Vitamin E is obtained only through the diet and has a number of important biological activities, including functioning as an antioxidant. Evidence that free radicals may contribute to pathological processes such as bronchopulmonary dysplasia (BPD), a disease of prematurity associated with increased lung injury, inflammation and oxidative stress, led to trials of the antioxidant vitamin E (α-tocopherol) to prevent BPD with variable results. These trials were all conducted at supraphysiologic doses and 2 of these trials utilized a formulation containing a potentially harmful excipient. Since 1991, when the last of these trials was conducted, both neonatal management strategies for minimizing oxygen and ventilator-related lung injury and our understanding of vitamin E isoforms in respiratory health have advanced substantially. It is now known that there are differences between the effects of vitamin E isoforms α-tocopherol and γ-tocopherol on the development of respiratory morbidity and inflammation. What is not known is whether improvements in physiologic concentrations of individual or combinations of vitamin E isoforms during pregnancy or following preterm birth might prevent or reduce BPD development. The answers to these questions require adequately powered studies targeting pregnant women at risk of preterm birth or their premature infants immediately following birth, especially in certain subgroups that are at increased risk of vitamin E deficiency (e.g., smokers). The objective of this review is to compile, update, and interpret what is known about vitamin E isoforms and BPD since these first studies were conducted, and suggest future research directions.

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease associated with premature birth, most commonly seen among extremely preterm infants (prior to 28 weeks of gestation) requiring treatment for respiratory distress syndrome (RDS). The USA has the highest rate of preterm birth among high-income countries [1]. Advances in neonatal care have improved the survival of extremely preterm infants who are at the highest risk of developing BPD. In spite of major advances in the treatment of RDS, the incidence of BPD has not changed over the last several decades. Substantial evidence suggests that oxidative stress likely plays an important role in the development of certain phenotypes of BPD [2]. Understanding the mechanisms underlying the role of oxidative stress as a risk factor for BPD or in the pathogenesis of BPD is of substantial interest, as interventions that safely prevent or ameliorate oxidative stress might serve as prevention strategies for this disease.

One such potential intervention is vitamin E, which is known to neutralize free radicals and reduce oxidative stress. Vitamin E is also well tolerated as an oral supplement throughout pregnancy and infancy, and is routinely present in total parenteral nutrition (TPN) for premature infants, making it an attractive option for BPD prevention or treatment. This review will focus on outlining the association between oxidative stress, vitamin E, and BPD pathophysiology. We will then review new developments in understanding of individual vitamin E isoforms since the initial vitamin E trials were conducted in BPD. Finally, we will discuss knowledge gaps that should be the focus of future research.

The most commonly applied definition of BPD is a requirement for oxygen at 36 weeks of corrected gestational age, although the physiologic usefulness of this definition has been questioned [3] and is being actively studied [4, 5]. BPD was once thought to be a natural progression of RDS and therefore ameliorable by surfactant administration; however, the incidence of BPD has not decreased since surfactant became widely available [6]. Despite a multifactorial approach involving antenatal steroid therapy, early administration of surfactant, careful oxygen saturation targeting, avoidance of volutrauma and atelectasis, and an emphasis on intubation avoidance and early extubation, the incidence of BPD has remained stable [3, 7-13]. Demographically and pathologically, however, BPD is substantially different now [12, 14-16]. In the current era, many infants diagnosed with BPD at 36 weeks gestational age have minimal respiratory distress at birth [6, 17], and the new clinical and histological picture of BPD is conceived as a failure or arrest of normal alveolar and lung vascular formation in the setting of extreme prematurity, uncommon in infants greater than 1,200 g and greater than 30 weeks gestation [18, 19]. In addition, it is increasingly recognized that there are different phenotypes of BPD with variable contributions of oxidative stress, lung injury, lung repair, genetic predisposition, and epigenetic influences, among other factors [3].

