Plain language summary
Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birthweight infants
Vitamin A is a group of fat-soluble compounds used by the body for regulation and promotion of growth and differentiation of many cells, including cells in the retina of the eye and the cells that line the lung. Preterm infants have low vitamin A levels at birth. This may contribute to an increased risk of developing chronic lung disease, and hence a requirement for oxygen. It is possible that additional vitamin A supplement may reduce complications of prematurity, including abnormal development of the retina (retinopathy), bleeding in the brain (intraventricular haemorrhage), and damage to the gut from inflammation (necrotising enterocolitis) as well as reducing respiratory infections. Too much vitamin A is potentially harmful as it can raise intracranial pressure and cause skin and mucous membrane changes (injury or lesions), and vomiting. Nine trials were included in this review, eight comparing vitamin A with a control (placebo or no supplementation) and one comparing different vitamin A regimens. Supplementing very low birthweight infants with vitamin A by intramuscular injection or in the milk formula was associated with a trend toward a reduced number of deaths or oxygen requirement at one month of age compared to placebo. For surviving infants with birthweight less than 1000 g (three trials, 824 infants of which at least 96% had a birthweight < 1000 g), fewer infants required oxygen at 36 weeks' postmenstrual age compared to the control; the number needed to treat for one to benefit was 13 (95% confidence interval 7 to 100). Three trials with information on retinopathy of prematurity suggested a trend towards reduced incidence in infants receiving vitamin A supplementation. The one trial that investigated neurodevelopmental status at 18 to 22 months of age correcting for prematurity found no evidence of benefit or harm associated with vitamin A supplementation compared to control. No adverse effects of vitamin A supplementation were reported, but it was noted that intramuscular injections of vitamin A were painful.
Resume En Langage Simplifie
Supplémentation en vitamine A pour prévenir la mortalité et la morbidité à court et à long terme chez les nourrissons de très faible poids de naissance
La vitamine A est un groupe de composés liposolubles utilisés par le corps pour réguler et favoriser la croissance et la différenciation de nombreuses cellules, notamment les cellules de la rétine et celles qui tapissent le poumon. Les prématurés présentent des taux de vitamine A faibles à la naissance. Ils risquent ainsi davantage de développer une maladie pulmonaire chronique, et donc d'avoir besoin d'oxygène. Il est possible qu'un supplément en vitamine A réduise les complications dues à la prématurité, notamment le développement anormal de la rétine (rétinopathie), une hémorragie cérébrale (hémorragie intraventriculaire) et des troubles intestinaux dus à une inflammation (entérocolite nécrosante), ainsi que les infections respiratoires. Les excès en vitamine A sont potentiellement dangereux, car ils peuvent augmenter la pression intracrânienne, modifier la peau et les muqueuses (lésions) et entraîner des vomissements. Neuf essais ont été inclus dans cette revue, huit comparant la vitamine A avec un témoin (placebo ou absence de supplémentation) et un comparant différents régimes riches en vitamine A. La supplémentation en vitamine A des nourrissons de très faible poids de naissance par injection intramusculaire ou dans le biberon a été associée à une tendance en faveur d'une réduction du nombre de décès ou de besoins en oxygène à un mois d'âge par comparaison avec un placebo. Quant aux nourrissons survivants dont le poids de naissance était inférieur à 1 000 g (trois essais, 824 nourrissons, dont au moins 96% avaient un poids de naissance < 1 000 g), le nombre de nourrissons ayant eu besoin d'oxygène à 36 semaines d'âge post-menstruel était moindre par rapport au témoin; le nombre de sujets à traiter pour observer un bénéfice du traitement était de 13 (intervalle de confiance à 95% 7 à 100). Trois essais présentant des données sur la rétinopathie de la prématurité ont suggéré une tendance en faveur de la baisse de l'incidence chez les nourrissons bénéficiant d'une supplémentation en vitamine A. Le seul essai à avoir étudié le statut neurodéveloppemental entre 18 et 22 mois d'âge corrigé pour tenir compte de la prématurité n'a trouvé aucune preuve d'un avantage ou d'un préjudice associé à la supplémentation en vitamine A par comparaison avec le témoin. Aucun effet indésirable lié à la supplémentation en vitamine A n a été signalé, mais il a été noté que les injections intramusculaires de vitamine A étaient douloureuses.
