Vitamin A is a critical micronutrient, essential to optimal growth and development during infancy and childhood. It comprises compounds including retinol, retinaldehyde, and retinoic acid.1 Metabolism of vitamin A relies on a unique protein, cellular retinol binding protein (RBP) type 2.1 Infants born at term have adequate stores of vitamin A, effective RBP, and receive additional supplementation via breast milk or infant formula that ensures normal growth and development for the first 6 months. At around this time, vitamin A is received from nutritional sources with the introduction of complementary solid foods in the infant diet.

Unlike the term infant, preterm infants are born deficient in vitamin A, have low plasma concentrations of both retinol and RBP at birth, and are unable to tolerate routine oral supplementation.1,2 These factors are problematic for this group of infants who are especially vulnerable to complications of the eye, as well as respiratory disease, where vitamin A has been shown to be an effective measure of prevention.1-4 The use of vitamin A has been shown to decrease the risk of chronic lung disease in extremely low-birth-weight (ELBW) infants,4,5 with follow-up studies showing no impact on death or neurodevelopmental impairment associated with vitamin A supplementation.6 Thus, in many newborn intensive care units (NICU), vitamin A was administered to preterm infants. This practice began to change toward the end of 2010 when the sole manufacturer of vitamin A injections (Hospira, Inc Lake Forest, IL) changed manufacturing sites from a third party manufacturer to in-house manufacturing, causing a delay in production and drug shortage.7

It has been reported that Hospira now has vitamin A (Aquasol A) injection available, with a resupply date pending.7 As a result, this medication will again be an available option in the care of preterm infants. With the possible reintroduction of vitamin A in practice, reviewing the evidence and considering some of the issues associated with administration of this medication are timely.

VITAMIN A AND NEONATAL CHRONIC LUNG DISEASE

Neonatal chronic lung disease or benign pulmonary dysplasia (BPD) remains a leading cause of mortality and morbidity for ELBW infants. These infants are at risk for BPD for multiple reasons, including vitamin A deficiency. Inadequate vitamin A contributes to lung disease in preterm infants as a result of impaired lung healing, increased loss of cilia, increased squamous cell metaplasia, increased susceptibility to infection, and decreased numbers of functional alveoli.5,8 Several studies have shown that preterm infants are deficient in vitamin A,2,4,5 and studies including a large randomized controlled trial and a Cochrane review have shown that vitamin A supplementation can reduce the risk of BPD in the ELBW patient population.4,9 However, while these studies have demonstrated a proven benefit to administration of vitamin A on the primary outcome of death or chronic lung disease at 36 weeks' postmenstrual age (55% vs 62%, P = .03; relative risk [RR] = 0.89 [95% confidence interval: 0.80-0.99]; number needed to treat [NNT] = 14-15) and on the secondary outcome of chronic lung disease at 36 weeks' postmenstrual age (47% vs 56%, P = .03; RR = 0.85 (95% confidence interval: 0.73-0.98); NNT = 11),4 several centers did not implement the use of vitamin A prior to the recent drug shortage.

Survey research10 that queried both training and nontraining programs in neonatology found that the majority of programs, 68% and 84.5% respectively, gave vitamin A to less than 10% of their ELBW patient population. In training programs, just under 20% of survey respondents reported that they administered vitamin A to more than 90% of their patients, and in nontraining programs, less than 15% reported that they administered vitamin A to more than 90% of their patients. When asked why vitamin A was not administered, the reasons reported included benefit is small (39%) or not proven (33%), frequent intramuscular injections (27%), and possible risks (12%). More recent research on implementation of vitamin A for the prevention of BPD found wide discrepancies in practice and cited differences in provider attitudes and system characteristics as the rational for whether or not vitamin A is administered.11 It is important to better understand these reasons prior to the possible reintroduction of this medication into practice.

ISSUES ASSOCIATED WITH VITAMIN A ADMINISTRATION

The data reported from the large trial that was conducted on vitamin A in 1999 did show a significant reduction in chronic lung disease at 36 weeks' postmenstrual age, but the RR was 0.85 (0.73-0.98). The interpretation of these findings underscores that while there was some benefit in reducing the risk of BPD in ELBW infants, the reduction in risk was small, especially given the upper bound confidence interval of nearly 1.0 (indicating no difference in risk between the experimental and control groups). However, while this proven benefit was small, it is comparable with other interventions such as surfactant (RR = 0.83 [0.77-0.90]) and antenatal corticosteroids (RR = 0.69 [0.58-0.81]), and when compared with interventions such as diuretics12 and inhaled bronchodilators,13 the benefit is significant.

