Mike: Hello, I'm Mike Clarke, podcast editor for the Cochrane Library. The Cochrane Neonatal Group is one of the largest Cochrane groups, with more than 400 reviews published, many of which relate to the care of babies born before they reach full-term. These reviews were added to in April 2022 with a new review of the use of cyclo-oxygenase inhibitors and, in this podcast, one of the group’s researchers, Abbey MacLellan, talks with lead author Souvik Mitra, a neonatologist and clinical epidemiologist at Dalhousie University and IWK Health in Halifax Canada about this network meta-analysis.

Abbey: Hello Souvik. I know that co-oxygenase inhibitor drugs are often used in preterm infants to prevent problems related to a common heart condition called the patent ductus arteriosus or the PDA so, first of all, could you tell us how this type of therapy might work? Why use these drugs in the first place?

Souvik: Hello Abbey. We use these prophylactic COX-I drugs to close the PDA in preterm infants before it causes any adverse consequence and the drugs might also directly affect blood vessels in the brain and prevent a severe bleed called an intraventricular haemorrhage.

Abbey: So, why is it important to do a network meta-analysis on this question?

Souvik: Several prophylactic agents are currently available, including indomethacin, ibuprofen and acetaminophen and previous reviews from Cochrane Neonatal have separately compared placebo or no treatment against each of these. But there are no Cochrane Reviews that provide head- to-head comparisons between the three drugs. Now, with increased emphasis on non-pharmacological conservative management for these babies, a policy of ‘no prophylactic treatment’ has become increasingly adopted and we needed this network meta-analysis to provide evidence by directly and indirectly comparing these four available treatment options. This will help clinicians to choose between them and offer the best available treatment for the preterm infant. It helps to make sense of the information on nearly 4000 preterm infants in 28 clinical trials, which had compared prophylactic indomethacin, ibuprofen, or acetaminophen, with active medication, placebo, or no prophylaxis delivered within the first 72 hours after birth in preterm infants without documented evidence of a PDA.

Abbey: What did you look for in all this research?

Souvik: We looked at several patient-important outcomes but we were most interested in the evidence on death and severe intraventricular haemorrhage. These have been reported as the two most critical outcomes by parents and adults who were born preterm. 

Abbey: And were you able to produce the evidence that would help answer the question?

Souvik: Yes, compared to no treatment, prophylaxis with intravenous indomethacin probably results in a small reduction in severe intraventricular haemorrhage, and a moderate reduction in death and the need for PDA surgery. Prophylactic ibuprofen also probably results in a small reduction in severe intraventricular haemorrhage, a moderate reduction in need for PDA surgery, and may lead to a moderate reduction in death. However, for acetaminophen, the current evidence leaves us very uncertain about the effects on any of the clinically relevant outcomes. 

Abbey: What about the safety aspect? Are there any adverse effects related to the use of these drugs?

Souvik: Focusing on the two drugs which look most helpful, we found that prophylactic indomethacin is unlikely to cause two conditions of the intestines that people worry about: necrotizing enterocolitis and gastrointestinal perforation. However, it may result in a small increase in chronic lung disease. Prophylactic ibuprofen was also unlikely to worsen necrotizing enterocolitis, but the evidence is uncertain for GI perforation.

Abbey: Overall, what’s your take-home message about COX-I prophylaxis in preterm infants?

Souvik: In summary, prophylactic indomethacin and prophylactic ibuprofen both may be beneficial in reducing death or severe intraventricular haemorrhage in preterm infants. However, because we are not highly certain about the size of the benefit and given that this is a prophylactic therapy, parents should be involved, when possible, in the discussion on possible benefits and harms before making a clinical decision. We do not recommend prophylactic use of acetaminophen at this point, until further research evidence is available.

Abbey: Thanks Souvik. If people would like to read the review, how can they get hold of it?

Souvik: Thanks Abbey. They just need to go online to Cochrane Library dot com and type “COX-I and preterm infants” in the search box to see a link to our review.