High-Dose Vit A Fails Again for Serious Lung Disease in Premature Infants

High-dose enteral vitamin A supplementation in the early postnatal period was safe but failed to reduce the likelihood of moderate or severe bronchopulmonary dysplasia in extremely low birthweight (ELBW) infants, a randomized trial from Europe found.

Among more than 900 ELBW newborns needing oxygen supplementation or respiratory support, the rate of moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age was an identical 38% whether the infants received high-dose fat-soluble vitamin A supplementation or placebo on top of basic recommended vitamin A supplementation (adjusted OR 0.99, 95% CI 0.73-1.55), reported researchers led by Sascha Meyer, MD, of the Clinical Centre Karlsruhe in Germany.

Furthermore, serum retinol concentrations at the end of the intervention and end of trial were similar between groups, according to findings of the multicenter NeoVitaA study published in Lancet Respiratory Medicine.

Present in up to 45% of extremely preterm and ELBW infants, bronchopulmonary dysplasia occurs as a result of underdeveloped lungs. In moderate or severe cases, infants need oxygen supplementation or respiratory support. The disease is linked with an increased risk of mortality and can place children at greater risk for cerebral palsy or other neurodevelopmental impairments.

Vitamin A is known to play a key role in lung development and deficiency is common in ELBW infants, which may be a contributing factor to bronchopulmonary dysplasia.

More than two decades ago, a landmark randomized trial showed that high-dose intramuscular vitamin A injections slightly reduced the rate of bronchopulmonary dysplasia or death in a similar population of ELBW infants, but the intervention required multiple painful injections.

As a result, "the practice of vitamin A supplementation was not widely accepted because clinicians were not willing to administer regular intramuscular injections to achieve only a modest reduction in the incidence of bronchopulmonary dysplasia," noted J. Jane Pillow, MD, PhD, and Abhijeet Rakshasbhuvankar, MD, both of the University of Western Australia in Crawley, in an invited editorial.

To date, three other smaller randomized trials testing high-dose enteral vitamin A supplementation, including water-soluble forms, have failed to reduce rates of bronchopulmonary dysplasia in ELBW infants. Other interventions for the condition have proved to be no help as well, including hydrocortisone and omega-3 fatty acid docosahexaenoic acid.

"Vitamin A supplementation is likely to be effective only in those infants who are deficient," the editorialists said. "Contemporary cohorts of extremely preterm infants might not be sufficiently deficient in vitamin A to show a beneficial effect of additional vitamin A supplementation on the prevention or amelioration of bronchopulmonary dysplasia."

In the current study, all infants received basic vitamin A supplementation (1,000 IU/kg per day) as recommended by guidelines. The study authors suggested that as a result, high retinol concentrations in the control group "could have obscured any beneficial effect of high-dose supplementation."

Continued research, said Pillow and Rakshasbhuvankar, will depend on how the high-dose enteral vitamin A trials are interpreted.

If the takeaway is that delivery is an issue, then "further research needs to focus on the formulation and improving the absorption of the water-soluble form or other innovative routes of delivery," they wrote. But "perhaps the study by Meyer and colleagues indicates that we should draw a line under vitamin A supplementation for the prevention of bronchopulmonary dysplasia and agree that we have reached a dead end for this intervention."

The phase III NeoVitaA trial randomized a total of 915 infants from 29 neonatal intensive care units across Germany and Austria to high-dose enteral vitamin A supplementation (5,000 IU/kg per day of fat-soluble oral drops, branded as Vitadral) for 28 days or a peanut oil placebo.

In order to be included in the trial, infants needed to weigh between 400 g and 1,000 g and have a gestational age of 32 weeks postmenstrual age or younger at birth. Additionally, the infants had to need mechanical ventilation, non-invasive respiratory support, or supplemental oxygen during the first 72 hours of postnatal age.

Three-fourths of the trial participants were born before 28 weeks' gestational age, and more than 85% were white. Most were singleton births (70%), and the average birth weight was 763-770 g. More than three-fourths had respiratory stress and nearly two-thirds were intubated at the time of randomization.

For the individual components of the study's primary outcome, moderate or severe bronchopulmonary dysplasia occurred in 32% of the two groups each at 36 weeks postmenstrual age, with most of the cases being severe, while death occurred in 6% of the high-dose vitamin A group and 7% of the placebo group (P=0.80).

There were also no significant differences between groups in regard to any secondary endpoints, including retinopathy of prematurity, duration of positive pressure ventilation or support, and intraventricular haemorrhage, among others.

At the time of baseline measurements, the serum retinol concentration for the intervention group was 179.1 µg/L, while the concentration for the placebo group was 171.2 µg/L. After treatment these increased in both groups to 204.9 µg/L and 201.5 µg/L, respectively, and then decreased to 156.8 µg/L and 173 µg/L at 36 weeks' postmenstrual age.

Adverse events were observed in 57% of the high-dose vitamin A group and 60% of the placebo group, though only 1% of these in each arm were considered related to treatment. In each group, 15% of infants experienced a serious adverse event.

"Although high-dose fat-soluble enteral vitamin A can be considered safe based on evidence from this trial, higher doses than those proposed in the guideline by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (1,333-3,300 international units per kg per day) cannot be recommended in ELBW infants," wrote Meyer and colleagues.

The investigators cited a number of limitations to their study, including the mostly white European population, a modified definition of bronchopulmonary dysplasia used in the trial, the potential that the negative results were due to insufficient retinol absorption, and that the COVID pandemic hampered enrollment.

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