Vitamin A can be given enterally, intramuscularly, or intravenously. However, enteral doses given to ELBW infants have not been shown to increase plasma concentrations of vitamin A or improve outcomes.1 Given that this population is at greatest risk of complications associated with vitamin A deficiency, these infants must be supplemented via a parenteral route. Unfortunately, the use of intravenous administration is problematic. Vitamin A is photosensitive, degrading in light, and a significant amount of the vitamin is absorbed in the tubing.1 Thus, the recommended approach to intravenous administration of vitamin A is to mix it with lipid emulsion prior to infusion. However, this approach is discouraged, as the recommended dose has not been shown to provide supplementation adequate to maintain the optimal plasma level of retinol in the ELBW infant when vitamin A is mixed with lipid emulsion. For these reasons, the recommended route of administration for vitamin A in the ELBW infants is via intramuscular injection.

Injections are painful procedures. As a result, medication administration via injection is rarely seen as the preferred route for drug delivery to nurses caring for ELBW infants in the NICU. Pain management techniques commonly used for injections, such as topical local anesthetic (ie, EMLA cream), are not thought to be safe in ELBW infants. This leaves very few effective pain management interventions available to the NICU nurse administering injections to ELBW infants. This is relevant because the administration of vitamin A results in as many as 12 additional painful procedures during the early neonatal period for ELBW infants (vitamin A supplementation is recommended 3 times per week for 4 weeks). The justification of these 12 additional painful procedures for a small reduction in the risk of BPD and overall improvement in short-term respiratory outcome has been questioned.14 However, this argument must be balanced against the findings relative to the number of painful procedures ELBW infants experience during the first 28 days of life. In the work reported by Smith and colleagues,15 the mean number of painful procedures per day over the first 28 days was 10 (SD = 5), with a maximum of 20 procedures per day. While no one caring for ELBW infants wants to add even a single painful procedure at any point in their care, given the number of painful procedures that these infants are already experiencing, we must be thoughtful about whether or not 12 more spread over the first 28 days is a strong enough rationale for not administering vitamin A.

The final rationale reported for not administering vitamin A to ELBW infants was associated with the possible risks of the medication.10 The possible risks that may occur with vitamin A include increased intracranial pressure, vomiting, bone and joint pain, mucocutaneous lesions, and hepatic dysfunction.4,9 None of these risks have been reported in the literature, and no clinical or biochemical evidence of vitamin A toxicity was reported in the large trial that was conducted on vitamin A in ELBW infants.4 That said, any medication can cause an unintended side effect and these risks must be balanced against the benefits of vitamin A supplementation in ELBW infants.

CONCLUSION

Vitamin A supplementation has been shown to be beneficial to ELBW infants. The benefit demonstrated is small, and future analyses are needed to better understand whether or not there are specific cohorts of ELBW infants who would benefit more or less from this intervention. Whether or not clinicians decide to implement intramuscular injections of vitamin A for the prevention of BPD will likely depend on the incidence of this neonatal outcome within a specific NICU.9

With the anticipated resupply of vitamin A and reintroduction to the NICU, nurses have an opportunity to identify best practices in administration of injections to ELBW infants. Perhaps, this will become a platform on which we can partner with scientists who are pioneering biotechnologies focused on needleless injections.16,17 This technology is likely to be very well suited to the care needs of infants in the NICU. While I expect that the reintroduction of vitamin A will likely come with some controversy, NICU nurses can help lead the way forward in developing best practices in injection science for drugs such as vitamin A. In doing so, they will help ensure that every proven intervention can be as painless as possible for ELBW infants in the NICU, making vitamin A supplementation worth a shot.

-Katherine E. Gregory, PhD, RN

Senior Nurse Scientist

Department of Newborn Medicine

Department of Nursing

Brigham and Women's Hospital

Boston, Massachusetts

References