Oxidative stress results from the disrupted balance between the generation of free radicals (such as reactive oxygen species) and their removal by free radical scavenging systems [20]. Reactive oxygen species exist, therefore, in a delicate balance in the human body. They are generated by multiple enzyme systems and act as intermediates of normal cellular metabolism [21], performing essential roles as second messengers [22], in induction of cell death and apoptosis [23], and as local mediators of infection control and inflammation [24].

Multiple investigators have noted that in the first few days of life there is a difference in oxidation of lipids and proteins in preterm infants who develop BPD compared to full-term infants and adults [14], and compared to preterm infants who do not develop BPD [2]. These differences manifest as increased presence of free iron, transferrin, ferritin and lactoferrin in bronchoalveolar secretions, which in the presence of oxygen become free radicals [25-28]. In settings of local increases of reactive oxygen species, the imbalance triggers downstream damage to the neonatal lung, possibly via nitric oxide-dependent pathways of lung development [29, 30] or another downstream pathway that causes activation of the immune system and local inflammatory destruction of lung architecture. Thus, multiple studies suggest a role for free radical generation and lipid peroxidation in the presence of inhaled oxygen either causing or being a biomarker for BPD development [25-28].

Interventions that mitigate or control oxidative stress might therefore prevent the development of BPD in at-risk infants. Vitamin E is a potent antioxidant, known to be essential for human health, and its easy tolerability as a normal part of the diet represents a feasible and acceptable potential antioxidant intervention. In 2015, Miller et al. [31] concluded that increasing first trimester maternal plasma α-tocopherol is associated with differential neonatal airway epithelial cell inflammatory mediator release, especially a decrease in tumor necrosis factor-α production, suggesting that α-tocopherol may be an important local anti-inflammatory factor in the neonatal lung. Hereafter, we will review what is known about vitamin E, its isoforms, and their potential role/association in the development of BPD.

Vitamin E is one of the essential fat-soluble vitamins, but it is not synthesized by the human body and requires intake from food sources, typically oils (Fig. 1). There are 8 isoforms of vitamin E, known as α-, β-, γ-, and δ- tocopherol and α-, β-, γ-, and δ-tocotrienol [32]. The 2 best-studied isoforms of vitamin E are α-tocopherol and γ-tocopherol. Dietary consumption of each isoform varies by food source [33]. At present, many foods and the majority of neonatal formulas in the USA deliver much greater γ-tocopherol than α-tocopherol [34]. The functions of each isoform in the human body, while not fully described, appear to be different, some with anti-inflammatory and some with proinflammatory properties [35]. Human tissues preferentially retain α-tocopherol and metabolize the other forms at higher rates [36, 37]. The main carrier vehicle for tocopherols in the body are lipid particles (chylomicrons, LDL and HDL) [38]. Increased lipids can elevate measured plasma tocopherols, and decreased lipids can lower measured plasma tocopherols [39]. Premature infants on TPN can have elevations in measured cholesterol compared to infants on enteral breastmilk [40]. Simultaneous measurement of tocopherols and lipids is currently recommended for scientific investigations, and is important to identify measurements of plasma tocopherols that have been altered by extremes of lipid status [39, 41].

Fig. 1.

Metabolism of vitamin E isoforms α- and γ-tocopherol during pregnancy. Tocopherols are found only in the diet and are transported via lipid pathways. The main site of tocopherol action is in tissues, where they are incorporated into cellular membranes and act to stabilize lipids and prevent lipid peroxidation by free radicals. The illustration was modified from a public image (image modified with licensed permission; artist: Blamb; source: www.shutterstock.com).

Fig. 1.

Metabolism of vitamin E isoforms α- and γ-tocopherol during pregnancy. Tocopherols are found only in the diet and are transported via lipid pathways. The main site of tocopherol action is in tissues, where they are incorporated into cellular membranes and act to stabilize lipids and prevent lipid peroxidation by free radicals. The illustration was modified from a public image (image modified with licensed permission; artist: Blamb; source: www.shutterstock.com).

