were included regardless of the vitamin E intakes of the infants' mothers during pregnancy.
After obtaining all possibly eligible trials, it became evident that many trials assessing the effect of vitamin E on important outcome variables in neonates had used birth weight rather than gestational age. Therefore, eligibility criterion were modified to either gestational age less than 37 weeks or birth weight less than 2500 grams.

 

Types of interventions

Randomized or quasi-randomized allocation of the infant to routine supplementation with vitamin E in the treatment group versus either placebo, no treatment or another type, dose or route of administration of vitamin E. Studies were accepted regardless of the vitamin E content of the infant's feedings (human milk or formula). The treatment group may have received vitamin E supplement either enterally or parenterally, and at any dose. However, studies assessing the effect of another intervention, to which vitamin E was only a co-intervention (e.g., studies assessing the effect of erythropoietin on hemoglobin concentration, in which vitamin E and iron were provided only in the treatment group) were excluded.

 

Types of outcome measures

Primary outcome measures included mortality, combined outcome at 18 months including mortality [mortality, bronchopulmonary dysplasia, blindness, mental retardation or cerebral palsy], and combined outcome at 18 months excluding mortality [bronchopulmonary dysplasia, blindness, mental retardation or cerebral palsy].

Secondary outcome measures include the following:
E-Ferol-related "clinical syndrome" as defined earlier (Arrowsmith 1989), combined outcome (either mortality before discharge, bronchopulmonary dysplasia, severe retinopathy of prematurity, severe cerebral abnormality, blindness, mental retardation, or cerebral palsy), bronchopulmonary dysplasia (current definition: continuous positive airway pressure or oxygen requirement at 36 weeks corrected age), patent ductus arteriosus, sepsis, severe intraventricular hemorrhage (Papile grade III or IV), mild-to-moderate intracranial hemorrhage (Papile stage I or II), severe cerebral abnormality [either intraventricular hemorrhage grade III or IV, cystic periventricular leukomalacia or severe ventricular dilatation], severe retinopathy of prematurity (grade 3 or worse), retinopathy of prematurity, necrotizing enterocolitis with gastrointestinal perforation, necrotizing enterocolitis not requiring surgery, renal failure (serum creatinine concentration above 1.5 mg/dl), signs of hemolysis (anemia, reticulocyte count, hemoglobin concentration, need for transfusion, number of transfusions, bilirubin concentration), platelet count, coagulation tests, and local reaction at the injection site. Studies which reported only serum or plasma tocopherol levels but none of the above mentioned clinical outcomes were not included.

 

Search methods for identification of studies

See Collaborative Review Group Strategy.
MEDLINE accessed using PubMed in October 2002 (1966 - 2002), EMBASE in March 2002 (1974 - 2002), and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2003 and Issue 1, 2007. We examined reports in any language as long as the report included an abstract in English. The MEDLINE search was repeated in April 2003 and March 2007.
The MEDLINE search was done using the following search terms: (<vitamin E> OR <tocopherol>). The search was limited to <birth -23 months> AND (<randomized clinical trial> OR <controlled clinical trial>). Because this search yielded many studies conducted in children, it was re-done using (<vitamin E> OR <tocopherol>) AND (prematurity OR preterm).
The EMBASE search was done using the following search terms: (Exp alpha tocopherol OR vitamin E.mp. OR *tocopherol/) AND (exp prematurity/ OR preterm.mp.). The search was limited to (human and infant < to one year>).
Selection was done independently by three investigators; any disagreement was resolved by discussion.
The CCTR does not accept searches using single-letter words. Therefore the search was done using the following search terms: Tocopherol AND (prematurity OR preterm) AND infant.
Personal files were searched and reviewed relevant references cited in the other manuscripts.

 

Data collection and analysis

The standard methods of the Cochrane Neonatal Review Group (CNRG) were used.
http://neonatal.cochrane.org/
"Organization and Methodology of a Systematic Review for CNRG (Guidelines for Reviewers & Editors)"
These included independent review of all candidate studies by all reviewers. The methodological quality of the trials was assessed by analyzing the risk of four types of bias: selection, performance, attrition and detection.
Standard methods of the CNRG were used for estimating treatment effects with 95% confidence interval (CI) and a fixed effect model. Dichotomous variables were assessed using relative risk (RR), risk difference (RD), and number needed to treat/harm. Data were extracted on as many randomized patients as possible, and analyzed on an intent-to-treat basis, using as denominator for dichotomous variables the total number of randomized patients. Since several studies have reported specific outcome variables only in selected subgroups subject to attrition bias (e.g., survivors) the names of the variables were modified accordingly. Exceptionally, the total number of patients in each arm of the study was not available because the authors have excluded patients from the study after randomization; in this case, the maximum number of available patients was used instead of the total number of randomized patients. Data reported in very low birth weight infants were treated as separate variable, to allow subgroup analyses in this important population. Continuous variables are presented as mean ± 1 standard deviation (SD). Where justified clinically, we merged two or more subgroups of a published study, using standard formulae to calculate the weighted mean and to estimate the weighted standard deviation (Altman 1991; Brion 1990; Zahr 1984). Continuous variables were assessed by the weighted mean difference (WMD) between the treatment group and the control group.
Additional data including those obtained after or pending publication were requested from the authors, if necessary.

I. Original plan:

To analyze studies separately according to the amount of vitamin E provided to the mother during pregnancy, and according to the amount, type or route of vitamin E supplementation of the infants in the control group:
1. Analysis excluding studies with documented prolonged (>1 week) high-dose (>= 400 mg/day) vitamin E supplementation during pregnancy
1.1 Infant provided with placebo, with total daily dose of vitamin E < 10 mg/100 kcal
1.2. Infant provided with another dose of vitamin E (total intake >10 mg/100 kcal)
1.3. Infant provided with another type or route of vitamin E formulation
2. Analysis of studies with documented prolonged (> 1 week) high-dose (>=400 mg/day) vitamin E supplementation during pregnancy
2.1. Infant provided with placebo, with total daily dose of vitamin E < 10 mg/100 kcal
2.2. Infant provided with another dose of vitamin E (total intake >10 mg/100 kcal)
2.3. Infant provided with another type or route of vitamin E formulation

Subgroup analyses planned:
1. Gestational age:
1.1. >= 29 weeks
1.2. < 29 weeks
If gestational age is not available or is not the cut-off for the trials:
1.3. Birth weight > 1000 g
1.4. Birth weight <= 1000 g

2. Medication given in the treatment group:
2.1. Route of administration and formulation:
2.1.1. Enteral
2.1.1.1. Enteral lipid form - isotonic to mildly hypertonic (< 400 mOsm/kg)
2.1.1.2. Enteral lipid form - hypertonic (>= 400 mOsm/kg)
2.1.1.3. Enteral aqueous form
2.1.2. Parenteral
2.1.2.1. Parenteral, excluding polysorbate
2.1.2.2. Parenteral colloidal, excluding polysorbate
2.1.2.3. Parenteral colloidal with polysorbate
2.1.2.4. Parenteral olive oil

3. Total dose of vitamin E provided (iv + diet + supplement)
3.2.1. <25 mg/kg/day
3.2.2. >= 25 mg/kg/day

4. Time of onset of vitamin E supplementation in the treatment group
4.1. Within the first 48 hours of life
4.2. After the first 48 hours of life
4.3. After 4 weeks of life

5. Other nutritional components which may modify the effects of or the need for vitamin E
5.1 Iron supplementation
5.1.1. Iron supplementation > 2 mg/kg/day in both groups
5.1.2. Iron supplementation > 2 mg/kg/day in treatment group only
5.1.3. Iron supplementation <= 2 mg/kg/day

5.2. PUFAs
5.2.1. Formula with PUFAs >400 mg/100 ml formula in both groups
5.2.2. Formula with PUFAs <400 mg/100 ml formula in both groups
5.2.3. Formula with PUFAs >400 mg/100 ml formula in treatment group

5.3. Dietary or parenteral supplementation with one or more other antioxidants (in both groups)
5.3.1. Selenium fortification >= 3 mcg/kg/day
5.3.2. Vitamin A supplementation (>= 1500 U/day)
5.3.3. Selenium fortification >= 2 mg/100 ml formula and vitamin A supplementation (>=1500 U/day)
5.3.4. Neither

6. According to study design:
6.1. Randomized studies only
6.2. All studies

II. Modifications to the original plan:

Studies of vitamin E administration to preterm infants have been conducted for more than fifty years, during which standard of care including baseline vitamin E intake in pregnancy and in very low birth weight infants has changed considerably. Furthermore, the definitions of chronic lung disease of prematurity or bronchopulmonary dysplasia and of retinopathy or prematurity or retrolental fibroplasia have changed several times during the last decades. Several methods have been used to administer vitamin E, and some of the differences in design among studies became clear only during completion of the protocol.

Outcome variables in the available trials were often reported only is specific subgroups, e.g., very low birth weight infants. Because very low birth weight infants are the only ones at risk for some of the complications potentially treated or prevented by vitamin E (e.g., severe retinopathy of prematurity), separate outcome variables were created in that weight group to allow subgroup analyses. This was the only way to determine which (or whether any) specific method of vitamin E administration (dose, duration, level, etc) is both efficient and nontoxic in very low birth weight infants. Subgroups among very low birth weight infants are referred to as "all studies" when they included all studies irrespective of the weight cut-off (either 1500 grams or 1000 grams), "equal to or less than 1500 grams" or "equal to or less than 1000 grams", as appropriate for each specific weight cut-off. For many outcome variables the first subgroup includes "all infants in all studies."

An additional outcome variable that had not been anticipated was added as a post-hoc analysis: retinal hemorrhage.

In order to limit the number of comparisons, the main planned comparisons (listed in above sections 1 and 2) were replaced by the following:
1. Vitamin E versus placebo
2. Vitamin E versus another form or route of vitamin E (intramuscular versus enteral, intravenous versus intramuscular, intramuscular in olive oil versus intramuscular in colloidal form)

Many trials used combination of enteral and parenteral vitamin E supplementation, so these entries were modified as follows:
2. Route of administration and formulation:
2.1. Enteral
2.1.1. Enteral hypertonic formulation at pharmacologic dose
2.2. Parenteral with or without enteral
2.2.1. Parenteral with hypertonic enteral formulation at pharmacologic dose
2.2.2. Parenteral colloidal with polysorbate
2.2.3. Intravenous (with or without other routes of administration)
2.2.4. Excluding intravenous administration

The cut-off value for vitamin E intake were clarified as follows:
3. Total daily dose of vitamin E provided (iv + diet + supplement) to the treatment group, target serum level
3.1. <=20 mg d-alpha-tocopherol equivalents/kg/d OR 30 IU/kg/d, i.e., 30 mg/kg/d dl-alpha-tocopheryl acetate*
3.2. > 20 mg d-a-tocopherol equivalents/kg/d OR 30 IU/kg/d, i.e., 30 mg/kg/d dl-alpha-tocopheryl acetate*
* If the dose is expressed in IU/day or mg/day, we used mean birth weight (estimated, if necessary, to be 1000 g for studies on infants with birth weight < 1500 grams) in the group for the calculations.

Based on Johnson 1995 an entry based on serum tocopherol levels at the end of the period of vitamin supplementation was added:
3.3. Serum tocopherol level <=3.5 mg/dl (81 micromoles/L)
3.4. Serum tocopherol level >3.5 mg/dl

Subgroup analyses were added based on duration of the treatment:
4. Time of onset and duration of vitamin E supplementation in the treatment group
4.1. Within the first 48 hours of life
4.2. After the first 48 hours of life
4.3. Duration of treatment <= 1 week (7 daily doses)
4.4. Duration of treatment > 1 week (7 daily doses)

Since only randomized trials were included for this review, the subgroup analysis of randomized trials was eliminated.

Vitamin E administration during pregnancy and dose of vitamin E in the control group is addressed as subgroup analyses instead of main comparisons:
6. Vitamin E provided during pregnancy
6.1. Documented prolonged high-dose (at least 400 IU/day for a week) vitamin E during pregnancy

7. Total dose of vitamin E provided to the control group
7.1. <= 10 mg vitamin E/100 kcal
7.2. > 10 mg vitamin E/100 kcal

Subgroup analyses based on other nutritional components that may modify the effects of or the need for vitamin E were assessed as planned, except comparisons in which vitamin E was a co-intervention with one of those supplements were eliminated.

Because these studies have spanned more than 50 years of research, definitions of outcome variables such as retrolental fibroplasia (retinopathy of prematurity) and bronchopulmonary dysplasia have changed. Only entries for which we found relevant studies are presented in the Table of Comparisons.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

The MEDLINE search retrieved 128 studies, the EMBASE search 35 studies and the CCTR search 14 studies. Review of personal files and reading of documents obtained by the initial searches and by screening all references listed in manuscripts yielded more than 50 additional studies. An updated search of the MEDLINE and the CCTR conducted in March 2007 yielded one additional retrospective study (Liu 2005). After excluding ineligible studies and after merging multiple publications of the same studies, a total of 62 trials remained. Twenty-six randomized clinical trials (range of patients per trial: 10-914) were included in this systematic review. Among these 26 trials, five were conducted in the 1970's, 17 in the 80's, three in the 90's and one in 2003.

Only those trials that prospectively compared a group of vitamin E-supplemented neonates with a control group are reported in the Tables of Included and Excluded Studies. Thirty-five studies are listed in the Table of Excluded Studies. Studies were placed in this group for the following reasons (some studies for more than one reason): (1) trials (n=18) that did not assess any of the predefined outcomes or did not provide analyzable outcomes because either mean and variability (standard error of the mean or standard deviation), frequencies or individual data were not available, (2) studies (n=7) in which the experimental group and the control group were not enrolled simultaneously, (3) quasi-randomized trials (n=12, of which three had at least one additional criterion of exclusion), defined as trials in which patients were not randomly allocated to the treatment and the control arms of the study, (4) trials (n=3, two of which also fitted the first criterion) in which either no preterm infants had been enrolled or a mixture of full-term and preterm infants had been enrolled and (5) trials (n=1) in which vitamin E was only a co-intervention. A complete list of 51 additional publications (case series, reviews, retrospective chart reviews) that were considered but are not reported in this systematic review is available upon request.

Although the classical definition of very low birth infants is a birth weight less than 1500 grams, studies assessing the effect of vitamin E on outcomes in preterm infants used a birth weight equal to or less than 1500 grams. In order to shorten the text, the term "very low birth weight infants" is used to refer to this latter group.