Description of the condition
Vitamin A is the generic name for a group of fat-soluble compounds which have the biological activity of the primary alcohol retinol. Vitamin A is involved in the regulation and promotion of growth and differentiation of many cells and in maintaining the integrity of the epithelial cells of the respiratory tract. Vitamin A is also necessary for formation of photosensitive visual pigment in the retina, reproductive functions, and immuno-competence. Caretenoids, dietary precursors of vitamin A, have antioxidant properties.
The fetus accumulates vitamin A in the third trimester. The transport mechanism of vitamin A across the placenta and its regulation are not fully established. Premature infants have reduced hepatic stores (of retinyl ester). In the plasma, vitamin A is bound to a specific carrier protein, retinol-binding protein (RBP), and the resulting complex is further complexed with transthyretin (formerly prealbumin) (Mactier 2005). Premature infants have lower concentrations of plasma RBP than term infants, and most preterm infants have low plasma vitamin A concentrations and low plasma retinol/RBP molar ratios, suggesting they are vitamin A deficient (Shenai 1993). Inadequate provision and delivery of vitamin A postnatally may exacerbate the problem.
Description of the intervention
Preterm infants who are unable to tolerate oral feeds are routinely fed parenterally with both an amino-acid/dextrose mixture and a lipid emulsion. Multivitamin preparations containing retinol or an equivalent are commonly added to the amino-acid/dextrose mixture and infused over 24 to 48 hours, but significant losses in delivered vitamin A have been shown to result from light degradation and from adsorption to the tubing. Alternatively, the multivitamins may be added to the lipid infusate (Greene 1987). Kennedy 1997 demonstrated improved serum retinol concentrations following intramuscular injections given three days per week. This route of administration has been adopted in several recent studies. In preterm infants who are able to tolerate enteral feeds, the absorption of enteral vitamin A by the immature gut may be poor.
The 'adequate' concentration of plasma vitamin A in very low birthweight infants is not known. Concentrations below 200 μg/L (0.70 μmol/L) have been considered deficient in premature infants, and concentrations below 100 μg/L (0.35 μmol/L) indicate severe deficiency and depleted liver stores. Both the plasma RBP response (Shenai 1990) and the relative rise in serum retinal concentration (Zachman 1996) following intramuscular vitamin A administration have been described as useful tests to assess functional vitamin A status. However, in a recent review, Mactier 2005 concluded that the relationship between measures of vitamin A concentration and functional vitamin A status in preterm infants is not clear.
Vitamin A deficiency in laboratory animals produces a sequence of histopathological changes in the respiratory tract epithelium including necrotising tracheobronchiolitis and squamous metaplasia. These changes can be reversed by restoration of adequate vitamin A status. Similar changes are observed in ventilated infants with chronic neonatal lung injury, leading to the suggestion that vitamin A deficiency may contribute to such injury and supplementation with vitamin A may facilitate healing and recovery (Chytil 1992; Shenai 1993). Two earlier studies reported that very low birthweight infants who developed chronic lung disease had lower concentrations of vitamin A than similar infants without chronic lung disease (Hustead 1984; Shenai 1985), although other studies from an era when all infants received more adequate supplementation have given conflicting results (Chabra 1994; Spears 2004).
How the intervention might work
In the 1920s, vitamin A was considered to be an anti-infective agent. There is increasing evidence that vitamin A does have a role in immune function (Bates 1995). Several studies in areas of the world where there is generally poor nutritional status have suggested vitamin A supplementation in infancy may be associated with decreased mortality and morbidity. In infants in Indonesia, Humphrey 1996 reported that a single dose of 52 μmol (50,000 IU) given orally to term infants at birth reduced infant mortality and the prevalence of severe respiratory infections compared with placebo. A Cochrane Review concluded that two oral doses of 200,000 IU in children under two years of age with measles are associated with a reduced risk of overall mortality and of pneumonia-specific mortality (Huiming 2005).