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Both α-tocopherol and γ-tocopherol have been called anti-inflammatory, but their downstream effects appear to be different, as outlined in Table 1. α-Tocopherol has been more extensively studied, as has its documented anti-inflammatory profile [42]. γ-Tocopherol also has anti-inflammatory effects [42], especially in animal models and subjects with neutrophilic inflammation [43-51]. However, γ-tocopherol has also been reported to promote type II inflammation in the lungs and in other organs [33, 52, 53]. In human subjects with asthma, increased serum concentrations are associated with lower forced expiratory volume in 1 s (FEV1) [54]. Supplementation of primarily γ-tocopherol was shown to reduce plasma and urine concentrations of α-tocopherol via undefined competitive mechanisms [55]. Subsequently, α- and γ-tocopherol were noted by Marchese et al. [54] to have different primary roles in lung inflammation, with the isomers appearing to antagonize each other’s metabolism. In human studies, higher α-tocopherol is associated with a significantly decreased risk of asthma development, but the relationship of γ-tocopherol with asthma development is unclear [56].

Table 1.

Comparing the effects of α- and γ-tocopherol isoforms of vitamin E on lung growth and lung inflammation

Comparing the effects of α- and γ-tocopherol isoforms of vitamin E on lung growth and lung inflammation
Comparing the effects of α- and γ-tocopherol isoforms of vitamin E on lung growth and lung inflammation

Maternal prenatal factors including nutrition play a vital role in fetal and infant lung growth, and the normal development of the lungs may be interrupted by preterm birth. Amongst other nutrients, maternal α-tocopherol intake during pregnancy has been shown to be an important growth factor for fetal respiratory system development and other outcomes (Fig. 2) [57]. Murine models of BPD show accelerated growth in hypoplastic lung, increased lung complexity, and increased air surface with maternal supplementation of vitamin E containing α-to copherol and γ-tocopherol [58, 59].

Fig. 2.

Beneficial and adverse effects of α-tocopherol on pregnancy, perinatal and early childhood outcomes, with strength of evidence: low birth weight [57, 94]; preeclampsia [95-99]; intrauterine growth restriction [57, 94]; intraventricular hemorrhage [78]; retinopathy of prematurity [74, 77, 78, 100-104, 109]; BPD anemia [105]; sepsis [78]; intracranial hemorrhage [78]; asthma [54, 56, 106-108]; viral infection [110-114].

Fig. 2.

Beneficial and adverse effects of α-tocopherol on pregnancy, perinatal and early childhood outcomes, with strength of evidence: low birth weight [57, 94]; preeclampsia [95-99]; intrauterine growth restriction [57, 94]; intraventricular hemorrhage [78]; retinopathy of prematurity [74, 77, 78, 100-104, 109]; BPD anemia [105]; sepsis [78]; intracranial hemorrhage [78]; asthma [54, 56, 106-108]; viral infection [110-114].

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In 1988, Falciglia et al.[60-62] noted that premature infants born at less than 33 weeks gestational age with RDS who went on to develop BPD had lower total plasma vitamin E at 3 days of life (0.58 ± 0.43 mg/dL) compared to those with RDS who recovered without the development of BPD (1.29 ± 0.54 mg/dL, p < 0.05). Decreased cord blood α-tocopherol and selenium concentrations in premature infants less than 30 weeks gestation who were on a standardized respiratory and ventilatory protocol for RDS were subsequently found to predict increased risk of developing BPD [61]. Haga et al. [63] reported that even healthy, term infants appear to have a lower transport capacity for vitamin E compared with adults, resulting in lower plasma concentrations in cord blood samples compared to maternal plasma concentrations at delivery. Initial plasma concentrations of vitamin E in infancy have been shown to be associated with maternal concentrations prior to birth [64-66]. Placental transfer of tocopherol isoforms to the infant is limited due to maternal metabolism of excess tocopherols compared to postnatal breastfeeding [64-66]. Preterm infants who are not receiving breastmilk may also have lower measured α-to copherol concentrations after birth. Breastfeeding typically provides a higher α-tocopherol content in colostrum and transitional milk compared with formula and TPN [67, 68].