1. Vitamin E versus placebo
This group included 25 randomized trials that assessed the effects of vitamin E supplementation by enteral route only (n=8), intramuscular with or without enteral (n=15), or intravenous with or without other routes (n=2). Vitamin E supplementation was initiated within the first 48 hours of life in all treated patients in 20 studies, and after 48 hours in all treated patients in four studies. The duration of vitamin E supplementation was up to one week in eleven studies and greater than one week in all patients in thirteen studies. The total dose of vitamin E intake in the treated group was equal to or less than 30 IU/kg/day in fifteen studies and greater than 30 IU/kg/day in nine studies. Serum tocopherol levels were up to 3.5 mg/dl in fifteen studies and greater than 3.5 mg/dl in eight studies. The total dose of vitamin E intake in the control group was up to 10 mg/100 kcal in 22 studies and greater than 10 mg/100 kcal in three studies.

Chiswick 1982 is a randomized trial assessing the effect of four daily intramuscular injections of 20 mg/kg/dose of dl-alpha-tocopheryl acetate as an aqueous colloidal solution (Ephynal®, Hoffmann-La Roche, Basel, Switzerland) starting at 24 hours of age on mortality and intraventricular hemorrhage in preterm infants. Entry criteria were: preterm infants without major congenital malformations. The concentration of the solution was 1000 mg/2 ml, and individual doses greater than 0.5 ml were divided and given in two different injection sites. Controls received no injection of vitamin E. Only five infants, i.e., those without respiratory distress, received formula (SMA Gold Cap Milk®, Wyeth Laboratories, Slough, England) during the first four days of life. The total number of patients entered into the study was 35, including 14 in the treatment group and 21 in the control group. Gestational ages ranged from 25 to 36 weeks (average 29.1±3.3 weeks in the treated group and 29.3±3.3 weeks in the control group) and birth weights from 550 to 1750 g (average 1.21±0.29 kg in the treated group and 1.25±0.33 kg in the control group). Intraventricular hemorrhage was diagnosed by computerized tomography, clinical findings (uniformly blood-stained cerebrospinal fluid, seizures, tense anterior fontanel) or autopsy. Because not all infants had a computerized tomography (number not provided) or an autopsy (n =1), it is possible that some cases of intraventricular hemorrhage may not have been diagnosed; for the calculations we only used demonstrated cases of intraventricular hemorrhage (in contrast with the authors who assumed that one patient had a hemorrhage). Outcome variables included mortality and intraventricular hemorrhage.

Chiswick 1983 is a randomized trial assessing the effect of three intramuscular injections of 20 mg/kg/dose of dl-alpha-tocopheryl acetate as an aqueous colloidal solution (Ephynal®, Hoffmann-La Roche, Basel, Switzerland) given at 12, 36 and 60 hours of age on intraventricular hemorrhage in preterm infants. Entry criteria were gestational age less than 37 weeks and birth weight less than 1751 g. Controls received no injection of vitamin E. No information is provided about enteral intake of vitamin E. Intraventricular hemorrhage was diagnosed by ultrasonogram performed within the first 48 hours of life and at least once after 72 hours; repeat examinations were done where possible daily during the first week and less often afterwards. The total number of patients was 44, including 21 in the treatment group and 23 in the control group. Mean gestational ages and birth weights in the whole study population are not provided. Outcome variables included mortality, germinal matrix/intraventricular hemorrhage, and intraventricular hemorrhage.

Cruz 1983 is a randomized controlled trial assessing the effect of four intramuscular injections of 25 mg/kg of vitamin E (on days one, two, four and eight, respectively) on hematologic parameters in preterm infants. Entry criteria were: (1) mothers admitted with threatened premature delivery at 26-34 weeks of gestation, (2) infants born to mothers admitted for threatened preterm delivery at 26-34 weeks of gestation and delivered with a weight less than 2300 g. All mothers of infants in the randomized trial received 900 mg of vitamin E (Ephynal®, Roche) daily for three days, followed by 100 mg daily until delivery. A non-randomized third group of infants, born to non-supplemented mothers, received no intramuscular vitamin E supplementation. All infants were fed banked breast milk, followed by an infant formula (Allomin). All infants received oral multivitamin drops starting on day five of life; this provided two mg of vitamin E daily. Among 55 infants enrolled in this trial, 27 were randomized to the experimental group and 28 to the control group. Mean gestational ages were 32.8±1.9 weeks and 32.4±1.9 weeks, respectively, in the experimental and in the control group, and mean birth weights were, respectively, 1808±361 and 1817±357 g. Outcome variables included retrolental fibroplasia, and bronchopulmonary dysplasia.

Ehrenkranz 1982 is a double-blind randomized trial assessing the effect of repeated intramuscular injections of 20 mg/kg of Vitamin E Injectable® (Hoffmann-LaRoche) on neonatal outcomes. Entry criteria included respiratory distress syndrome and informed consent. Injections were given upon admission to the study and 24, 48, and 168 hours later. Additional doses were given twice weekly as long as infants received oxygen therapy and could not tolerate feedings and vitamin supplements. Patients in the control group received same volumes of placebo, i.e., the vehicle. All infants initially received an intravenous protein solution containing vitamin E 2.5 U/L. Enteral feedings 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 less than 1000 g and 25 IU/day if weight was greater than 1000 g. Among 100 patients enrolled into the study, 47 were in the experimental group and 53 in the control group. Average gestational ages were 30.3±2.7 and 30.5±2.9 weeks , respectively, in the experimental group and in the control group, and average birth weights were, respectively, 1427±432 and 1425±466 g. Outcome variables included mortality (NY Acad Sciences 1982, table I, page 454; with one additional later death in the treated group and three in the control group [page 458]), bronchopulmonary dysplasia (diagnosis based on clinical, radiologic and/or pathologic evidence), patent ductus arteriosus, patent ductus arteriosus requiring therapy, intraventricular hemorrhage, and retrolental fibroplasia (numerator: Table 5A (revised), Ehrenkranz, Ophthalmol 1982; 89: page 988; denominator: Ehrenkranz, Ann NY Acad Sci 1982, table I, page 454; data for very low birth weight: Hittner, NEJM 1982 page 868, Figure 1). A stage II retrolental fibroplasia in this study corresponds to a stage III from the current classification (NEJM 1982).

Ferlin 1998 is a randomized trial assessing the effect of oral supplementation with 25 IU/day of vitamin E and 4 mg/kg/day of elemental iron (provided as iron sulfate) on hematologic parameters in preterm infants. Entry criteria included: 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, and absence of interfering events that would require discontinuation of medications. Patients were randomly allocated into one of four groups: group I: placebo started on the fifteenth day of life, iron starting at two months of age; group II: 4 mg/kg/day iron started on the fifteenth day of life; group III: 4 mg/kg/day iron and 25 IU/day alpha-tocopherol (Roche) orally started on the fifteenth day of life; group IV: 25 IU/day vitamin E started on the fifteenth day of life. All infants received 1.5 IU vitamin E/day and 0.1 mg iron (in multivitamin preparation) starting on the seventh day of life. Iron supplementation was started at 2 months of age in patients who had not been supplemented with iron yet. The 40 patients enrolled in the study were distributed equally among the four groups. Median birth weights and quartiles were 1395 g (1210, 1510), 1315 g (1210,1430), 1310 g (1290,1420) and 1385 g (1260,1540), respectively, in groups I through IV. For this systematic review we compared group III (treatment) with group II (control) and group IV (treatment) with group I (control). The only analyzable outcome variable is hemoglobin concentration at two months of age; for this purpose, the individual data from Figure 2 was used.

Finer 1982 is a randomized trial assessing the effect of serial intramuscular injections of vitamin E on neonatal outcomes in preterm infants. Entry criteria included: birth weight between 750 and 1500 g, appropriate for gestational age, and informed consent. Infants in the treated group received 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 three days for five doses; then either 100 U daily orally or (if feeds not tolerated) 20 mg intramuscularly every three days. Infants in the control group did not receive any injections. The osmolality of the oral preparation, used as a 1:1 dilution, was 2,025 mOsm/kg. Among 126 infants entered into the trial, 62 were allocated to the treatment group and 64 to the control group. Average birth weights and ranges were 1197 g (820-1460) in the treatment group and 1207 g (760-1500) in the control group, and average gestational ages were, respectively, 29.3 weeks (26-34) and 29.3 weeks (26-35). Outcome variables included bronchopulmonary dysplasia, patent ductus arteriosus, and necrotizing enterocolitis. Outcomes described in some Infants only include: acute or cicatricial stage of retrolental fibroplasia [Lancet 1982, Table V, page 1089] (patients surviving at least one month) and blindness from retrolental fibroplasia (patients examined).

Fischer 1987 is a double-blind randomized trial assessing the effect of oral administration of d-alpha-tocopherol polyethylene glycol-1000-succinate, 50 mg/day for three doses on bilirubin and hemoglobin in preterm infants. However, several infants received only 25 mg/day. Entry criteria included birth weight less than 1,500 g, normal size for gestational age, and informed consent. Control infants received placebo. The total number of patients entered into the study was 28, including seventeen in the treatment group and 11 in the control group. Average birth weights were 1220±170 g in the treatment group and 1250±150 g in the control group, and average gestational ages were, respectively, 30±1 weeks and 32±2 weeks. Outcome variables included hemoglobin and bilirubin concentrations.

Fish 1990 is a double-blind randomized trial assessing the effect of dl-alpha-tocopherol (Ephynal®, Hoffmann-La Roche) intramuscularly on neonatal outcomes in preterm infants. Entry criteria included birth weight equal to or less than 1000 g, postnatal age equal to or less than 24 hours, and informed consent. Exclusion criteria were: extremely poor condition upon admission or major congenital abnormalities. Vitamin E was provided in four intramuscular doses at 15, 10, 10 and 10 mg/kg on days one, two, four and six of life, respectively, in preterm infants. Doses of dl-alpha-tocopherol 10 mg/kg were administered intramuscularly every three days if the attending neonatologist felt that the infant could not tolerate oral vitamin E after 7 days of life. Control patients received a placebo. All neonates received oral dl-alpha-tocopheryl acetate (Aquasol E) 100 mg/kg/day beginning at admission; the dose was adjusted after day 7 to maintain total serum tocopherol level 0.5-3.5 mg/dl. The total number of patients entered into the study was 149, of which two were excluded after entry, 73 were in the treatment group and 74 in the control group. Average birth weights in the treatment group and in the control group were, respectively, 782±70 g and 783±76 g, and average gestational ages were, respectively, 26±1 weeks and 26±1 weeks. Outcome variables included mortality, intracranial hemorrhage, necrotizing enterocolitis, sepsis, patent ductus arteriosus, and local reaction at injection site.

Graeber 1977 is a randomized trial assessing the effect of vitamin E supplementation (2 doses tested) and that of iron supplementation on neonatal outcomes in preterm infants. Entry criteria included birth weight less than 1500 g and gestational age less than 34 weeks. Exclusion criteria included 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. Patients were divided into six groups according to the amount of vitamin E (none, 100 , 125 or 150 mg/kg intramuscularly) and the amount of iron-dextran complex (none or 25 mg intramuscularly on days 7, 14, 21 and 28). Each vitamin E dose was divided into four doses on days one and two, and days seven and eight, respectively. For this systematic review we regrouped patients according to vitamin E allocation. Among 35 infants entered into the study twenty were randomized to vitamin E supplementation (treatment) and fifteen to no supplementation (control). Birth weight ranged from 940 to 1470 g (mean 1270 g). Outcomes included bronchopulmonary dysplasia and retrolental fibroplasia.

Gross 1977 is a randomized trial assessing the effect of intramuscular administration of a total dose of 125 mg/kg tocopheryl acetate (Roche) on hemoglobin concentration in preterm infants. Entry criteria included birth weight less than 2,500 g, gestational age less than 36 weeks, well, breathing room air, and hemoglobin concentration greater than 13 g/dl on the third day of life. Exclusion criterion was either Rh or ABO isoimmunization. Vitamin E was given in eight divided doses, an injection in each thigh, on days four, five, six and seven of life. Controls received no injection. Neither group received iron supplementation. The twenty patients entered into the study were equally divided into the treatment group and the control group. Mean gestational ages in the treatment group and in the control group were, respectively, 33.5±1.7 and 33.2±1.4 weeks, and mean birth weights were, respectively, 1717±176 and 1631±397 g. The outcome variable was hemoglobin concentration.

Gross 1979 is a randomized controlled trial assessing the effect of intramuscular administration of a total dose of 50 mg/kg dl-alpha-tocopheryl acetate (Roche) administered intramuscularly in 6 divided doses, an injection in each thigh on days one, two and three of life. Entry criteria were birth weight between 1000 and 2000 g, and appropriate for gestational age. Exclusion criteria included hemoglobin concentration less than 13 g/dl, and Rh or ABO isoimmunization. Infants in the control group received no injection. Neither group received iron supplementation. Among the 40 patients entered into the study, twenty were assigned to the treatment group and twenty to the control group. Eligible infants had a birth weight between 1000 and 2000 g and were appropriate for gestational age; average weight values are not provided. The outcome variable we used for this review was serum bilirubin concentration on day four of life.

Hittner 1981 is a randomized trial assessing the effects of enteral administration of 100 mg/kg/day of dl-alpha-tocopheryl acetate (Aquasol E®, preparation containing Tween 80, propylene glycol, sorbitol, oil of anise, sodium saccharin, imitation butterscotch flavor) from the first day of life until discharge. Entry criteria included birth weight less than or equal to 1500 g, requiring oxygen for respiratory distress, admitted to the unit within the first 24 hours of life, and informed consent. Exclusion criteria included necrotizing enterocolitis preventing oral administration of vitamin E (n = 1). Patients who died within four weeks (n = 48) were excluded from all other outcomes. Osmolality of the enteral vitamin E preparation was 3000 mOsm/L (Hittner 1984). Control infants received a placebo solution. The total number of patients entered into the study was 150, including 75 allocated to the treatment group and 74 to the control group. Mean gestational ages in the treatment group and in the control group were, respectively, 29.3±2.2 and 29.4±2.0 weeks, and mean birth weights 1093±245 and 1113±245 g. Outcome variables included (1) mortality (data from NEJM 1981, Figure 1, page 1367), and (2) among patients surviving at least four weeks and without necrotizing enterocolitis: bronchopulmonary dysplasia, patent ductus arteriosus, sepsis, periventricular-intraventricular hemorrhage and retrolental fibroplasia.