Vitamin A has a role early in gestation in the development of the cardiovascular system (Mactier 2005). Animal models suggest higher vitamin A concentrations may accelerate postnatal constriction of the ductus arteriosus. The possibility that vitamin A supplementation may ameliorate other complications of prematurity, including retinopathy, intraventricular haemorrhage, and necrotising enterocolitis, has been suggested by a number of authors, although the basis for any effect is not clearly established.
Vitamin A is potentially toxic, and raised intracranial pressure and vomiting have been described in infants receiving large doses. In children and adults, chronic hypervitaminosis A may include bone and joint pain, and mucocutaneous lesions and hepatic dysfunction, but the syndrome has not been recognised in preterm infants.
Why it is important to do this review
Although a role for vitamin A in neonatal chronic lung disease is not in doubt, uncertainty exists regarding the efficacy of supplementation and whether additional benefit may be obtained by achieving concentrations beyond sufficiency.
This is an update of previous versions of this Cochrane Review (Darlow 1998; Darlow 2000; Darlow 2002; Darlow 2007).
To evaluate supplementation with vitamin A with a control (placebo or no supplementation) on the incidence of death and/or neonatal chronic lung disease and long-term neurodevelopmental disability in very low birthweight infants; and to consider the effect of the supplementation route, dose, and timing.
This Cochrane Review includes nine randomised controlled trials, eight comparing vitamin A with placebo and one comparing different vitamin A regimens. Tyson 1999 is the largest trial included in the review with a sample size (807 infants) more than twice that of the next largest trial (154 infants, Wardle 2001).
The first version of this review (Darlow 1998) reported a significant reduction in death or oxygen use at one month of age in vitamin A-treated infants (RR 0.75, 95% CI 0.62 to 0.91), but the addition of Tyson 1999, which found no difference in outcome at one month, to the pooled data resulted in the meta-analysis showing only a trend of borderline significance towards reduction in death or oxygen use at this time (RR 0.93, 95% CI 0.86 to 1.00) (Darlow 2000). Wardle 2001, the only trial to give supplemental vitamin A via the enteral route, had a moderate sample size (154) and found no significant benefit for supplementation; however, the further addition of data from this trial resulted in the meta-analysis showing a small but significant reduction in this outcome (RR 0.93, 95% CI 0.88 to 0.99; RD -0.05, 95% CI -0.10 to -0.01; NNTB 20, 95% CI 10 to 100).
Three trials reported outcomes at 36 weeks' postmenstrual age (Ravishankar 2003; Tyson 1999; Wardle 2001). Tyson 1999, which gave intramuscular vitamin A to supplemented infants, reported a significant reduction in oxygen use in vitamin A-treated infants (RR 0.85, 95% CI 0.73 to 0.98), and a trend towards reduction in death or oxygen use of borderline significance (RR 0.89, 95% 0.79 to 1.00). Pooling the data from the three trials did not alter these conclusions. From the meta-analysis of the combined data, the NNTB in one infant with regard to oxygen requirement at 36 weeks is 13, and with regard to death or oxygen requirement at 36 weeks is 17. It is important to note that the 95% confidence intervals are wide, being 7 to 100 and 8 to 1000 respectively. It is also noteworthy that there was no difference in other outcomes, including days of ventilation and length of stay, between vitamin A supplemented and control infants in Tyson 1999.
Some differences between the trials may be explained by the differences in patient populations (birthweight and ethnicity), by the differences in both the route of vitamin A supplementation (intramuscular, intravenous in lipid emulsion, or enteral), and the dose given. Tyson 1999 and Wardle 2001 included somewhat lower birthweight infants (401 to 1000 g and < 1000 g respectively) than most other trials, whereas other trials used various lower weight limits (500 g for Ravishankar 2003; 700 g for Pearson 1992 and Shenai 1987; 725 g for Werkman 1994; and 1000 g for Bental 1994). The incidence of supplemental oxygen requirement at one month of age in vitamin A-supplemented infants was higher at 73% in Tyson 1999 and 83% in Wardle 2001; this is consistent with their lower birthweight and gestational age compared with a range of 34% to 67% in the other trials. For the smallest infants, the outcome at 36 weeks' postmenstrual age may be more clinically relevant.