Wu and Chou [65] measured α- and γ-tocopherol isoforms and lipid concentrations from venous blood in term infants of 38–42 weeks gestation and preterm infants of 28–34 weeks gestation to establish a comparison between the 2 infant groups. The 28- to 34-week-gestation infants had significantly lower serum mean α-to copherol concentrations compared to the older infants, but they had similar ratios of overall vitamin E to total lipids. There was a statistically significant correlation between neonatal and maternal vitamin E to total lipids ratios [65]. Better understanding of the effects of postnatal supplementation with various tocopherol isoforms will be crucial, because at the present time dietary supplementation of vitamin E in neonatal care may be predominantly γ- and δ-tocopherol based, as is also the case with prenatal vitamins [69].

Vitamin E has been extensively studied as an essential nutrient for the growth and development of infants, especially in its role as a potent antioxidant. It was hypothesized to be important in decreasing lung damage caused by the toxic effects of oxidant stress and oxygen toxicity [70]. Early studies, such as those by Ehrenkranz et al. [70, 71], measured infant vitamin E concentrations following birth and demonstrated a protective effect of higher vitamin E concentrations on pressure-related lung injury. These early observational studies did not account for the interaction (and likely opposing effects) of the vitamin E isoforms α- and γ-tocopherol on airway inflammation and lung disease risk that have subsequently been demonstrated [33, 54, 72].

Investigators hypothesized that α-tocopherol supplementation might prevent either the oxidative lung injury or altered lung growth seen in preterm infants with BPD, and 7 randomized controlled trials of α-tocopherol supplementation in preterm infants were conducted for the prevention of BPD, 4 of which studied the development of BPD as the primary outcome [70, 71, 73, 74] and 3 which studied it as a secondary outcome [75-77] (Table 2). The results of these studies differ, with 1 reporting statistically significant reductions in BPD, and 6 showing nonsignificant reductions in BPD or no difference. A Cochrane meta-analysis of these same studies reported no association between vitamin E and BPD (estimated RR 0.91, 95% CI 0.73 to 1.14; risk difference –0.02, 95% CI –0.07 to 0.03) with wide confidence intervals suggesting that studies of BPD and vitamin E have been underpowered, even when combined in this way [78]. What all 7 studies have in common is utilization of high-dose vitamin E supplementation rather than normalization of deficiency, lack of prestratification of participants into categories at risk for vitamin E deficiency, delivery of the intervention in the neonatal period rather than during pregnancy, and failure to quantify and account for an interaction effect of γ-tocopherol or its potential presence in the product being delivered [33]. Of note, all 7 provided α-tocopherol formulated by 1 company. Of more concern, 2 of the negative studies, in particular the same 2 with reported increased side effects of necrotizing enterocolitis, utilized a preparation which included a carrier of polyoxyethylated castor oil [75, 77]. Polyoxyethylated castor oil is not biologically inert, as was believed at the time, and may cause serious adverse reactions, including direct epithelial damage [79].

Table 2.

Randomized controlled trials of vitamin E supplementation in premature neonates for prevention of BPD

Randomized controlled trials of vitamin E supplementation in premature neonates for prevention of BPD
Randomized controlled trials of vitamin E supplementation in premature neonates for prevention of BPD

There is hesitancy on the part of neonatologists to reopen investigations into vitamin E isoforms, due to reported adverse events such as necrotizing enterocolitis, noted during the trial period in which the investigational product was being administered [77]. In undertaking this review, however, it appears that side effects may have been more likely related to the carrier vehicles [79, 80], to osmolality of preparations [81], or to the selection of supraphysiologic doses and target levels (Table 2). Lower concentrations of vitamin E are routinely included in the enteral feeds and TPN given to preterm infants without increased adverse effects, suggesting that more careful selection of vehicles and cautious dose finding trials prior to use would protect against adverse effects seen in previous trials. In addition, supportive pilot trials of specific vitamin E isoforms demonstrating improvements in established biomarkers for the development of BPD would be important prior to initiating large randomized controlled trials.