Hittner 1984 is a randomized trial assessing the effect of intramuscular administration of dl-alpha-tocopherol, 55 mg/ml (Ephynal®, Hoffman-La Roche, preparation containing benzyl alcohol, propylene glycol, ethyl alcohol, Emulphor E1-620, and buffering salts) at doses of 15, 10, 10, and 10 mg/kg on days 1, 2, 4 and 6 of life, respectively, in preterm infants. Entry criteria included birth weight equal to or less than 1,500 g, oxygen requirement for respiratory distress, admission within 24 hours, and informed consent. Patients who died before 10 weeks of life (n = 33) were excluded from all other outcomes. Controls received placebo injections. Vitamin E 100 mg/kg/day was given orally to all infants starting within the first 24 hours of life and until vascularization of the retina was complete. Oral vitamin E was provided as an emulsion of dl-alpha-tocopheryl acetate in gelatin, silicon dioxide, polysorbate 80, and medium chain triglycerides; the osmolality was 150 mOsm/kg. Among the 168 patients entered into the study, 79 were allocated to the treatment group and 89 to the control group. Average gestational ages were 28.7±1.9 and 29.4±2.0 weeks, respectively, in the experimental group and in the control group, and average birth weights were, respectively, 1091±233 and 1113±245 g. Outcome variables included (1) mortality (Pediatrics 1984, Table 4 and Figure 1) and (2) 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 (primary reference).

Jansson 1978 is a randomized trial assessing the effect of iron and vitamin E on hematologic parameters in preterm infants. Entry criterion was a birth weight less than 2500 g. Patients who died before ten weeks (n =33) were excluded from all other outcomes. Patients were randomly allocated into three groups. Group I (control) received ferrous succinate starting at three weeks of age (elemental iron 2-3 mg/kg/day); group II received 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; and group III received tocopheryl acetate 15 mg/day started at 10 days and ferrous succinate started at 10 weeks. Among the 57 enrolled patients, 24 were allocated to Group I, 17 to group II and 16 to group III. For this systematic review we compared groups I and II, in which iron was initiated at the same postnatal age. Average birth weights in groups I (control) and II (treatment) were 1899 and 1767 g for those < 2 kg and 2135 and 2330 g for those 2.000-2.499 kg, respectively (variability not provided). Mean gestational ages were, respectively, 34.6 and 35 weeks for those with a birth weight less than 2 kg, and 37.5 and 36.4 weeks for those with a birth weight between 2.000 and 2.499 kg. Outcome variables included hemoglobin concentration, reticulocyte count and platelet count.

Johnson 1989 is a double-blind randomized trial assessing the effect of parenteral vitamin E (under a FDA-approved IND) on retinopathy of prematurity in preterm infants. Entry criteria included: (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, and admission within 5 days of age. Treatment included: (1) for infants receiving intravenous feeding: 15 mg/kg vitamin E intramuscularly and 15 mg/kg intravenously (given at a 1:100 dilution over an 8-hour period) at study admission, followed by 15 mg/kg intravenously the next day; (2) for infants receiving oral feedings: 15 mg/kg vitamin E intramuscularly and 100 mg/kg/day divided in aliquots in the feeds. Subsequent investigational vitamin E dosage was provided until retinal vascularization was complete or active ROP had subsided, to maintain serum tocopherol level of 5 mg/dl. Parenteral vitamin E was provided as free dl-alpha-tocopherol 50 mg/ml (55 IU/ml) emulsified with Emulfor E1-620. Enteral vitamin E was provided as free dl-alpha tocopherol 50 mg/ml with 180 mg/ml polysorbate 80, and 700 mg/ml propylene glycol 80. Controls received placebo both for oral and parenteral preparations, with dosage adjustments to mimic those in the control group. In infants in whom severe ROP had developed, the study medication was replaced with vitamin E. Among 914 infants enrolled into the study, 454 were allocated to the treatment group and 460 to the control group. Average birth weight was 1461±457 g in the treatment group and 1444±439 g in the controls. Average gestational age was 31.5±2.7 weeks in the treatment group and 31.6±2.8 weeks in the controls. Age at study entry was 1.6±1.2 days for patients in the treatment group and 1.5±1.0 days for controls. The only outcome variables available in the whole study population (Birth Defects 1988, page 226) was intraventricular hemorrhage. 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 (Pediatrics 1985 & 1989) included mortality, bronchopulmonary dysplasia (diagnosed radiographically), patent ductus arteriosus, patent ductus arteriosus requiring treatment, sepsis after study entry, intraventricular hemorrhage (Birth Defects page 226), 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: Pediatrics 1980), and amount of blood transfusion (subset of very low birth weight infants: Pediatrics 1989).

Melhorn 1971 is a randomized trial assessing the effect of iron and vitamin E on hemoglobin concentration in infants admitted to the premature nursery. Exclusion criteria included: 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. After stratification for gestational age and birth weight within the first 48 hours of life, patients were randomized to one of four groups: Group 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. Among the 234 enrolled into the study, data are available in 186, including 45 randomized to group I, 47 to group II, 44 to group III and 50 to group IV. In category A, mean gestational age in each ranged from 30 to 31 weeks and mean birth weight ranged from 1170 grams to 1280 grams. In category B, mean gestational age was 34 weeks in each group, and mean birth weight ranged from 1700 grams to 1775 grams. In category C, mean gestational age in each group ranged from 37 to 38 weeks and mean birth weight from 2168 grams to 2243 grams. For this review, the effect of vitamin E was assessed by comparing group II with group I (no iron) and group IV with group III (iron). Outcome variables in categories A and B included hemoglobin at ten weeks of age and reticulocyte count.

Pathak 2003 is a double-blind randomized trial assessing the effect of enteral administration of vitamin E 50 IU/day on hemoglobin concentration and reticulocyte count in very low birth weight infants receiving erythropoietin and iron. Entry criteria included: 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, and mean airway pressure less than or equal to 8 cm of water). Exclusion criteria included: a disease involving any major organ system, life-threatening congenital malformations or sepsis, isoimmunization with clinically apparent hemolytic anemia, hemolytic disorder, and intraventricular hemorrhage grade III or greater. Controls received placebo. All patients entered into the study were receiving 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-tocopheryl acetate/ml at a 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. Among 30 patients entered into the study, 15 were allocated to the treatment group and 15 to the control group. Average birth weights in the treatment group and in the control group were, respectively, 928±170 grams and 899±159 grams, average gestational ages were, respectively, 27.9±1.9 and 27.9±1.5 weeks, and postnatal ages at the time of study entry were, respectively, 24.4±15.5 days and 28.1±10.1 days. Outcome variables included mortality, patent ductus arteriosus requiring treatment, sepsis, necrotizing enterocolitis, hemoglobin concentration, reticulocyte count, number of transfusions, and total volume of blood transfused.

Phelps 1987a is a double-blind randomized trial assessing the effect of intravenous administration of a dose of 20 mg/kg of an investigational drug [nonesterified dl-alpha-tocopherol in alcohol or its vehicle (10% ethyl alcohol, 10% propylene glycol, 10% Emulphor, 1% benzyl alcohol, and buffering salts)] provided within 24 hours of birth and repeated on day two (and sometimes day three). Entry criteria included: birth weight less than 1500 g 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. Doses were adjusted to achieve plasma tocopherol levels of 3-3.5 mg/dl. Average daily intramuscular dose was 14.4±4.7 mg/kg/day during the first week, and ranged between 4.1 and 7.0 mg/kg/day during the subsequent weeks. Infants fed enterally received enteral vitamin E (free tocopherol), which was started at a dose of 100 mg/kg/day and adjusted according to the serum level. Supplemental intramuscular injections were given to infants with plasma levels lower than 2.5 mg/dl despite oral doses exceeding 200 mg/kg/day. Average oral dose (after the initial parenteral administration) was 69±66 mg/kg/day; 56 of 108 patients with oral vitamin E administration received intramuscular supplementation (one to four doses). Control infants received placebo. All infants fed intravenously received 1.2 mg/kg/day of tocopheryl acetate in standard multivitamin supplements. Controls received therapeutic vitamin E if they developed hemolytic anemia associated with a plasma level of tocopherol less than 0.5 mg/dl. Infants requiring surgery or chest tube placement were given vitamin A 2500 IU/day for a week. The total number of patients entered into the study was 287, including 140 in the treatment group and 147 in the control group. Average birth weights in the treatment group and in the control group were, respectively, 1181±307 grams and 1205±319 grams, and average gestational ages were, respectively, 29.5±2.5 weeks and 29.9±1.5 weeks. Outcome variables included (1) among all infants: mortality, sepsis after 48 hours, periventricular-intraventricular hemorrhage and necrotizing enterocolitis, (2) among 232 infants with ophthalmologic examination: retinal hemorrhage, and (3) among 196 surviving infants: retinopathy of prematurity.

Rönnholm 1989 is a randomized trial assessing the effect of intramuscular administration of dU-rac-alpha-tocopheryl acetate 20 mg/kg/day (Ephynal®, Hoffmann-La Roche) during the first three days of life in preterm infants. The entry criterion was a birth weight less than or equal to 1520 g. Patients in both groups received oral administration of water soluble vitamin E dl-alpha-tocopheropolyethylene glycolol 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. Controls received oral vitamin E only. Iron supplementation was started gradually at two weeks of age, and increased until six weeks of age to reach four mg/kg/day if birth weight was <= 1000 grams and 3 mg/kg/day if birth weight was > 1000 grams. Vitamin A was supplemented as retinol palmitate (1500 IU/day), starting at twelve weeks of postnatal age, or approximately 42 weeks of postmenstrual age, i.e., after all outcomes of interest had already been assessed. Patients were also randomly supplemented with human milk protein, medium-chain triglycerides, both or neither. The total number of patients entered into the study was 54, including 23 allocated to the treatment group and 31 to the control group. Absolutely no data are provided about the three patients who died from respiratory distress syndrome or from cerebral hemorrhage. Average birth weights in the treatment group and in the control group were, respectively, 1153±245 grams and 1222±228 grams, and average gestational ages were, respectively, 29.9±1.9 weeks and 30.4±2.1 weeks. Outcome variables among the 51 survivors included bronchopulmonary dysplasia, intraventricular hemorrhage, retrolental fibroplasia, and necrotizing enterocolitis.

Rudolph 1989 is a randomized controlled trial assessing the effect of intramuscular administration of dl-alpha-tocopherol (Hoffman-La Roche) at dose of 25 mg/kg within 12 hours of birth, with repeated injections 24 hours later, and at 4, 5, 10, 20 and 30 days of age, yielding a total cumulative dose of 175 mg/kg on neonatal outcome. Entry criteria included: preterm delivery, birth weight 750-1500 g, and intensive care. Controls received no vitamin E supplementation. All infants fed intravenously received 2.5 IU vitamin E per liter of parenteral solution. Among the 29 patients entered into the study, thirteen were allocated to the treatment group and sixteen to the control group. Average birth weights in the treatment group and in the control group were, respectively, 1202±198 grams and 1187±198 grams, and average gestational ages were, respectively, 30.7±2.3 weeks and 30.5±1.6 weeks. Outcome variables included mortality, patent ductus arteriosus (assessed clinically), severe retinopathy of prematurity and necrotizing enterocolitis.

Saldanha 1982 is a randomized controlled trial assessing the effects on intramuscular administration of 25 mg of dl-alpha-tocopherol (Hoffman-La Roche) upon entry into the study and daily thereafter until serum tocopherol level rose above 2-4 mg/dl or until oxygen was no longer required. Entry criteria included gestational age less than 37 weeks, hyaline membrane disease, oxygen requirement at least 60% in first 24 hours or 80% thereafter, and informed consent. Exclusion criteria included cyanotic heart disease, multiple malformations, and known infectious disease. Controls received no injection. The total number of patients entered into the study was 44, including 21 in the treatment group and 23 in the control group. Average birth weights in the treatment group and in the control group were, respectively, 1458±491 grams and 1554±557 grams. Average gestational ages among patients surviving ten days were, respectively, 32.4±2.1 weeks and 32.9±2.9 weeks. Outcome variables among patients surviving ten days or more included: bronchopulmonary dysplasia and patent ductus arteriosus (diagnosed clinically).

Schiller 1980 is a randomized trial assessing the effect of intramuscular administration of dl-alpha-tocopherol (175 mg/kg over a 30-day period) on patent ductus arteriosus. Entry criteria were: preterm infant, and birth weight < 1750 g. Time of onset is not provided. Controls did not receive any injection. Among the 29 infants entered into the study, sixteen were allocated to the treatment group, and thirteen to the control group. The outcome variable was patent ductus arteriosus.

Sinha 1987 is a randomized trial assessing the effect of intramuscular administration of alpha-tocopheryl acetate (Ephynal®, Hoffman-La Roche) 20 mg/kg daily for three doses commencing within two hours after randomization (first day of life). Entry criteria included gestational age equal or less than 32 weeks, admitted from January 1984 to September 1985. No exclusion criteria were used before randomization; however, patients randomized before delivery and found after birth to have lethal malformations were excluded from the study. Controls received no placebo. The mothers 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. Among the 231 patients entered into the study, no data are provided on the three infants with lethal malformations, so that the total number of patients retained in the study is 228 (presumably 115 treated patients and 113 controls, based on totals in Table II plus numbers of excluded patients in the second paragraph of the discussion). Only partial data are provided in 18 patients with a hemorrhage on the initial ultrasonography obtained within two hours of life or (if out born) upon admission to the unit. In the manuscript, several data are presented only in the 210 patients with negative initial scan (102 patients in the treatment group and 108 in the control group), including birth weights in the treatment group and in the control group (respectively, 1273±315 grams and 1214±346 grams), gestational ages (respectively, 29.3±2.0 weeks and 28.8±2.2 weeks), and complete information about the classification of the intracranial hemorrhage. The authors used a classification in 3 grades; therefore, grade 3 was re-coded into Papile's grade IV (intraparenchymal hemorrhage). Outcome variables available in all patients included mortality, periventricular-intraventricular hemorrhage (adding numbers in Table II and those in the second paragraph of the discussion), necrotizing enterocolitis, and reaction at site of injection.

