Another trial of high dose enteral vitamin A supplementation was unable to reduce bronchopulmonary dysplasia rates in very low birthweight babies, with scientists suggesting that it might be time “to agree we have reached a dead end for this intervention”.
The randomised trial in Europe confirmed that high-dose enteral vitamin A supplementation in the early postnatal period, although safe, was unsuccessful in reducing the likelihood of moderate or severe bronchopulmonary dysplasia in extremely low birthweight (ELBW) infants, reports Medpage Today.
The researchers, led by Sascha Meyer, MD, of the Clinical Centre Karlsruhe in Germany, found that 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).
Furthermore, serum retinol concentrations at the end of the intervention and end of trial were similar between groups, according to findings of their multicentre NeoVitaA study published in The Lancet Respiratory Medicine.
Present in up to 45% of extremely preterm and ELBW infants, bronchopulmonary dysplasia results from underdeveloped lungs. In moderate or severe cases, infants need oxygen supplementation or respiratory support. The disease is linked to an increased risk of mortality, and of 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 randomised 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.
“Thereafter, vitamin A supplementation was not widely accepted because clinicians were not willing to administer regular intramuscular injections to achieve only a modest reduction in … bronchopulmonary dysplasia”, noted 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 or smaller randomised 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 have proved unsuccessful 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 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 must focus on the formulation and improving the absorption of the water-soluble form or other innovative routes of delivery”.
“But perhaps the study by Meyer and colleagues indicate we should draw a line under vitamin A supplementation for the prevention of bronchopulmonary dysplasia and agree we have reached a dead end for this intervention.”
The phase 3 NeoVitaA trial randomised 915 infants from 29 neonatal ICUs 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.
Infants needed to weigh between 400g and 1 000g and have a gestational age of 32 weeks’ postmenstrual age or younger at birth. Additionally, they had to need mechanical ventilation, non-invasive respiratory support, or supplemental oxygen during the first 72 hours of postnatal age.
Three-fourths of them were born before 28 weeks’ gestational age, and more than 85% were white. Most were singleton births (70%), and the average birthweight was 763g-770g.
More than three-fourths had respiratory stress and nearly two-thirds were intubated at the time of randomisation.
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 regarding 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, Haepatology 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 enrolment.
Study details
Early postnatal high-dose fat-soluble enteral vitamin A supplementation for moderate or severe bronchopulmonary dysplasia or death in extremely low birthweight infants (NeoVitaA): a multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial
Sascha Meyer, Johannes Bay, Jutta Petzinger et al.
Published in The Lancet Respiratory Medicine on 18 April 2024
Summary
Background
Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation.
Methods
This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32+0 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24.
Findings
Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73–1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups.
Interpretation
Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations.
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