It is also important to acknowledge that there are some studies in opposition to the hypothesis that supplementation of α-tocopherol is sufficient to protect against the development of BPD. The predictive model of Falciglia et al. [61] for which preterm human infants went on to develop BPD did not demonstrate the protective effect of α-tocopherol to be independent of the effect of selenium. As selenium-deficient rats had been shown to have increased metabolism of vitamin E [82], this group speculated that vitamin E may be metabolized more quickly due to selenium deficiency in preterm infants under conditions of oxidative stress [61]. In another study, Berger et al. [83] administered high doses of α-tocopherol to premature baboons exposed to prolonged hyperoxia (FiO2 of 1.0) and, despite increasing α-tocopherol plasma concentrations, BPD was not prevented. In one of the human trials performed by Watts et al. [73], additional supplementation of 16 mg dl-α-tocopherol (an amount less than what is currently contained in daily consumption of standard infant formula) starting in the first week of life in 266 infants weighing less than 1,500 g did not prevent BPD, defined at that time as continued oxygen requirement at 28 days of postnatal life. It is noteworthy that at least 40% of both the control and treatment groups in this study were receiving inspired oxygen concentrations that were much higher (FiO2 > 0.8) than those typically used with close oxygen saturation targeting in neonatal intensive care units today [84]. Watts et al. [73] speculated that their study might have been underpowered for effect size, and that the lack of response could possibly be explained by the fact that predisposition for BPD may require vitamin E deficiency to be both severe and chronic (i.e., present in utero), with exposure therefore dependent on maternal status (and not infant status) at birth. Another possible explanation for some of the contradictory studies is that beyond a certain concentration of hyperoxia, antioxidant defenses, no matter how replete, may simply be inadequate to compensate for the damage caused by high fractions of inspired oxygen, free radical generation and inflammation. A third explanation is that the current definition of BPD could encompass some phenotypes which are mechanistically connected to oxidative stress, and others which are not [3]. Demonstrating a protective dose response or threshold effect of α-tocopherol based on delivered inspired oxygen concentrations may be helpful in delineating this relationship.

Fifty years after the original description of BPD, it remains a major complication of premature birth [85, 86]. However, not all extremely premature infants develop BPD, suggesting that BPD can be prevented, if premature birth cannot. The original hypotheses driving studies of vitamin E on BPD are worth revisiting, even in the presence of conflicting and negative trials. Previous trials conducted utilizing lower dose oral supplements of vitamin E were underpowered [73, 74], and studies utilizing parenteral dosing remain in the shadow of adverse outcomes related to supraphysiologic doses with a possibly toxic vehicle [75-77]. Lastly, none of the trials targeted prenatal supplementation, as all were delivered postnatally.

As vitamin E is a required vitamin, and deficiency is associated with increased BPD risk, a definitive understanding of the role vitamin E isoforms play in BPD development is needed to inform potential prevention efforts. Table 3 outlines what we know about vitamin E and BPD, and important remaining gaps in our knowledge. Observational studies could identify infants and mothers at risk of vitamin E deficiency and BPD, such as those born to mothers who smoke [87], and could determine the optimal concentration ranges of each isoform to minimize BPD risk in premature neonates. Proof of concept studies could reveal the optimal timing of vitamin E isoform delivery on biomarkers of BPD risk, and demonstrate potential mechanisms of action of individual isoforms. Mechanistic studies could help to elucidate how individual vitamin E isoforms affect lung growth and lung inflammation. Any future tocopherol-based intervention will have to account for and quantify the content of individual isoforms. In particular, we feel that renewed study of the α-tocopherol isoform should be considered given its protective association with the development of respiratory health outcomes such as asthma, allergic airway inflammation, and with improved lung growth parameters, compared with γ-to copherol [33, 57, 88].