Smith 1985 is a double-blind randomized trial assessing the effect of oral administration of dl-alpha-tocopheryl polyethylene glycol-succinate (Mead Johnson) 50 mg/day once a day for three consecutive days; the first dose was given before 24 hours of life. Entry criteria included: gestational age 30-36 weeks, birth weight 970-2610 g, healthy, lack of pulmonary disease or oxygen requirement, no ABO or Rh isoimmunization, and no other sources of bilirubin production, such as hematoma or bruising. The only exclusion criterion was infection. Control patients received placebo. All infants were fed either breast milk or a proprietary formula without iron (vitamin E contents ranging from 12 to 25 IU/L). Decisions regarding phototherapy were made by staff physicians who were unaware of the study results. Among 30 patients entered into the study, seventeen were allocated to the treatment group and thirteen to the control group. Average birth weights were 1.79±0.38 kg in the treatment group and 1.83±0.33 kg in the control group; average gestational ages were 32.6±1.6 weeks and 33.4±1.5 weeks, respectively. Outcome variables included bilirubin concentration and hemoglobin concentration.

Zipursky 1987 is a double-blind randomized trial assessing the effect of enteral (gavage) supplementation of 25 IU vitamin E daily provided as 16 mg dl-alpha-tocopherol (Hoffman-La Roche) for six weeks in preterm infants smaller than 1500 g on anemia, coagulation tests and serum tocopherol levels. Entry criteria included birth weight < 1500 g, expected survival greater than 48 hours, and informed consent. Exclusion criteria included major congenital anomalies and Rhesus hemolytic disease. Infants in the control group received placebo (Tween 80). Age at entry into the trial was 2.7±3 days in treatment group and 2.9±2 days in control group. Infants in both groups also received recommended amounts of vitamin E, either in breast milk (5.4 IU/L and 0.8 mg/g of PUFA), SMA 20 (10 IU/L or 1.3 mg/g of PUFA) or SMA 24 (12 IU/L or 1.3 mg/g of PUFA). The range of PUFA content in milk used was 4-6 g/L. No added iron was provided, although SMA 20 and SMA 24 contained, respectively, 12.7 and 15.2 mg/L of iron sulfate. Individual or group amounts of feeding are not provided, so that total amount of iron cannot be calculated. The total number of patients is not the same in the two follow-up manuscripts (266 in Milner 1981 and 268 in Watts 1991). Assuming that these differences represent loss to follow-up (two patients lost to follow-up acknowledged in Milner 1981), the total number of patients is presumed to be 269 infants entered into the study, with 135 allocated to the treatment group and 134 to the control group. Average birth weights were 1149± 244 g and 1158±251 g in the treatment group and in the control group, respectively, and average gestational ages were 29.2±2.7 and 29.1±2.7 weeks, respectively. Mean age at entry into the trial was 2.7±3 days in the treatment group and 2.9±2 days in the control group. Baseline characteristics (number of infants < 1000 g, percentage of infants with severe illness) were similar in the two groups. Outcome variables included mortality and stages III or IV bronchopulmonary dysplasia (defined, respectively, by bilateral cystic lesions without or with fibrosis) and retrolental fibroplasia, and among specific subsets, hemoglobin concentration, reticulocyte count, platelet count, and coagulation tests.

2. Vitamin E versus another type or route of vitamin E formulation
Only one study was in this group. Bonati 1991 compared between two formulations of intramuscular vitamin E the amount of drug absorption and clinical outcomes in live born infants with gestational age less or equal to 32 weeks. Entry criteria included: live born infant, gestational age equal or less than 32 weeks, no malformations, born in participating centers over 3 months, and admitted to a neonatal intensive care within two hours of birth. Patients received three daily doses of 20 mg/kg of vitamin E starting at 8 hours of life. Infants were randomly allocated to the treatment group, receiving dl-alpha-tocopheryl acetate as an aqueous colloidal solution (Ephynal®, Hoffmann-La Roche, Basel, Switzerland), or to the control group, receiving alpha-tocopherol in olive oil solution (Evio Forte®, Bracco, Milan). The exact amounts of vitamin E administered enterally and by transfusion are not provided. Infants received 2-98 ml/kg/day of enteral feeding, including breast milk (vitamin E content 1.11±0.53 mg/100 ml) or formula (vitamin E content 0.23±0.08 mg/100 ml). Among 50 enrolled patients, 44 (22 in each group) completed the study. Birth weights ranged from 670 g to 1800 g with an average of 1217±311 g. Average gestational age was 29.0±2.5 weeks.

 

Risk of bias in included studies

Among the 26 randomized clinical trials selected for this systematic review, ten were double-blinded.

1. Vitamin E versus placebo
Chiswick 1982: No information is provided about the method of randomization or about blinding of allocation. Since patients in the control group did not receive intramuscular injection of vitamin E, intervention and outcome were not blinded. Although information is provided on all patients entered into the study, the exact number of patients with intraventricular hemorrhage is not provided, because not all patients had a computerized tomography or an autopsy. The authors assumed that all patients who died had an intraventricular hemorrhage; in one case, neither computerized tomography nor autopsy was available to confirm this assumption. For the purpose of this review, only confirmed cases of intraventricular hemorrhage were used.

Chiswick 1983: No information is provided about the method of randomization or about blinding of allocation. Since patients in the control group did not receive intramuscular injection of vitamin E, intervention and outcome were not blinded. The number of patients with intraventricular hemorrhage may have been underestimated because not all patients had ultrasonograms performed after 3 days of age.

Cruz 1983: No information is provided about the method of randomization or about blinding of allocation. Since patients in the control group did not receive intramuscular injection of vitamin E, intervention and outcome were not blinded. Follow-up was complete.

Ehrenkranz 1982 is a double-blind randomized controlled trial. The method of randomization is not provided. Allocation, intervention and outcome were blinded. Follow-up was complete; however, assessment for intraventricular hemorrhage by ultrasonogram or computerized tomography was obtained in only 27 of 47 patients in the experimental group and 39 of 53 in the control group. Therefore, the rate of intraventricular hemorrhage may have been underestimated.

Ferlin 1998 is a randomized controlled trial with four parallel arms. The methods for randomization and blinding of allocation are not provided. Intervention and outcome were blinded. Completeness of follow-up is unclear; by design, only patients with regular follow-up visits after discharge were included.

Finer 1982: For randomization the authors used sealed envelopes, and stratification by birth weight and by severity of respiratory distress (requirement for oxygen and endotracheal intubation). Since controls did not receive placebo injections, intervention was not blinded. In contrast, the main outcome variable for the trial (retrolental fibroplasia) was blinded. Most data are available only for the 99 infants who completed the trial, i.e., survived for at least one month.

Fischer 1987 is a double-blind randomized trial. The method of randomization is not provided. Intervention and outcome were blinded. Follow-up was complete.

Fish 1990 is a double-blind randomized trial. Randomization was performed by the pharmacy after stratification by birth weight. Although a placebo was given to the control group, the intervention was not entirely blinded because tocopherol levels were available to the clinicians, who were adjusting the dose accordingly after day seven of life. Two infants were excluded from statistical analysis because of initial inapparent structural anomalies (congenital heart disease and hydranencephaly). Outcome was blinded.

Graeber 1977: The method of randomization is not provided. Intervention and outcome were not blinded. Follow-up was complete.

Gross 1977: The method of randomization is not provided. Intervention and outcome were not blinded. Follow-up was complete.

Gross 1979: The method of randomization is not provided; however, randomization was stratified by weight (1000-1500 g and 1501-2000 g). Neither intervention, nor outcome were blinded. Follow-up was complete.

Hittner 1981 is a double-blind randomized trial. Randomization was performed using a random-number table, after stratification by weight. Allocation, intervention and outcome were blinded. Follow-up was not complete: information on 49 patients is incomplete. One patient with necrotizing enterocolitis was excluded (no information on treatment allocation), and one patient was excluded for necrotizing enterocolitis preventing oral administration of vitamin E (n=1). Patients who died before four weeks (n=48) were excluded from all other outcomes.

Hittner 1984 is a double-masked randomized trial. Randomization was conducted using a random-number table, after stratification by weight. Allocation, intervention and outcome were blinded. Mortality was reported only until ten weeks of life. None of the other outcomes are reported for the 33 patients who died before 10 weeks.

Jansson 1978: The method of randomization was not provided; randomization was stratified by weight (1000-1999 and 2000-2499 g). Neither treatment allocation, nor intervention, nor outcome was blinded. All patients were followed.

Johnson 1989 is a double-blind randomized controlled trial. The method of randomization is not provided. Randomization was stratified by hospital and by birth weight. Allocation, intervention and outcome were blinded. Complete data are available in only 755 of 914 enrolled.

Melhorn 1971: The method of randomization is not provided. Randomization was stratified by weight and gestational age. Data are provided on only 186 patients. Whether allocation was blinded is unclear. Neither intervention nor outcome were blinded.

Pathak 2003 is a randomized double-blind trial. Randomization was done using sealed envelopes in the pharmacy. Allocation, intervention, and outcome were blinded. Follow-up was complete.

Phelps 1987a is a randomized double-blind trial. Randomization was performed using sealed envelopes stratified by study center, sex, and birth weight, opened at the pharmacy (center 1) or drug control center (center 2). Numbers were balanced by groups of eight. Multiple births were randomized separately so that one of each pair received placebo and one tocopherol. Allocation, intervention and outcome were blinded. 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. Among the 80 infants who developed retinopathy of prematurity, 53 completed the study, eighteen were lost to follow-up and nine died with active retinopathy of prematurity.

Rönnholm 1989: The method of randomization is not provided, so that blinding of allocation cannot be assessed. Neither intervention, nor outcome was blinded. Three patients died of respiratory distress or cerebral hemorrhage and were excluded from the analysis.

Rudolph 1989: The method of randomization is not provided. Blinding of allocation cannot be assessed. The intervention was not blinded, but the outcome, assessed by a cardiologist, was blinded. Follow-up was complete.

Saldanha 1982: Randomization was performed by drawing of a card from a randomized deck. Neither allocation, nor intervention, nor outcome was blinded. Incomplete data provided on nine babies who died before 10 days of age.

Schiller 1980: The method of randomization is not provided. Blinding of allocation cannot be assessed. The intervention was not blinded, whereas outcome was blinded. Whether follow-up was complete is unclear.

Sinha 1987 is a randomized trial using sealed envelopes and thus allocation was blinded. However, controls did not receive a placebo, so that intervention was not blinded. Whether outcome was blinded is unclear. Three inborn infants randomized before birth had lethal major malformations and were excluded from the study. Eighteen infants had a periventricular-intraventricular hemorrhage on the initial scan; for these infants, only partial information is provided about the severity of the bleeding during the study.

Smith 1985 is a randomized double-blind trial, so that allocation, intervention and outcome should be blinded; nevertheless, no information is provided about the method of randomization. Follow-up was complete.

Zipursky 1987 is a double-blind randomized controlled trial in which the authors used a computerized randomization generated in the pharmacy and stratified by birth weight and by severity of illness. Allocation, intervention and outcome were blinded. Information on chronic lung disease was available in 266 of 269 enrolled infants, while only 225 infants had an eye examination. In the treatment group, hemoglobin levels, reticulocyte counts, and platelet counts were available in 44, 31, and 32 infants, respectively, at 6 weeks of age. In the control group, hemoglobin levels, reticulocyte counts, and platelet counts were available in 46, 33, and 36 infants, respectively, at 6 weeks.

2. Vitamin E versus another type or route of vitamin E formulation
Bonati 1991: No information is provided about method of randomization of the first baby within each center. Subsequent infants were given alternating medication, so that allocation, intervention and outcomes were not blinded. In each participating center, the first enrolled infant was randomly allocated to one of the two formulations; allocation was alternated in each subsequent infant. Among 50 patients in this study, only 44 completed the three-day schedule of vitamin E; no data are provided on the other infants. Outcome variables included mortality, patent ductus arteriosus, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, sepsis, phototherapy, exchange transfusion and tocopherol levels.

 

Effects of interventions

No relevant data for the following subgroup analyses was found: gestational age >= 29 weeks, gestational age < 29 weeks, parenteral vitamin E in colloidal form with polysorbate, selenium fortification, and vitamin E supplementation started after four weeks of life (although controls in Pathak 2003 were started on placebo at an average age of 28 days).

VITAMIN E VERSUS PLACEBO OR NO TREATMENT (COMPARISON 01):
Primary outcomes:
Mortlaity:

Mortality until discharge (Outcome 01.01):
Mortality was assessed in twelve studies, involving a total of 994 treated patients and 1034 controls. Vitamin E supplementation did not significantly affect mortality (typical estimate, relative risk [RR] 0.97, confidence interval [CI] 0.83, 1.14; risk difference [RD] -0.01, CI -0.04, +0.03).

Subgroup analyses: data available for analysis by birth weight (see section 01.02), by route of administration, total dose, serum level, onset and duration of therapy in the treatment group, by dose of vitamin E in the control group, and by intake of iron and PUFA. Vitamin E supplementation did not significantly affect mortality in any of the analyses.

Mortality until discharge among very low birth weight infants (Outcome 01.02):
Mortality was assessed in seven studies, involving a total of 628 treated patients and 648 controls. Vitamin E supplementation did not significantly affect mortality (typical estimate RR 0.97, CI 0.80, 1.16; RD -0.01, CI -0.05, +0.04).

Subgroup analyses: data available for analysis by birth weight, by route of administration, total dose, serum level, onset and duration of therapy in the treatment group, by dose of vitamin E in the control group, and by intake of iron, and PUFA. Vitamin E supplementation did not significantly affect mortality in any of the analyses.

COMBINED OUTCOMES:
No trial assessed combined outcome at eighteen months including mortality [mortality, bronchopulmonary dysplasia, blindness, mental retardation or cerebral palsy], nor combined outcome at 18 months excluding mortality [bronchopulmonary dysplasia, blindness, mental retardation or cerebral palsy].

Secondary outcomes:
Bronchopulmonary dysplasia:

Bronchopulmonary dysplasia (Outcome 01.03):
Bronchopulmonary dysplasia was assessed in six studies, involving a total number of 558 treated patients and 569 controls. Vitamin E supplementation did not significantly affect the risk of bronchopulmonary dysplasia (typical estimate RR 0.91, CI 0.73, 1.14; RD -0.02, CI -0.07, +0.03).

Subgroup analyses: data available for analysis by birth weight (see section 01.04), by route of administration, total dose, serum level, onset and duration of therapy in the treatment group, by dose of vitamin E in the control group, and by intake of iron, PUFA and vitamin A. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Bronchopulmonary dysplasia among very low birth weight infants (Outcome 01.04):
Bronchopulmonary dysplasia was assessed in four studies, involving a total number of 484 treated patients and 488 controls. Vitamin E supplementation did not significantly affect the risk of bronchopulmonary dysplasia (typical estimate RR 0.89, CI 0.71, 1.13; RD -0.02, CI -0.08, +0.03).