In all the included trials there were higher vitamin A or retinol concentrations at most time periods studied in the infants in the vitamin A group compared with the control group. Kennedy 1997 reported that an intramuscular dose of 5000 IU vitamin A three times per week was required to achieve serum concentrations > 250 μg/L in most very low birthweight infants. This was the dose used by Tyson 1999 and was generally greater than the dose used in earlier studies; for example, Bental 1994 used 4000 IU three times weekly, Papagaroufalis 1988 used 4000 IU on alternate days while the infant was ventilated, Pearson 1992 and Shenai 1987 used 2000 IU on alternate days, and Ravishankar 2003 used between 1500 IU and 3000 IU for only three doses. Nevertheless, in Tyson 1999, 25% of infants who received supplemental vitamin A and 54% of controls (data from the first 300 enrolled infants) had vitamin A concentrations below 200 μg/L on day 28. Similar percentages, 22% of those who received supplemental vitamin A and 45% of controls, had a relative dose response (change in the serum retinol concentration divided by the preinjection concentration) of more than 10% following an intramuscular dose of 2000 IU. Taken together, these data suggested that an even higher dose of vitamin A given intramuscularly may be required to achieve vitamin A sufficiency in very premature infants.
In Wardle 2001, infants received a much higher cumulative dose of supplemental vitamin A than in other studies (140,000 IU in 28 days compared with 60,000 IU in Tyson 1999), but by the enteral route. Vitamin A concentrations were only measured in the first 84 infants enrolled, and the median concentration 24 hours after the first dose was significantly higher in supplemented infants (230 μg/L versus 150 μg/L). At seven and 28 days of age, however, there were no significant differences in vitamin A concentrations between the groups, and the median concentration in both groups was less than 200 μg/L at these times. Vitamin A absorption is less efficient using the enteral route. Rush 1994 compared the same dose of vitamin A (2000 IU/kg on alternate days) given by intramuscular injection or orally and reported the former route gave higher plasma vitamin A concentrations after one week. Landman 1992 reported that enteral supplementation with 5000 IU vitamin A daily resulted in similar plasma concentrations at 32 days of age to those resulting from 2000 IU vitamin A on alternate days by the intramuscular route.
There were also quite marked differences in the vitamin A dose received by the control groups. This has previously been suggested to account for differences in outcome between the early studies (Lorch 1994). Infants in the control group in Pearson 1992 received higher doses of vitamin A and had mean vitamin A concentrations in weeks three and four of greater than 200 μg/L. This is higher than in infants in the control group in Shenai 1987 in which mean vitamin A concentrations were less than 150 μg/L at these times. One interpretation is that Shenai 1987 demonstrated a benefit of supplemental vitamin A in a population with vitamin deficiency, while Pearson 1992 showed a minimal benefit of additional supplementation in a population with more adequate vitamin status. However, Georgieff 1989 reported that postnatal steroids led to a near doubling of plasma vitamin A concentrations, and this finding was confirmed in Tyson 1999. Certainly variability in exposure to postnatal steroids complicates interpretation of these data. Two trials included in this review reported the incidence of treatment with postnatal steroids (Pearson 1992, 46% in vitamin A group and 44% in controls; Wardle 2001, 39% and 34% respectively), while two others noted that steroids were used in some infants (Bental 1994; Tyson 1999) .
Further information on the optimal dosage of intramuscular vitamin A for infants with birthweight 401 to 1000 g is available from the Ambalavanan 2003 trial. Ambalavanan 2003 compared the dose regimen used by Tyson 1999 (5000 IU 3 x weekly for four weeks) with both a higher dose (10,000 IU 3 x weekly for four weeks) and a once-a-week dose (15,000 IU weekly for four weeks) in 120 infants. Only two infants received postnatal steroids between study day 21 and 28. Compared with the standard regimen, the higher dose regimen was not associated with a significantly higher mean retinol concentration at 28 days and there were no differences between the groups in the proportion of infants having concentrations < 200 μg/L at this time (26% versus 21%). The once-a-day regimen, however, was associated with significantly lower mean concentrations at 28 days and increased the risk of infants having concentrations < 200 μg/L at this time by a factor of 2.5 (26% versus 65%).