Table 3.

Use of vitamin E isoforms in therapy or prevention of BPD: review of what is known and key questions that need to be answered

Use of vitamin E isoforms in therapy or prevention of BPD: review of what is known and key questions that need to be answered
Use of vitamin E isoforms in therapy or prevention of BPD: review of what is known and key questions that need to be answered

As part of this strategy, properly conducted epidemiology studies to identify subgroups of mothers and infants at greater risk of vitamin E deficiency should take higher initial priority. In addition to vitamin E, vitamin C and selenium are also known to be important in the interdependent human antioxidant system [32, 82]. Infants of mothers who smoke have already been shown to gain significant increases in lung function and decreased likelihood of wheezing in a randomized controlled trial of supplementation of another antioxidant micronutrient, vitamin C, during pregnancy [89, 90]. The status of vitamin E isoforms, vitamin C, and selenium should be examined in the maternal, infant and cord blood of smoking mothers who deliver preterm, in order to determine their association with risk of subsequent BPD.

Proof of concept studies will also be of great value moving forward. Determining the optimal timing and delivery of a tocopherol intervention will be especially important. Maternal supplementation may only lead to increased transmission of tocopherol metabolites [66], as only very specific isomers of α-tocopherol cross the placenta [91, 92]. This does not necessarily mean that the antioxidant activity is diminished, as the primary transmissible metabolite (α-carboxyethyl hydroxychroman) has also been shown to have good in vitro antioxidant activity [93], but with limited evidence of in vivo antioxidant activity [94]. Prenatal supplementation favoring very specific placentally transmissible isomers of α-to copherol, such as naturally derived RRR-α-tocopherol [91, 92], in a supplement with a high overall α-tocopherol to γ-tocopherol ratio may yield the best strategy for influencing postnatal lung outcomes. For infants at risk in the postnatal environment, the administration of tocopherol interventions may need to occur immediately after birth to prevent, rather than treat, lung damage leading to BPD. Because the intravenous route of administration of vitamin E in very low birth weight infants may carry an increased risk of sepsis and other adverse outcomes, and because poor vehicle selection may have contributed to toxicity in the past, we think that future intervention trials should focus on the enteral route or on modification of existing TPN formulas, and be appropriately cautious with the target dose [78].

At present, there is insufficient evidence about the benefits and risks of vitamin E in BPD prevention to make evidence-based recommendations about supplementation. However, new data on the effects of the individual vitamin E isoforms on lung health should make us relook at this essential dietary factor as a potential preventive or treatment intervention for BPD. Adequately powered studies will be needed to address whether supplementation of specific vitamin E isoforms either in pregnant women at risk of preterm birth, or in at-risk premature infants immediately following birth, reduces the development of BPD and subsequent long-term pulmonary morbidity in childhood and adult life.

The authors have no financial relationships or conflicts of interest relevant to this article to disclose.

NIH/NHLBI T32 HL87738 (C.A.S.), UG3OD023288, HL105447, and HL129060 (C.T.M.), UG3OD023320 (J.L.A.), U01HL101456 (J.L.A., P.E.M., T.V.H.), NIH K24 AI 077930, 7 UG3 OD023282 (T.V.H.).

Dr. Stone and Dr. Hartert: conceived of the topic for review, conducted literature searches and research, wrote the paper, and have primary responsibility for the final content.

Dr. McEvoy, Dr. Aschner, and Dr. Walsh: conducted literature searches and research, edited the report and contributed to the neonatology content.

Ms. Kirk: conducted literature searches and research.

Dr. Rosas-Salazar and Dr. Moore: conducted literature searches and research, and contributed to the pulmonology content.

Dr. Cook-Mills: conducted literature searches and research, and contributed to the nutrition content.

All authors read and approved the final manuscript.

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