Subgroup analyses: data available for analysis by birth weight, by route of administration, total dose, serum level, onset and duration of therapy in the treatment group, by dose of vitamin E in the control group, and by intake of iron, PUFA and vitamin A. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Bronchopulmonary dysplasia among surviving patients (Outcome 01.05):
This outcome was assessed in four studies, involving a total of 159 treated patients and 163 controls. Vitamin E supplementation did not significantly affect the risk of bronchopulmonary dysplasia (typical estimate RR 1.15, CI 0.84, 1.58; RD 0.04, CI -0.05, +0.13).

Subgroup analyses: data available for analysis by birth weight (see section 01.06), by route of administration, total dose, serum level, onset and duration of therapy in the treatment group, by dose of vitamin E in the control group, and by intake of iron. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Bronchopulmonary dysplasia among surviving very low birth weight infants (Outcome 01.06):
This outcome was assessed in two studies, involving a total of 118 treated patients and 118 controls. Vitamin E supplementation did not significantly affect the risk of bronchopulmonary dysplasia (typical estimate RR 1.07, CI 0.70, 1.64; RD 0.02, CI -0.10, +0.13).

Subgroup analyses: data available for analysis by birth weight, by route of administration, total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Radiographic signs of bronchopulmonary dysplasia at six weeks to two months of age (Outcome 01.07):
This outcome was analyzed in four studies, involving a total of 176 treated patients and 188 controls. Vitamin E did not significantly affect the risk of radiographic signs of bronchopulmonary dysplasia (typical estimate RR 0.99, CI 0.67, 1.46; RD 0.00, CI -0.09, +0.08).

Subgroup analyses: data available for analysis by birth weight (see section 01.08), by route of administration, total dose, serum level, onset and duration of therapy in the treatment group, by dose of vitamin E in the control group, and by intake of iron and PUFA. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Radiographic signs of bronchopulmonary dysplasia at six weeks to two months of age among very low birth weight infants (Outcome 01.08):
This outcome was analyzed in two studies, involving a total of 129 treated patients and 135 controls. Vitamin E did not significantly affect the risk of radiographic signs of bronchopulmonary dysplasia (typical estimate RR 0.95, CI 0.61, 1.47; RD -0.01, CI -0.11, +0.09).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, by dose of vitamin E in the control group, and by intake of iron and PUFA. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Patent ductus arteriosus:

Patent ductus arteriosus (Outcome 01.09):
Patent ductus arteriosus was assessed in six studies, involving a total number of 481 treated patients and 495 controls. Vitamin E supplementation did not significantly affect the risk of patent ductus arteriosus (typical estimate RR 1.07, CI 0.93, 1.23; RD 0.03, CI -0.03, +0.09).

Subgroup analyses: data available for analysis by birth weight (see section 01.10), by route of administration, total dose, serum level, onset and duration of therapy in the treatment group, by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Patent ductus arteriosus among very low birth weight infants (Outcome 01.10):
Patent ductus arteriosus was assessed in four studies, involving a total number of 418 treated patients and 429 controls. Vitamin E supplementation did not significantly affect the risk of patent ductus arteriosus (typical estimate RR 1.09, CI 0.93, 1.28; RD 0.04, CI -0.03, +0.10).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Patent ductus arteriosus among surviving patients (at ten days to ten weeks of age) (Outcome 01.11):
This outcome was assessed in three, involving a total of 136 treated patients and 135 controls. Vitamin E supplementation did not significantly affect the risk of patent ductus arteriosus (typical estimate RR 0.98, CI 0.70, 1.38; RD -0.01, CI -0.11, +0.10).

Subgroup analyses: data available for analysis by birth weight (see section 01.12), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Patent ductus arteriosus among surviving very low birth weight infants (at ten days to ten weeks of age) (Outcome 01.12):
This outcome was assessed in two studies, involving a total of 118 treated patients and 118 controls. Vitamin E supplementation did not significantly affect the risk of patent ductus arteriosus (typical estimate RR 0.85, CI 0.57, 1.27; RD -0.04, CI -0.15, +0.07).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Patent ductus arteriosus requiring treatment (Outcome 01.13):
This outcome was assessed in three studies, involving a total number of 332 treated patients and 343 controls. Summary statistics showed no significant effect of vitamin E on patent ductus arteriosus (typical estimate RR 1.02, CI 0.79, 1.31; RD 0.00, CI -0.06, +0.07) with significant heterogeneity among studies both for RR (chi-square 5.99, p = 0.05) and RD (chi-square 6.78, p=0.034).

Subgroup analyses: data available for analysis by birth weight (see section 01.14), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by iron intake. Vitamin E supplementation significantly reduced the risk for patent ductus arteriosus requiring therapy in the following subgroup analyses: (1) excluding intravenous therapy (01.13.06) (typical estimate RR 0.56, CI 0.32, 0.97; RD -0.17, CI -0.31, -0.02), (2) Duration of treatment greater than one week (01.13.12) (typical estimate RR 0.56, CI 0.32, 0.97; RD -0.17, CI -0.31, -0.02); (3) vitamin E intake greater than 10 mg/100 Kcal in the control group (01.13.14) in a single study (estimate RR 0.54, CI 0.31, 0.95; RD -0.22, CI -0.40, -0.03). Ehrenkranz 1982 was the only study showing significant effect of vitamin E on this outcome; vitamin E was provided intramuscularly at high dose, starting within 48 hours and for more than one week in the treatment group, and vitamin E intake was greater than 10 mg/100 Kcal in the control group.

Patent ductus arteriosus requiring treatment among very low birth weight infants (Outcome 01.14):
This outcome was assessed in three studies, involving a total number of 285 treated patients and 290 controls. Summary statistics showed no significant effect of vitamin E on patent ductus arteriosus (typical estimate RR 1.20, CI 0.89, 1.60; RD 0.04, CI -0.03, +0.11).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by iron intake. Vitamin E did not significantly affect this outcome in any of the analyses.

Sepsis

Sepsis after study entry (Outcome 01.15):
Sepsis was assessed in four studies, involving a total number of 498 treated patients and 511 controls. Summary statistics showed a significant increase in risk of sepsis (typical estimate RR 1.52, CI 1.13, 2.04; RD 0.06, CI 0.02, 0.11). There was significant heterogeneity among studies for RD (chi-square 8.15, p=0.04) but not for RR (chi-square 2.89, p=0.41).

Subgroup analyses: data available for analysis by birth weight (see section 01.16), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by iron intake. Vitamin E significantly increased the risk of sepsis in the following subgroup analyses: (1) parenteral with or without enteral (01.13.03) or parenteral with hypertonic enteral formulation at pharmacologic dose (01.15.04) (typical estimate RR 1.57, CI 1.15, 2.14; RD 0.06, CI 0.02, 0.11); (2) Intravenous administration (01.15.05) (typical estimate RR 1.54, CI 1.07, 2.21; RD 0.05, CI 0.01, 0.10). However, there was significant heterogeneity among studies for RD (chi-square 6.25, p=0.01) but not for RR (chi-square 2.13, p=0.14); (3) Total dose of vitamin E in the treatment group greater than 30 IU/kg/day (01.15.07) (typical estimate RR 1.57, CI 1.15, 2.14; RD 0.06, CI 0.02, 0.11); (4) Serum tocopherol level in the treatment group greater than 3.5 mg/dl (01.15.09) (typical estimate RR 1.72, CI 1.24, 2.40; RD 0.10, CI 0.04, 0.15); (5) Onset of treatment within 48 hours of life (01.15.10) (typical estimate RR 1.57, CI 1.15, 2.14; RD 0.06, CI 0.02, 0.11); (6) Total dose of vitamin E in the control group equal to or less than 10 mg vit E/100 kcal (01.15.13) (typical estimate RR 1.48, CI 1.05, 2.08; RD 0.05, CI 0.01, 0.10).

Sepsis after study entry among very low birth weight infants (Outcome 01.16):
This outcome was assessed in four randomized trials, involving a total number of 400 treated patients and 407 controls. Summary statistics showed a significant increase in risk of sepsis (typical estimate RR 1.53, CI 1.13, 2.08; RD 0.07, CI 0.02, 0.13).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by iron intake. Vitamin E supplementation significantly increased the risk of sepsis in the following subgroups: (1) Birth weight less or equal to 1500 grams (01.16.02) (typical estimate RR 1.65, CI 1.13, 2.40; RD 0.08, CI 0.02, 0.14); (2) Subgroup characterized by parenteral with or without enteral (01.16.05), by total dose of vitamin E in the treatment group greater than 30 IU/kg/day (01.16.09) and by onset of therapy within 48 hours of life (01.16.12) (typical estimate RR 1.59, CI 1.15, 2.18; RD 0.08, CI 0.03, 0.13); (3) Intravenous vitamin E administration (01.16.07) (typical estimate RR 1.56, CI 1.07, 2.27; RD 0.07, CI 0.01, 0.12); (4) Serum level in the treatment group > 3.5 mg/dl (01.16.11) (typical estimate RR 1.72, CI 1.24,2.40; RD 0.10, CI 0.04,0.15); and (5) total dose of vitamin E in the control group <= 10 mg/100 kcal (01.16.15) (typical estimate RR 1.49, CI 1.04, 2.13; RD 0.06, CI 0.01, 0.12).

Sepsis after study entry among very low birth weight infants treated for more than one week (Outcome 01.17):
This outcome was assessed in four randomized trials, involving a total number of 362 treated patients and 364 controls. Summary statistics showed a significant increase in risk of sepsis (typical estimate RR 1.63, CI 1.17, 2.26; RD 0.08, CI 0.03, 0.13).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E and iron intake in the control group. Vitamin E supplementation significantly increased the risk of sepsis in the following subgroups: (1) Birth weight less or equal to 1500 grams (01.17.02) (typical estimate RR 1.79, CI 1.27, 2.53; RD 0.10, CI 0.04, 0.16); (2) Subgroup characterized by parenteral vitamin E with or without enteral administration (01.17.05), by total dose of vitamin E in the treatment group greater than 30 IU/kg/day (01.17.08) and by onset of therapy within 48 hours of life (01.17.11) (typical estimate RR 1.70, CI 1.20, 2.41; RD 0.08, CI 0.03, 0.14); (3) Intravenous vitamin E administration (01.17.06) (typical estimate RR 1.72, CI 1.11, 2.66; RD 0.07, CI 0.02, 0.13); (4) Serum level in the treatment group > 3.5 mg/dl (01.17.10) (typical estimate RR 1.90, CI 1.31, 2.75; RD 0.11, CI 0.05, 0.16); and (5) total dose of vitamin E in the control group <= 10 mg/100 kcal (01.17.13) (typical estimate RR 1.61, CI 1.08, 2.41; RD 0.07, CI 0.02, 0.13).

Sepsis among surviving very low birth weight infants (Outcome 01.18):
This outcome was assessed in two trials, involving 143 treated patients and 141 controls. Summary statistics showed no significant effect of vitamin E on sepsis (typical estimate RR 0.88, CI 0.48, 1.62; RD -0.02, CI -0.09, +0.06).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Germinal matrix/intraventricular hemorrhage

Germinal matrix/intraventricular hemorrhage (Papile's classification, grade I-IV) (Outcome 01.19):
This outcome was assessed in seven studies involving 864 treated patients and 891 controls. Vitamin E supplementation significantly reduced the risk of germinal matrix-intraventricular hemorrhage (typical estimate RR 0.85, CI 0.73, 0.99; RD -0.04, CI -0.08, 0.00). There was significant heterogeneity among studies for RD (chi-square 17.81, p=0.0067) but not for RR (chi-square 8.54, p=0.2).

Subgroup analyses: data available for analysis by birth weight (see section 01.20), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation significantly reduced the risk of hemorrhage in the following subgroups: (1) parenteral vitamin E administration with or without additional enteral vitamin E (01.19.03) (typical estimate RR 0.84, CI 0.72, 0.98; RD -0.04, CI -0.08, -0.01); (2) excluding intravenous vitamin E administration (01.19.06) (typical estimate RR 0.71, CI 0.58, 0.87; RD -0.14, CI -0.22, -0.06); (3) total dose of vitamin E in the treatment group less than or equal to 30 IU/kg/day (01.19.07) (typical estimate RR 0.65, CI 0.50, 0.85; RD -0.18, CI -0.29, -0.08); (4) onset of treatment within 48 hours of life (01.19.11), involving all patients in all studies for this outcome (for typical estimates see summary statistics); and (5) duration of vitamin E treatment less than or equal to one week (01.19.12) (typical estimate RR 0.65, CI 0.50, 0.85; RD -0.18, CI -0.29, -0.08).

Germinal matrix/intraventricular hemorrhage (Papile's classification, grade I-IV) among very low birth weight infants (Outcome 01.20):
This outcome was assessed in three studies involving 385 treated patients and 392 controls. Vitamin E did not significantly affect the risk of hemorrhage (typical estimate RR 0.94, CI 0.75, 1.18; RD -0.02, CI -0.07, +0.04).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Germinal matrix/intraventricular hemorrhage (Papile's classification, grade I-IV) among infants with negative initial ultrasonogram (Outcome 01.21):
This outcome was assessed in a single study involving 102 treated patients and 108 controls. Vitamin E supplementation significantly reduced the risk for hemorrhage (estimate RR 0.57, CI 0.40, 0.80; RD -0.23, CI -0.36, -0.10).

Germinal matrix/intraventricular hemorrhage (Papile's classification, grade I-IV) among survivors (Outcome 01.22):
This outcome was assessed in three studies involving 166 treated patients and 169 controls. Vitamin E did not significantly affect the risk of hemorrhage (typical estimate RR 1.06, CI 0.70, 1.60; RD 0.01, CI -0.07, +0.10).

