When should we treat hyperbilirubinemia in preterm infants?

I missed this when it was first published, but it came up on one of my regular searches at the weekend. Hulzebos CV, et al. The bilirubin albumin ratio in the management of hyperbilirubinemia in preterm infants to improve neurodevelopmental outcome: a randomized controlled trial–BARTrial. PLoS One. 2014;9(6):e99466. The multi-centered Dutch group of authors randomized 615 preterms of less than 32 weeks gestation. Babies had their bilirubin treated according to some arbitrary nomograms for total serum bilirubin. They had to be arbitrary of course, because there are few good data to inform an evidence-based nomogram. The thresholds for treatment seem reasonable, and are all available on the free access web page where the article is published. The group randomized to have the bilirubin-albumin ratio taken into account were in addition treated if their B/A ratio exceeded a line on another nomogram, also somewhat arbitrary. The 2 nomograms were different for different strata of birthweight, and differed over the first couple of days of life.

The idea being that if you start treatment earlier for those babies with a low albumin, and a bilirubin/albumin ratio which is over the threshold, then they might have less bilirubin induced brain injury (often evident as motor disturbance later in life, they thought).

What this meant in the end was that the group with the B/A ratio included had an average of only 6 more hours of phototherapy (which was not statistically significant) and 2 exchange transfusions vs none in the TSB alone group. There were fewer deaths in the B/A group, 5.2% vs 8,1%, p=0.2, i.e. a difference which could easily be due to chance. The primary outcome was the composite motor score at 18 to 24 months corrected age.

There was no difference between the groups in the primary outcome. Or any indices of development at 2 years of age.

The only intervention which occurred as a result of this change in screening policy was a minor increase in the duration of phototherapy; I don’t think you can postulate that this was the cause of a minor reduction in mortality. The study was not designed, or powered, to show a difference in mortality. I think even doing the subgroup analysis that they present is really questionable, a subgroup analysis of an unexpected non-significant difference in a secondary outcome is something you should think twice about, and then think another three times, before presenting. It could easily mislead people into thinking that there was a real difference to worry about.

So either the B/A ratio is not of any value for directing therapy and improving motor outcomes in preterm infants, or the thresholds they created were not right. I guess its possible that a much stricter threshold for intervention would have shown some differences in outcome, which if it just led to more phototherapy might be a benign intervention. But on the other hand phototherapy is not entirely benign, it interferes with mother infant interactions, and affects developmentally sensitive care. Exchange transfusions are certainly not benign.

I think it is hard to believe that there will be another investigation of this issue, certainly not of this high quality. The difference in interventions would have to be greater that this to be able to show an effect. Perhaps another trial of prophylactic early phototherapy is warranted, as the large NICHD trial did show a reduction in “neurodevelopmental impairment”.

For now I think the thresholds for treatment suggested by Jeff Maisels and his pals are about as good as we can get.

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
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3 Responses to When should we treat hyperbilirubinemia in preterm infants?

  1. N. Ambalavanan MD says:

    Keith, I am not sure the “…large NICHD trial did show a reduction in “neurodevelopmental impairment”. The primary outcome of death or NDI did not differ between the “aggressive” and “conservative” phototherapy (http://www.ncbi.nlm.nih.gov/pubmed/18971491). Looking at a secondary outcome in a subset of infants may not be optimal – and if we do, we should not neglect the finding that there seemed to be an increase in mortality (39 vs. 34%, quite substantial) in the 501-750g infants. As you said, there is not much data to develop an evidence-based nomogram in preterm infants.

  2. Yes, thanks for the comment and you are right, I think a term such as “suggested there might be a reduction…” would be more accurate. If it had “shown” a reduction we could be much more confident in that finding. The direction of change of the 2 parts of the primary outcome were in different directions, another example of why we need to rethink this. I think. Thinking.. What do you think?

    • N. Ambalavanan MD says:

      I think it is possible that there may be both indirect effects as well as direct effects of an intervention such as phototherapy. Indirect effects may include improved ability to assess the infant who is better illuminated (which may also lead to more interventions!). Direct effects include not only effects on the bilirubin concentration but also on the circadian rhythm (e.g.http://www.ncbi.nlm.nih.gov/pubmed/25460255;http://www.ncbi.nlm.nih.gov/pubmed/24831970) which are known to impact survival in intensive care (at least in adults) (http://www.ncbi.nlm.nih.gov/pubmed/26118911), antioxidant status (not just bilirubin, e.g.http://www.ncbi.nlm.nih.gov/pubmed/24090867) etc.

      Similar to SUPPORT (where ROP and mortality may go in different directions with lower target SpO2), it is possible that the effect of phototherapy on different outcomes is different…I don’t think we have enough data to state what threshold of serum bilirubin is hazardous (or at what bilirubin level phototherapy should be initiated) for a given extremely preterm infant.

      I am generally comforted by the fact that there is no huge clinical effect in either direction – it probably does not make much difference in outcome (at a population level) what people practice, as long as they are within the usual range (ranging between aggressive and conservative) but are not outliers. We collect a lot of information on patient characteristics, but little on processes of care, or endotypes (subtypes of disease – not all NDI is going to result in long-term handicap, as we all know). I think unless we collect a lot more data on what exactly we are doing and more detail on how our patients are doing, we are going to take a long time to answer important questions (e.g. are diuretics effective as chronic therapy in BPD? what is the right management for a PDA? how do we prevent/manage Acute Kidney Injury?).
      Best regards

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