Many other variables will also affect the rate of chronic lung disease, which is known to vary considerably between centres. These factors include use of antenatal steroids (stated in four trials; Pearson 1992 where they were received by 26% study infants and 41% controls, Tyson 1999 where the rates were 76% and 74%, Wardle 2001 where the rates were 77% and 82%, and Ravishankar 2003 where the rates were 86% and 72%), exogenous surfactant (stated in three trials; Pearson 1992 where > 90% received an artificial surfactant, Tyson 1999 where > 80% received a natural surfactant, and Wardle 2001 where all but one infant in the control group received an artificial surfactant), mode of ventilation including early nasal continuous positive airway pressure, postnatal steroids, and criteria for prescribing supplemental oxygen.
Important information on follow-up at 18 to 24 months of infants who participated in the Tyson 1999 trial is now available in Ambalavanan 2005. Eighty-five percent of surviving infants were assessed. There was no difference between the groups in either neurodevelopment impairment (RR 0.89, 95% CI 0.74 to 1.08), or the combined outcome of death or neurodevelopmental impairment (RR 0.92, 95% CI 0.81 to 1.05). More infants who received supplemental vitamin A than controls were prescribed home oxygen (36% versus 32%) and were on home oxygen for more than 6 months (20% versus 26%), although these differences were not significant. Although this trial was not powered appropriately to assess long-term outcomes, there was no evidence of either benefit or harm from repeat intramuscular vitamin A following birth.
The data do suggest that, in the dosages employed, supplemental vitamin A is safe and free from adverse effects, although Pearson 1992 noted repeat intramuscular injections may have been painful.
We are grateful to Dr K Kennedy, University of Texas Southwestern Medical Center, Dallas, for supplying some original data and for helpful advice. We are also grateful to Drs Bengal, Wardle, Gelb (with regard to the Ravishankar 2003 trial), and Ambalavanan for supplying some original data for earlier versions of this Cochrane Review.
The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
The 2010 update was completed centrally by Roger Soll of the Cochrane Neonatal Group with the approval of the authors.
The authors thank the Cochrane Editorial Unit for the support in preparing the risk of bias tables and the Summary of Findings tables for the 2010 update.
Protocol first published: Issue 4, 1998
Review first published: Issue 2, 2000
|12 June 2008||Amended||Converted to new review format.|
|15 July 2007||New search has been performed|
This review updates the existing review "Vitamin A supplementation for preventing morbidity and mortality in very low birthweight infants", published in the Cochrane Database of Systematic Reviews in 2002, Issue 2 (Darlow 2002).
One further small trial has been identified and data from this trial added to the pooled data for the meta-analysis. There are now data on the neurodevelopmental status at 18 to 22 months postmenstrual age for infants included in the largest vitamin A supplementation trial, and this information has been included in this review. In addition, data from one trial that compared three different intramuscular vitamin A dosing regimens have been included.
The previous version of this review concluded that supplementing very low birthweight infants with vitamin A is associated with a reduction in oxygen requirement among survivors at 36 weeks postmenstrual age, as well as a reduction in death or oxygen requirement at one month of age. With data from the additional study, these conclusions remain the same. The information on follow-up at 18 to 22 months postmenstrual age from the largest included trial showed no evidence or benefit or harm from the intervention.
Based on biochemical data, the one study that investigated different intramuscular vitamin A dosing regimens suggested that the regimen used in the largest trial (5000 IU 3x weekly for four weeks) was optimal even though some infants still had poor vitamin A status.
The conclusion remains unchanged: clinicians must decide whether to utilise repeat intramuscular doses of vitamin A based upon the incidence of supplemental oxygen requirement at 36 weeks postmenstrual age in extremely low birthweight infants in their unit and their own assessment, based upon the review, of the benefits of a modest reduction in this outcome balanced against lack of other proven benefits and the acceptability of treatment. The follow-up data would support a decision either to treat or not to treat.
|15 July 2007||New citation required but conclusions have not changed||Substantive amendment.|
Contributions of authors
The original review was conducted and written by Brian A Darlow and PJ Graham. Review update was facilitated by Roger Soll, Coordinating Editor of the Cochrane Neonatal Review Group and approved by the original authors.