Subgroup analyses: data available for analysis by birth weight (see section 01.23), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Germinal matrix/intraventricular hemorrhage (Papile's classification, grade I-IV) among surviving low birth weight infants (Outcome 01.23):
This outcome was assessed in two trials, involving 143 treated patients and 141 controls. Summary statistics showed no significant effect of vitamin E on germinal matrix/intraventricular hemorrhage (typical estimate RR 1.05, CI 0.69, 1.60; RD 0.01, CI -0.09, +0.11).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Severe intraventricular hemorrhage (grade III or IV) (Outcome 01.24):
This outcome was assessed in three studies, involving a total of 315 treated patients and 329 controls. Vitamin E supplementation did not significantly affect the risk of severe intraventricular hemorrhage (typical estimate RR 0.91, CI 0.60, 1.38; RD -0.01, CI -0.06, +0.04). There was significant heterogeneity among studies both for RR and RD (chi-square 6.98, p=0.03).

Subgroup analyses: data available for analysis by birth weight (see section 01.25), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Severe intraventricular hemorrhage (grade III or IV) among very low birth weight infants (Outcome 01.25):
This outcome was assessed in two studies, involving a total of 213 treated patients and 221 controls. Vitamin E supplementation did not significantly affect the risk of severe intraventricular hemorrhage (typical estimate RR 1.03, CI 0.67, 1.60; RD +0.01, CI -0.06, +0.07). There was significant heterogeneity among studies both for RR (chi-square 4.80, p = 0.029) and RD (chi-square 4.89, p=0.027).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Severe intraventricular hemorrhage (grade III or IV) among surviving very low birth weight infants (Outcome 01.26):
This outcome was analyzed in three studies, involving a total of 158 treated patients and 162 controls. Vitamin E supplementation did not significantly affect the risk of hemorrhage (typical estimate RR 0.76, CI 0.41, 1.39; RD -0.03, CI -0.10, +0.04 with significant heterogeneity among the studies for RD (chi-square 7.48, p=0.024).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Subgroup analysis showed that vitamin E supplementation significantly reduced the risk of hemorrhage (1) in the subgroup of patients with birth weight less than 1000 grams (01.26.03) (typical estimate RR 0.31, CI 0.10,0.92; RD -0.13, CI -0.24,-0.02), and (2) in that with serum levels greater than 3.5 mg/dl (01.26.11) (estimate RR 0.20, CI 0.05, 0.85; RD 0.20, CI 0.05, 0.85).

Parenchymal brain hemorrhage

Parenchymal brain hemorrhage (grade IV) (Outcome 01.27):
This outcome was assessed in two studies, involving 242 treated patients and 255 controls. Meta-analysis showed no significant overall effect of vitamin E on the risk of hemorrhage (typical estimate RR 1.35, CI 0.69, 2.67; RD 0.02, CI -0.02, +0.06) but showed substantial heterogeneity between the two studies both for RR (chi-square 5.31, p = 0.021) and RD (chi-square 7.73, p=0.0054).

Subgroup analysis: data available for analysis by birth weight (see section 01.28), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Subgroup analysis suggests that the significant difference in results between the two studies could be attributed to dose (01.27.06-07), duration (01.27.10-11) and type of administration (01.27.03-05): Phelps 1987a used high-dose, intravenous and prolonged administration of vitamin E, in contrast with Sinha 1987, which used low-dose, intramuscular vitamin E for less than one week.

Parenchymal brain hemorrhage (grade IV) among very low birth weight infants (Outcome 01.28):
This outcome was assessed in a single study, involving 42 treated patients and 43 controls. Vitamin E supplementation in infants less than 1000 grams significantly increased the risk for hemorrhage (estimate RR 9.21, CI 1.22, 69.58; RD 0.19, CI 0.06, 0.032). This study used high-dose, intravenous and prolonged administration of vitamin E.

Parenchymal brain hemorrhage (grade IV) among patients with negative initial ultrasonogram (Outcome 01.29):
This outcome was assessed in a single study, involving 102 treated patients and 108 controls. Vitamin E supplementation did not significantly affect the risk for hemorrhage (estimate RR 0.30, CI 0.06, 1.42; RD -0.05, CI -0.10, + 0.01).

Parenchymal brain hemorrhage (grade IV) among surviving very low birth weight infants (Outcome 01.30):
This outcome was assessed in two studies, involving 118 treated patients and 118 controls. Vitamin E supplementation did not significantly affect the risk of hemorrhage (typical estimate RR 1.46, CI 0.46, 4.66; RD 0.02, CI -0.04, +0.07).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Retinopathy of prematurity or retrolental fibroplasia

Retinopathy of prematurity or retrolental fibroplasia (Outcome 01.31):
This outcome was assessed in seven studies, involving 662 treated patients and 680 controls. Vitamin E supplementation did not significantly affect the risk of retinopathy of prematurity or retrolental fibroplasia (typical estimate RR 0.90, CI 0.75, 1.09; RD -0.02, CI -0.07, +0.02).

Subgroup analyses: data available for analysis by birth weight (see section 01.32), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E and intake of iron, vitamin A and PUFA in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Retinopathy of prematurity or retrolental fibroplasia among very low birth weight infants (Outcome 01.32):
This outcome was assessed in five studies, involving 489 treated patients and 486 controls. Vitamin E supplementation did not significantly affect the risk of retinopathy of prematurity or retrolental fibroplasia (typical estimate RR 0.88, CI 0.73, 1.07; RD -0.03, CI -0.09, +0.02).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron, vitamin A and PUFA. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Retinopathy of prematurity or retrolental fibroplasia among infants examined/survivors (Outcome 01.33):
This outcome was assessed in eight studies, involving 821 treated patients and 845 controls. Vitamin E did not significantly affect the risk of retinopathy or prematurity or retrolental fibroplasia (typical estimate RR 0.90, CI 0.78, 1.03; RD -0.03, CI -0.07, +0.01).

Subgroup analyses: data available for analysis by birth weight (see section 01.34), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron and PUFA. Vitamin E did not significantly affect the risk of retinopathy or prematurity or retrolental fibroplasia in any of the analyses.

Retinopathy of prematurity or retrolental fibroplasia among very low birth weight infants examined/survivors (Outcome 01.34):
This outcome was assessed in seven studies, involving 540 treated patients and 550 controls. Vitamin E did not significantly affect the risk of retinopathy or prematurity or retrolental fibroplasia (typical estimate RR 0.94, CI 0.82, 1.07; RD -0.03, CI -0.08, +0.03).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron and PUFA. Vitamin E did not significantly affect the risk of retinopathy or prematurity or retrolental fibroplasia in any of the analyses.

Severe retinopathy of prematurity or retrolental fibroplasia (grade III or worse) (Outcome 01.35):
This outcome was assessed in six studies, involving a total of 767 treated patients and 798 controls. Vitamin E did not significantly affect the risk of severe retinopathy of prematurity or retrolental fibroplasia in the treated group (typical estimate RR 0.72, CI 0.41, 1.25; RD -0.01, CI -0.03, +0.01).

Subgroup analyses: data available for analysis by birth weight (see section 01.36), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron and PUFA. Vitamin E significantly reduced the risk of retinopathy or prematurity or retrolental fibroplasia in the subgroup of studies with serum tocopherol level vitamin E in the treatment group greater than 3.5 mg/dl (01.35.10): typical estimate RR 0.39, CI 0.16, 1.00; RD -0.02, CI -0.04, 0.00.

Severe retinopathy of prematurity or retrolental fibroplasia (grade III or worse) among very low birth weight infants (Outcome 01.36):
This outcome was assessed in six studies, involving a total of 482 treated patients and 492 controls. Vitamin E did not significantly affect the risk of severe retinopathy of prematurity or retrolental fibroplasia in the treated group (typical estimate RR 0.59, CI 0.32, 1.08; RD -0.02, CI -0.05, 0.00).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron and PUFA. Vitamin E significantly reduced the risk of retinopathy or prematurity or retrolental fibroplasia (1) in the subgroup with birth weight equal to or less than 1500 grams (01.36.02) typical estimate RR 0.40, CI 0.18, 0.87; RD -0.03, CI -0.05, -0.01 and (2) in the subgroup with serum level in the treatment group greater than 3.5 mg/dl (01.36.12): typical estimate RR 0.34, CI 0.13, 0.87; RD -0.04, CI -0.07, 0.01.

Severe retinopathy of prematurity or retrolental fibroplasia among infants examined (Outcome 01.37):
This outcome was assessed in seven studies, involving a total of 783 treated patients and 804 controls. Vitamin E did not significantly affect the risk of severe retinopathy of prematurity or retrolental fibroplasia, typical estimate RR 0.67, CI 0.40, 1.12; RD -0.01, CI -0.03, 0.00.

Subgroup analyses: data available for analysis by birth weight (see section 01.38), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron and PUFA. Vitamin E significantly reduced the risk of retinopathy or prematurity or retrolental fibroplasia in the subgroup with serum tocopherol level vitamin greater than 3.5 mg/dl in the treatment group (01.37.11): typical estimate RR 0.39, CI 0.15, 0.98; RD -0.02, CI -0.04, 0.00.

Severe retinopathy of prematurity or retrolental fibroplasia among very low birth weight infants examined (Outcome 01.38):
This outcome was assessed in seven studies, involving a total of 525 treated patients and 537 controls. Vitamin E significantly reduced the risk of severe retinopathy of prematurity or retrolental fibroplasia, typical estimate RR 0.58, CI 0.34, 1.00; RD -0.03, CI -0.05, 0.00.

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron and PUFA. Vitamin E significantly reduced the risk of retinopathy or prematurity or retrolental fibroplasia in the following subgroups: (1) birth weight <= 1500 grams (01.38.02) (typical estimate RR 0.44, CI 0.22, 0.85; RD -0.03, CI -0.05, -0.01); (2) serum level in the treatment group greater than 3.5 mg/dl (01.38.14) (typical estimate RR 0.34, CI 0.13, 0.88; RD -0.04, CI -0.07, -0.01); and (3) total dose of vitamin E in the control group equal to or less than 10 mg/100 kcal (01.38.18) (typical estimate RR 0.56, CI 0.31, 1.00; RD -0.03, CI -0.06, 0.00).

Retinal detachment among surviving infants (Outcome 01.39):
This outcome was assessed in three studies, involving a total of 215 treated patients and 217 controls. Vitamin E supplementation did not significantly affect the risk of retinal detachment, typical estimate RR 1.02, CI 0.06, 16.09; RD 0.00, CI -0.02, +0.02. However, the incidence of that complication was too low to reach any conclusion: it developed in only one patient in each group in a single study.

Subgroup analyses: data available for analysis by birth weight (see section 01.40), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E did not significantly affect the risk of retinal detachment in any of the analyses.

Retinal detachment among surviving very low birth weight infants (Outcome 01.40):
This outcome was assessed in three studies, involving a total of 160 patients in the treatment group and 161 in the control group. Vitamin E did not significantly affect this outcome, typical estimate RR 1.02, CI 0.07, 15.84; RD 0.00, CI -0.02, +0.02. However, the incidence of that complication was too low to reach any conclusion: it developed in only one patient in each group in a single study.

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E did not significantly affect the risk of retinal detachment in any of the analyses.

Cicatricial retrolental fibroplasia, any stage, among patients examined after discharge (Outcome 01.41):
This outcome was assessed in five studies, involving 530 patients in the treatment group and 522 in the control group. Vitamin E did not significantly affected this outcome (typical estimate RR 0.82, CI 0.52, 1.27; RD -0.01, CI -0.04, +0.02).

Subgroup analyses: data available for analysis by birth weight (see section 01.42), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Cicatricial retrolental fibroplasia, any stage, among very low birth weight infants examined after discharge (Outcome 01.42):
This outcome was assessed in five studies, involving 436 patients in the treatment group and 422 in the control group. Vitamin E did not significantly affected this outcome (typical estimate RR 0.75, CI 0.48, 1.15; RD -0.02, CI -0.06, +0.01).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Blindness from retrolental fibroplasia among very low birth weight infants examined (Outcome 01.43):
This outcome was assessed in four studies, involving 231 treated patients and 236 controls. Vitamin E significantly decreased the risk of blindness, typical estimate, RR 0.29, CI 0.10, 0.88; RD -0.04, CI -0.08, -0.01).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron and PUFA. Vitamin E supplementation significantly reduced the risk of blindness (1) among four subgroups which involved all four studies: birth weight less or equal to 1500 grams (01.43.02), excluding intravenous vitamin E supplementation (01.43.08), onset of therapy within 48 hours of life (01.43.13) and duration of treatment greater than one week (01.43.14) (typical estimate identical to that for the main analysis), (2) in the subgroup with total dose of vitamin E in the control group equal to or less than 10 mg/100 kcal (01.43.15) (typical estimate RR 0.29, CI 0.10, 0.88; RD -0.05, CI -0.08, -0.01).

Necrotizing enterocolitis

Necrotizing enterocolitis (Outcome 01.44):
This outcome was assessed in eight studies, involving a total of 711 treated patients and 732 controls. Vitamin E supplementation did not significantly affect this outcome (typical estimate RR 1.37, CI 0.96, 1.95; RD 0.02, CI 0.00, +0.05).

Subgroup analyses: data available for analysis by birth weight (see section 01.45), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron. Vitamin E supplementation significantly increased the risk for necrotizing enterocolitis among patients whose controls received less than or equal to 10 mg vit E/100 cal (01.44.15) (typical estimate RR 1.49, CI 1.03, 2.16; RD 0.03, CI 0.00, 0.06).

Necrotizing enterocolitis among very low birth weight infants (Outcome 01.45):
This outcome was assessed in six studies, involving a total of 475 treated patients and 487 controls. Vitamin E supplementation did not significantly affect this outcome (typical estimate RR 1.29, CI 0.90, 1.87; RD 0.03, CI -0.01 +0.07).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Necrotizing enterocolitis among very low birth weight infants treated with vitamin E for more than one week (Outcome 01.46):
This outcome was assessed in five studies, involving a total of 364 treated patients and 370 controls. Vitamin E supplementation did not significantly affect this outcome (typical estimate RR 1.51, CI 0.99, 2.30; RD 0.04, CI 0.00 +0.09).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron. Vitamin E supplementation significantly increased the risk of necrotizing enterocolitis in the following subgroups: (1) birth weight less than or equal to 1500 grams (01.46.02): typical estimate RR 1.62, CI 1.04, 2.51; RD 0.05, CI 0.01, 0.10; and (2) serum tocopherol level in the treatment group greater than 3.5 mg/dl (01.46.12): typical estimate RR 1.60, CI 1.02, 2.52; RD 0.05, CI 0.00, 0.11.

