Previous studies have shown that vitamin A supplementation can reduce the frequency of BPD, but the practice has not become widespread. In part, I think, it is because repeated intramuscular injections of vitamin A are the route that has been studied, and there is an understandable reluctance to subject the babies to this.

If you could ensure adequate vitamin A status by another route, and show efficacy, then perhaps that would change the common approach.

This new RCT succeeded in enrolling over 900 at-risk preterm infants. (Meyer S, et al. 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. Lancet Respir Med. 2024). Infants were 400-1000g and <30 weeks GA, had been intubated in the first 72 hours of life and were at least starting enteral feeds. Babies all received whatever vitamin A was in the breast milk with fortifier, or formula, and 1000 u/kg of vitamin A as oral drops or in their TPN. They were randomized to receive an additional 5000 u/kg of vitamin A or placebo.

In other words this was an RCT comparing an additional 6000 u/kg/day of vitamin A to an additional 1000 u/kg/day, on top of what was in their nutrition. Breast milk vitamin A is very variable, and varies from somewhere around 300 iu/100 mL in colostrum down to 60 iu/100 mL in mature term breast milk. Breast milk fortifiers tend to give close to 1000 iu when mixed with 100 mL of breast milk in the usual fortification to 87 kcal/100mL. In other words, a preterm baby, on 165 mL/kg/d of breast milk with standard fortification, should get somewhere around about 1700 iu/kg/day of enteral vitamin A.

The study found absolutely nothing. Every single outcome was close to identical between the 2 groups, BPD, and all the other 3-letter outcomes were very similar. Of note, the relative risk for NEC was 0.7, which reflected 6% with the high dose compared to 8% with the less high dose, but this was entirely consistent with a chance effect (95% CI for the RR 0.42-1.18). Which illustrates how many babies would be needed to prove a clinically important reduction in NEC in a prophylaxis RCT.

About half of the babies at each of 3 time points (before, during, and at the end of the trial) had serum retinol concentrations measured, and they were very similar between the 2 groups. It is likely that the mothers in this study were not malnourished, so it is likely that the vitamin A intakes from the basic nutrition that were calculated by the investigators have some accuracy, and they were indeed at least 1500 iu/kg/day in both groups even before the supplements were added.

A previous meta-analysis suggested that vitamin A supplementation was only effective among babies with a baseline vitamin A intake <1500 iu/kg/day. With another suggesting that it was only effective in lower risk babies.

This new RCT confirms that enteral vitamin A supplementation at 6000 iU/kg/day compared to 1000 iu/kg/day in addition to that provided by breast milk and fortifier (which the majority of babies were receiving) or formula, has no impact on BPD, in a population where mothers are likely to have diets sufficient in vitamin A.

As I have described, the control babies did get an extra 1000 iu/kg/day vitamin A already on top of their nutritional intake. I have never done that, I guess it must be frequent in Germany, where most of these centres were located. It probably isn’t necessary, the 1500 or so in regular fortified breastmilk or preterm formula may well be enough.

By now, my gentle readers probably know that I don’t think BPD is a useful measure of lung injury. In the supplemental material for this trial they describe other variables, such as duration of oxygen therapy, and duration of ventilatory support, but I can’t find any data. There have been other studies showing no impact on BPD, but nevertheless an impact on post-discharge clinically important outcomes (such as the SUPPORT trial CPAP arm), if there is funding, longer term follow up would be interesting, but to be honest, I would be very surprised if there was any difference in respiratory outcomes of importance to parents after discharge. Vitamin A is essential for lung growth and development, but once you have enough giving more doesn’t improve them further.