Necrotizing enterocolitis among survivors (Outcome 01.47):
This outcome was assessed in two studies, involving a total of 91 treated patients and 95 controls. Vitamin E supplementation did not significantly affect this outcome (typical estimate RR 1.31, CI 0.31, 5.65, z = 0.37, p = 0.7; RD 0.01, CI -0.05, +0.07, z = 0.34, p = 0.7).

Subgroup analyses: data available for analysis by birth weight (see section 01.48), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Necrotizing enterocolitis among surviving very low birth weight infants (Outcome 01.48):
This outcome was assessed in a single study, involving a total of 68 treated patients and 67 controls. Vitamin E supplementation did not significantly affect this outcome (estimate RR 1.31, CI 0.31, 5.65; RD 0.01, CI -0.06, +0.09).

Serum bilirubin concentration

Serum bilirubin concentration on day 3-5 (Outcome 01.49):
This outcome was assessed in three studies, involving a total of 54 treated patients and 44 controls. Meta-analysis showed no significant effect of vitamin E on this outcome (weighted mean difference [WMD] -0.30, CI -1.17, +0.57) but substantial heterogeneity (chi-square 9.90, p = 0.0071).

Subgroup analyses: data available for analysis by birth weight (see section 01.50), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron. Vitamin E supplementation significantly decreased serum bilirubin concentration in the subgroup with total vitamin E dose in the treatment group greater than 30 IU/kg/day (01.49.07) (mean difference [MD] -1.30, CI -2.60, 0.00).

Serum bilirubin concentration on day 3-5 in very low birth weight infants (Outcome 01.50):
This outcome was assessed in two studies, involving a total of 27 treated patients and 21 controls. Meta-analysis showed a significant decrease in serum bilirubin (WMD -1.46, CI -2.58, -0.33).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron. Vitamin E supplementation significantly decreased serum bilirubin concentration in the following subgroups: (1) Enteral (01.50.02) and total dose of vitamin E in the treatment group greater than 30 IU/kg/day (01.50.06) (MD -1.30, CI -2.60, 0.00); (2) Excluding intravenous (01.50.04), serum level in the treatment group equal to or less than 3.5 mg/dl (01.50.07), onset of treatment within 48 hours of life (01.49.08), duration of treatment less than or equal to one week (01.50.09) and total dose of vitamin E in the control group equal to or less than 10 mg/100 kcal (01.49.10), which included all patients from all studies (WMD -1.46, CI -2.58, -0.33).

Serum bilirubin concentration on day 3-5 in a specific group (no hemolysis, no polycythemia, no prior transfusion) (Outcome 01.51):
This outcome was assessed in a single study involving 31 treated patients and 31 controls. Vitamin E significantly increased serum bilirubin (MD =1.30, CI 0.20, 2.40).

Hemoglobin concentration

Hemoglobin concentration (Outcome 01.52):
Hemoglobin concentration was assessed in eight studies, involving 211 patients in the treatment group and 205 controls. Vitamin E supplementation significantly increased hemoglobin concentration (WMD 0.46 g/dl, CI 0.24, 0.69).

Subgroup analyses: data available for analysis by birth weight (see section 01.53), by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron and PUFA. Vitamin E supplementation significantly increased hemoglobin concentration in the following subgroups: (1) infants with birth weight > 1000 grams (01.52.02) (WMD 0.49, CI 0.20, 0.77), (2) enteral vitamin E supplementation (01.52.03) (WMD 0.48, CI 0.25, 0.71), (3) excluding intravenous vitamin E supplementation (01.52.05) (involving all available studies; typical estimate identical to the summary statistics for this outcome), (4) vitamin E dose less than or equal to 30 IU/kg/day (01.52.06) (WMD 0.52, CI 0.29, 0.76), (5) serum tocopherol level in the treatment group less than or equal to 3.5 mg/dl (01.52.08) (WMD 0.47, CI 0.23, 0.71), (6) onset of treatment within 48 hours of life (01.52.09) (WMD 0.48, CI 0.21, 0.75), (7) onset of treatment after 48 hours of life (01.52.10) (WMD 0.44, CI 0.02, 0.85), (8) duration of treatment greater than one week (01.52.12) (WMD 0.54, CI 0.30, 0.77), (9) total dose of vitamin E in the control group equal to or less than 10 mg/100 kcal (01.52.13) (WMD 0.46, CI 0.24, 0.69), (10) iron supplementation in both groups (01.52.14) (WMD 0.57, CI 0.24, 0.91), and (11) iron supplementation in neither group (01.52.15) (WMD 0.47, CI 0.16, 0.78).

Hemoglobin concentration in very low birth weight infants (Outcome 01.53):
This outcome was analyzed in four studies, involving 102 treated infants and 94 controls. Meta-analysis showed a significant increase in hemoglobin, WMD 0.43 g/dl, CI 0.09, 0.77, with significant heterogeneity among studies (chi-square 10.38, p =0.02).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron and PUFA. Vitamin E supplementation significantly increased hemoglobin concentration in the following subgroups: (1) Enteral vitamin E supplementation (01.53.02), excluding intravenous supplementation (01.53.03), serum tocopherol level vitamin E in the treatment group lower than or equal to 3.5 mg/dl (01.53.06), total dose of vitamin E in the control group equal to or less than 10 mg/100 kcal (01.53.11), all involving all subjects from all studies; (2) total dose of vitamin E in the treatment group less than or equal to 30 IU/kg/day (01.53.04) (WMD 0.53, CI 0.16, 0.90); (3) Onset of treatment in the treatment group within 48 hours of life (01.53.07) (WMD 0.42, CI 0.07, 0.78); (4) Duration of treatment greater than one week (01.53.10) (WMD 0.53, CI 0.17, 0.89); (5) Iron supplementation in both groups (01.53.12) (WMD 0.67, CI 0.23, 1.10); (6) Iron supplementation in neither group (01.53.13) (WMD 0.51, CI 0.17, 0.86).

Reticulocyte count

Reticulocyte count (expressed in percent of total red blood cell count) (Outcome 01.54):
This outcome was assessed in two studies, involving 102 treated patients and 99 controls. Meta-analysis showed that vitamin E supplementation significantly reduced reticulocyte count (WMD -1.66, CI -2.24, -1.07) and substantial heterogeneity among studies (chi-square 6.44, p = 0.011).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron and PUFA. Vitamin E supplementation significantly reduced reticulocyte count in the following subgroups: (1) subgroups involving all patients from both studies: enteral (01.54.02), excluding intravenous vitamin E supplementation (01.54.03), total dose of vitamin E in the treatment group equal to or less than 30 IU/kg/day (01.54.04), serum tocopherol level in the treatment group equal to or less than 3.5 mg/dl (01.54.05), onset of treatment within 48 hours of life (01.54.06), duration of treatment greater than one week (01.54.07), total dose of vitamin E in the control group less than or equal to 10 mg/100 kcal (01.54.08) (typical estimates identical to the summary statistics for this outcome); (2) iron supplementation in both groups (01.54.09) (MD -1.96, CI -2.89, -1.03); and (3) iron supplementation in neither group (01.54.10) (MD -1.47, CI -2.22, -0.72).

Reticulocyte count (expressed in percent of total red blood cell count) in very low birth weight infants (Outcome 01.55):
This outcome was assessed in a single study, involving 31 treated patients and 33 controls. Vitamin E supplementation did not significantly affect reticulocyte counts (MD -0.30, CI -1.50, +0.90).

Absolute reticulocyte counts (expressed in million per liter) (Outcome 01.56):
This outcome was assessed in two studies, involving 32 treated patients and 39 controls. Meta-analysis showed significant heterogeneity between the two studies (chi-square analysis 13.03, p = 0.0003) and a significant reduction in reticulocyte count in the treated group (WMD -34.0, CI -46.2, -21.8, z = 5.48, p < 0.00001).

Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron. Vitamin E supplementation significantly reduced reticulocyte count in the following subgroups, which involved all patients in both studies: enteral (01.56.02), excluding intravenous vitamin E supplementation (01.56.03), serum tocopherol level less than or equal to 3.5 mg/dl (01.56.05), onset of treatment after 48 hours of life (01.56.06), duration of treatment greater than one week (01.56.07), total dose of vitamin E intake in the control group equal to or less than 10 mg/100 kcal (01.56.08), and iron supplementation in both groups (01.56.09) (typical estimates identical to summary statistics for this outcome).

Absolute reticulocyte counts (expressed in million per liter) in very low birth weight infants (Outcome 01.57):
This outcome was assessed in a single study, involving 31 treated patients and 33 controls. Vitamin E supplementation significantly reduced absolute reticulocyte counts (MD -54.3, CI -70.7, -37.9).

Blood transfusion

Number of transfusions (Outcome 01.58):
This outcome was assessed in a single study involving 15 treated patients and 15 controls. Vitamin E supplementation did not significantly affect the number of transfusions (MD -0.20, CI -1.17, +0.77).

Number of transfusions among survivors (Outcome 01.59):
This outcome was assessed in a single study involving 68 treated patients and 67 controls. Vitamin E supplementation did not significantly affect the number of transfusions (MD +1.20, CI -1.42, +3.82).

Amount of blood transfused (ml per kg of body weight) among very low birth weight infants (Outcome 01.60):
This outcome was assessed in two studies involving 223 treated patients and 231 controls. Vitamin E supplementation did not significantly affect the number of transfusions (WMD -0.5, CI -16.9, +15.9).
Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Amount of blood transfused among survivors (Outcome 01.61):
This outcome was assessed in a single study involving 68 treated patients and 67 controls. Vitamin E supplementation did not significantly affect the number of transfusions (MD +18.1, CI -17.1, +53.3).

Other outcomes

Platelet count (Outcome 01.62):
Platelet counts were analyzed in two studies involving a total of 49 treated patients and 60 controls. Vitamin E supplementation did not significantly affect the platelet count (WMD -29.52, CI -88.81, +29.76).
Subgroup analyses: data available for analysis by birth weight, by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group, and by dose of vitamin E in the control group and by intake of iron. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Coagulation tests (Outcomes 01.63 - 01.65):
The effects of vitamin E on coagulation tests were analyzed in one study involving 23 treated patients and 24 controls (Zipursky 1987), which used low dose enteral administration Vitamin E administration did not significantly affect any of the coagulation tests, including prothrombin time, partial thromboplastin time, fibrinogen concentration and other factors not listed in this review.

Retinal hemorrhage among very low birth weight infants examined/survivors (Outcome 01.66):
This outcome was assessed in a single study, involving 111 treated patients and 121 controls, which used high-dose, intravenous administration of vitamin E. Vitamin E did not significantly affect the risk of retinal hemorrhage in the whole study population (estimate RR 2.18, CI 0.97,4.89; RD 0.08, 0.16). Subgroup analysis among extremely low birth weight infants (n=85) showed that vitamin E significantly increased the risk of retinal hemorrhage (estimate RR 3.58, CI 1.28,10.00; RD 0.24, CI 0.07, 0.41).

Reaction at the site of injection (Outcome 01.67):
This outcome was reported in two studies, involving 175 treated patients and 182 controls. Meta-analysis showed no significant effect of vitamin E on this outcome (typical estimate RR 4.13, CI 0.47, 36.69; RD 0.02, CI -0.01, +0.04).
Subgroup analyses: data available for analysis by birth weight (see section 01.67) and by route of administration, by total dose, serum level, onset and duration of therapy in the treatment group. Vitamin E supplementation did not significantly affect this outcome in any of the analyses.

Reaction at the site of injection in very low birth weight infants (Outcome 01.68):
This outcome was assessed in a single study involving 73 treated patients and 74 controls. Vitamin E supplementation did not significantly affect the risk of reaction, estimate RR 5.07, CI 0.25, 103.78; RD 0.03, CI -0.02, +0.074.

VITAMIN E VERSUS ANOTHER TYPE OR ROUTE OF VITAMIN E FORMULATION (COMPARISON 02):

Only one study was found in this category. Bonati 1991 did not show any significant difference in mortality (Outcome 02.01) and did not assess the other planned primary outcomes (long-term combined outcomes). This study did not show any significant difference in any of the analyzed secondary outcomes, including bronchopulmonary dysplasia (Outcome 02.02), patent ductus arteriosus (Outcome 02.03), sepsis (Outcome 02.04), intracranial hemorrhage (Outcome 02.05), parenchymal hemorrhage (Outcome 02.06), necrotizing enterocolitis (Outcome 02.07), or exchange transfusion (Outcome 02.08). Plasma levels of free tocopherol peaked on day three, after three injections of vitamin E. In the treatment group, plasma levels of tocopheryl acetate were one third of levels of free tocopherol. In the control group receiving tocopherol in olive oil, plasma levels of free tocopherol were within deficient range and significantly lower than those receiving the colloidal solution of tocopheryl acetate.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Index terms

SUMMARY OF THE RESULTS :

VITAMIN E VERSUS PLACEBO OR NO VITAMIN E (COMPARISON 01):
Primary outcomes:
Vitamin E supplementation did not significantly affect mortality in all patients and in very low birth weight infants; the strength of this inference is strong, based on more than 1500 randomized patients and no evidence of heterogeneity . No study assessed combined outcomes at 18 months of age.

Secondary outcomes:
Bronchopulmonary dysplasia :
Vitamin E supplementation did not significantly affect these outcomes (except for some subgroup analyses of patent ductus arteriosus requiring treatment). The strength of theses inferences is strong, based on 500-900 randomized patients and no evidence of heterogeneity.

Patent ductus arteriosus:
Vitamin E supplementation did not significantly affect patent ductus arteriosus. The strength of this inference is strong, based on 500-900 randomized patients and no evidence of heterogeneity. However, there was significant heterogeneity for patent ductus arteriosus requiring treatment, and some subgroup analyses reached statistical significance.

Sepsis:
Vitamin E supplementation significantly increased the risk of sepsis after study entry among all infants (typical estimate RR 1.52, CI 1.13, 2.04). The strength of this inference appears strong, based on a large number of randomized patients (>1000) and no evidence of heterogeneity. However, there is heterogeneity in RD. Vitamin E supplementation significantly increased the risk of sepsis after study entry among very low birth weight infants (typical estimate RR 1.53, CI 1.13, 2.08), and among very low birth weight infants treated for more than one week (typical estimate RR 1.63, CI 1.17, 2.26). The strength of this inference is strong, based on 500-900 randomized patients and no evidence of heterogeneity. Subgroup analysis showed that this effect was associated with parenteral vitamin E supplementation, intravenous supplementation, at dose greater than 30 IU/kg/day, starting within 48 hours after life, with serum tocopherol levels greater than 3.5 mg/dl, and with vitamin E intake in the control group that was equal to or lower than 10 mg/100 kcal. In contrast, vitamin E did not significantly affect the risk of sepsis among surviving very low birth weight infants (n=274).

Intracranial hemorrhage:
Vitamin E supplementation significantly reduced the risk for germinal matrix/intraventricular hemorrhage among all infants (n=1755) (typical estimate RR 0.85, CI 0.73, 0.99). The strength of this inference appears strong, based on a large number of randomized patients and no evidence of heterogeneity. However, there is heterogeneity in RD. Subgroup analyses suggest that this heterogeneity may be related in large part to differences in route of administration; specifically, subgroup analyses of intravenous versus other routes of administration completely eliminated this heterogeneity. Intravenous vitamin E supplementation did not significantly affect the risk of hemorrhage (01.19.05), whereas administration by other than the intravenous route (01.19.06) significantly reduced that risk (typical estimate RR 0.71, CI 0.58, 0.87; RD -0.14, CI -0.22, -0.06).
Among very low birth weight infants, vitamin E supplementation did not significantly affect the risk for germinal matrix/intraventricular hemorrhage; although the strength of this inference appears strong, based on a large number (n=777) of randomized patients and no statistical evidence of heterogeneity, a word of caution is required. Subgroup analysis excluding high-dose intravenous vitamin E only counted a single study (Fish 1990) involving only 147 patients and yielding an estimate RR of 0.70, CI 0.46,1.04, which is in the same range as that cited above in this paragraph for all premature infants.

The effect of vitamin E supplementation on severe intraventricular hemorrhage or on parenchymal hemorrhage was heterogeneous. Vitamin E supplementation did not significantly affect the risk of severe intraventricular hemorrhage or parenchymal hemorrhage among all infants or among very low birth weight infants. In extremely low birth weight infants vitamin E supplementation did not significantly affect the risk for severe hemorrhage (n=232) in studies analyzing the data on intention to treat basis, but significantly reduced the risk of severe intraventricular hemorrhage in survivors (n=133). This discrepancy resulted from the fact that vitamin E reduced the risk of severe hemorrhage only in survivors in Fish 1990. The effects of vitamin E on parenchymal hemorrhage could have resulted from several differences in design between two studies: intravenous high-dose, prolonged administration of vitamin E including in extremely low birth weight infants was associated with an increased risk in one study, whereas intramuscular, low-dose, short administration was associated with a reduced risk in another study.

Retinopathy of prematurity:
Vitamin E supplementation did not significantly affect the risk of retinopathy of prematurity (all grades) among all infants (typical estimate RR close to 1 in all analyses). The strength of this inference is strong, based on more than 1300 randomized patients and no evidence of heterogeneity.

Vitamin E supplementation did not significantly affect the risk of severe retinopathy of prematurity among all infants (typical estimate RR 0.72, CI 0.41,1.25) and among very low birth weight infants (typical estimate RR 0.59, CI 0.32,1.08) in an intention to treat analysis. The strength of this inference appears strong, based on more than 1300 randomized patients and no statistical evidence of heterogeneity. Nevertheless, the RR is not close to 1 in either of these analyses. Among examined very low birth weight infants, vitamin E significantly reduced the risk for severe retinopathy of prematurity (n=1062) (typical estimate RR 0.58, CI 0.34, 1.00) and the risk for blindness (typical estimate RR 0.19, CI 0.10, 0.88, n=467) but not retinal detachment (too rare to reach any solid conclusion) nor the risk for reaching a final cicatricial stage. The reduction in risk for severe retinopathy was observed with serum levels greater than 3.5 mg/dl (typical estimate RR 0.34, CI 0.13, 0.88 for all infants and 0.34, CI 0.13,0.87 for very low birth weight infants), but not with lower levels (typical estimates RR 0.83, CI 0.42, 1.61 and 1.01, CI 0.44,2.32, respectively). Reduced risk of blindness was observed in very low-birth weight infants receiving vitamin E starting within 48 hours of life and for more than a week.

Our results on retinopathy of prematurity are similar although not identical to those of a recent systematic review (Raju 1997), which analyzed retinopathy of prematurity after reclassifying individual outcomes according to the International Classification for Retinopathy of Prematurity. The odds ratio for retinopathy of prematurity among very low birth weight infants using an intention-to-treat analysis was 0.85 (CI 0.65, 1.11) in Raju 1997, compared with 0.83 (CI 0.62, 1.11) in our study. The odds ratio using an intention-to-treat analysis was 0.44 (CI 0.21, 0.87) for severe retinopathy (ROP 3+) in Raju 1997, compared with 0.57 (CI 0.30, 1.09) for ROP >=3 in our study; analysis among patients examined reached significance in Raju 1997 as well as in our analysis.

Necrotizing enterocolitis:
Vitamin E supplementation did not significantly affect the risk of necrotizing enterocolitis among all infants and among very low birth weight infants (typical estimate RR 1.37, CI 0.93, 1.95). The strength of this inference appears strong, based on more than 1340 randomized patients and no statistical evidence of heterogeneity. Nevertheless, the typical estimate RR is not close to 1 and RR in individual studies varies between 0.51 and 6.88.

Among 734 very low birth weight infants treated for more than one week, the typical estimate RR was 1.51 (CI 0.99, 2.30), reaching significance in infants with birth weight less than 1500 grams and in those with serum tocopherol levels greater than 3.5 mg/dl. The strength of this inference is limited by lack of intention-to-treat analysis and by heavy weighing of the results towards a single study using high-dose intravenous vitamin E administration (Johnson 1989).

Hematologic outcomes:
Vitamin E supplementation significantly increased hemoglobin by a small amount (0.4 g/dl) in more than 400 patients and without evidence of heterogeneity, and significantly reduced reticulocyte count. Nevertheless, it did not affect the need for transfusion. In very low birth weight infants, vitamin E significantly reduced serum bilirubin by 1.5 mg/dl.
Low-dose, enteral administration of vitamin E did not significantly affect platelet counts or coagulation tests.
High-dose intravenous administration of vitamin E significantly increased the risk of retinal hemorrhage among 85 extremely low birth weight infants in a single study (Phelps 1987a) but not among the whole set of 232 very low birth weight infants. This is the same study in which vitamin E significantly increased the risk of parenchymal intracranial hemorrhage (01.28). Rosenbaum had found a statistical association between severe intraventricular hemorrhage and later retinal hemorrhage (p<0.007, Fisher's exact test (Phelps 1987a). Mean peak tocopherol levels were 5.07+/-3.41 mg/dl in patients with retinal hemorrhage versus 3.49+/-3.22 mg/dl in those without retinal hemorrhage (p = 0.025).

Summary:
Summary statistics using intention-to-treat analyses showed that routine vitamin E supplementation significantly reduced the risk of germinal/intraventricular hemorrhage (RR 0.85, CI 0.73, 0.99) and increased the risk of sepsis after study entry (RR 1.52, CI 1.13, 2.04) but did not significantly affect mortality, bronchopulmonary dysplasia, patent ductus arteriosus, severe intraventricular hemorrhage, parenchymal hemorrhage, retinopathy of prematurity, platelet count, or coagulation studies. Hemoglobin concentration was significantly increased by a small amount (WMD 0.46, CI 0.24, 0.69). In very low birth weight infants, vitamin E supplementation significantly increased the risk for sepsis after study entry (RR 1.53, CI 1.13, 2.08) and, although with significant heterogeneity, the risk for parenchymal hemorrhage (RR 9.21, CI 1.22, 69.58); among those with known outcomes vitamin E significantly reduced the risk for severe retinopathy (RR 0.58, CI 0.34, 1.00) and blindness (RR 0.29, CI 0.10, 0.88).

Subgroup analyses showed that (1) serum tocopherol levels greater than 3.5 mg/dl in very low birth weight infants were associated with a significantly increased risk of sepsis after study entry (RR 1.72, CI 1.24, 2.40) , with increased risk of necrotizing enterocolitis among those treated for more than one week (RR 1.60, CI 1.02, 2.52) and with reduced risk for severe retinopathy among those examined (RR 0.34, CI 0.13, 0.88); and (2) intravenous, high-dose administration of vitamin E in very low birth weight infants was associated with a significantly increased risk of sepsis after study entry (RR 1.56, CI 1.07, 2.27), with increased risk of parenchymal hemorrhage in one study only and with increased risk of necrotizing enterocolitis among those treated for more than one week in another study.

Colloidal vitamin E versus vitamin E in olive oil:
Colloidal vitamin E resulted in higher serum levels, but did not significantly affect any of the analyzed outcomes.

Discussion:
In this systematic review, a large number of subgroup analyses was undertaken. This must lead to caution in inferring the likely effects of treatment when estimated in multiple subgroups.

Although this systematic review shows that high-dose intravenous vitamin E has toxic effects, these data should not be taken as evidence that intravenous vitamin E at any dose is toxic. Based on all the available evidence from this systematic review and from data presented in the background, the dose recommended by the American Society for Clinical Nutrition (2.8-3.5 IU/kg/day) (Greene 1988) for extremely low birth weight infants should remain the current standard of care for those fed parenterally.

The majority of the clinical trials available in this systematic review were conducted in the 1980s or earlier, so that too few surviving extremely preterm infants were available to permit subgroup analysis of this most vulnerable population. Thus, recommendations based on the available subjects must be viewed with caution when applied to the group of preterm infants inhabiting the modern neonatal unit. The current population includes many infants who are more premature and smaller than the infants on whom the recommendations were based. Furthermore, the only major long-term benefit of vitamin E supplementation demonstrated in this review was the prevention of blindness in very low birth weight infants, the incidence of which has been substantially reduced with laser photo coagulation.

Because the majority of clinical trials available for this review analyzed infants who currently are not the ones at high risk for threshold retinopathy of prematurity, and because severe retinopathy is relatively frequent in extremely low birth weight infants, it would appear justified to initiate a multicenter randomized trial assessing the effects in this population of supplementation with vitamin E (excluding high-dose intravenous administration) begun within 48 hours of birth and given for more than one week. Only three studies provided extremely low birth weight infants meeting these criteria and available for analysis in this systematic review: Ehrenkranz 1982; Fish 1990; Hittner 1981, in which mean serum tocopherol levels in the treatment group were, respectively, 3.89, 4.24 and 1.21 mg/dl. In the latter study, serum levels in control patients were compatible with vitamin E deficiency. Thus, only the first two studies should be used as baseline. The numbers of patients available to our analysis were 147 for mortality (01.02.03), sepsis (01.16.03), germinal matrix/intraventricular hemorrhage (01.20.03), severe intraventricular hemorrhage (grade III/IV) (01.25.02) and necrotizing enterocolitis (01.45.03), nine for retinopathy of prematurity among patients examined (01.34.03) and for severe retinopathy (grade 3 or more) (01.36.03) and blindness (01.43.03), and none for retinopathy of prematurity (any grade) (01.32.03), parenchymal hemorrhage (grade IV) (01.28), retinal detachment among survivors (01.40.03) and retinal bleeding (01.66.02). Among patients examined, the typical estimate RR was 1.67 for sepsis (01.16.03), 0.70 for germinal matrix/intraventricular hemorrhage (01.20.03), 0.59 for severe intraventricular hemorrhage (01.25.02), 0.27 for retinopathy of prematurity among patients examined (01.34), 0.12 for severe retinopathy of prematurity (01.38.03), not estimable for blindness (01.43.03), and 0.51 for necrotizing enterocolitis (01.45.03). Thus, preliminary analysis suggests that potential benefits might include a reduction of severe intraventricular hemorrhage and retinopathy and potential toxicity might include sepsis.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Index terms

 

Implications for practice

Available data show that vitamin E supplementation in very low birth weight infants reduces severe retinopathy at high serum tocopherol levels, i.e., those associated with sepsis. Doses of vitamin E greater than 30 IU/kg/day are also associated with sepsis. Thus, the "best" pharmacologic dose of vitamin E is unclear at this point. Evidence argues against the use of intravenous vitamin E supplementation, high doses or routes yielding serum tocopherol levels greater than 3.5 mg/dl in preterm infants including very low birth weight infants.

 
Implications for research

It would appear justified to initiate in extremely low birth weight infants a multicenter randomized trial assessing the effects of supplementation with vitamin E (excluding high-dose intravenous administration) begun within 48 hours of birth and given for more than one week. Such a study should examine the incidence of severe retinopathy of prematurity, blindness, severe intracranial hemorrhage, sepsis, and long-term neurodevelopmental outcome. The study should focus on the most immature infants (less than 28 weeks gestational age and less than 1000 grams birth weight ) because these infants are at the highest risk of complications of prematurity. If a new multicenter trial is to be undertaken, it should be designed to allow careful monitoring for toxicity, and, if doses greater than 30 IU/kg/day are to be tested, serum tocopherol levels should be monitored. It is unclear whether target levels should be below or above 3.5 mg/dl because high levels were those associated both with increased risk of sepsis and with reduced risk for severe retinopathy. Furthermore, such trial may be more controversial than other interventions which may reduce the risk of severe retinopathy of prematurity without apparent severe side effects, e.g., reducing oxygen administration and allowing a decrease in oxygen saturation (Tin 2001; Chow 2003).

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Index terms

We wish to thank Ms. Diane Haughton and Dr. Bosco Paes for providing us with a copy of Milner's 1981 manuscript (Zipursky 1987). We thank Ms. Melody Thompson, MS, RD, Ms. Mary L Banish and Mr. Jason Miller from Ross Products Division of Abbott Laboratories, who searched for additional references for this review. We thank Philip Roth, MD, PhD, for allowing us to present a study in press (Pathak 2003).

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Index terms
Download statistical data

 
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]

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Index terms

Last assessed as up-to-date: 30 March 2007.


DateEventDescription

20 May 2008AmendedConverted to new review format.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Index terms

Protocol first published: Issue 2, 2002
Review first published: Issue 4, 2003


DateEventDescription

31 March 2007New search has been performedThis updates the review "Vitamin E supplementation for prevention of morbidity and mortality in preterm infants" published in The Cochrane Library, Issue 4, 2003 (Brion 2003).

A repeated Medline search in March 2007 and a search of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007, yielded one additional retrospective study (Liu 2005) and another study that is now listed in the background section (Scholl 2006). One study (Pathak 2003), in press at the time of the original version of this review, has been published.

12 June 2003New citation required and conclusions have changedSubstantive amendment



 

Declarations of interest

  1. Top of page
  2. Background