One of Annie Janvier’s first research projects was a case control study of the influence of prophylactic indomethacin on intestinal perforations. Under my supervision she analyzed cases of spontaneous intestinal perforation (SIP), and we analyzed the influence of prophylactic indomethacin, which was highly significantly related.

As we knew at the time, there are numerous biases in this type of research. For one, we decided to do the study because we had just had a run of SIP; often such studies are stimulated by just this kind of phenomenon. Which immediately introduces bias: what you should probably do, if you have a cluster of adverse outcomes, is to take your suspicions and analyze data from a completely independent data set, of which you are not a part. But few of us have access to such data.

We had recently introduced indomethacin prophylaxis, and had this run of SIP, so the analysis did show an associations between the 2, which made us worry, but we certainly weren’t convinced that the association was causal, nor that our data were free of bias.

As an aside, Annie, a fellow at the time, was really pissed off when a well known senior researcher, who shall remain nameless, walked past her poster and sniggered. Don’t do that folks (most of my good friends and colleagues wouldn’t dream of it): even if there are flaws in the research, we should encourage junior people to be thoughtful, to try and analyze their experiences and find ways to ask and answer questions.

That is a long introduction to a new publication from the NICHD database.

And another beef, is it really necessary, when someone does an analysis of the NICHD database, that there are 19 authors?  Did all 19 have a substantial intellectual contribution to this work? Or is it more of a little present thrown to the waiting hordes, a sort of quid pro quo, you scratch my data, I’ll scratch your CV?

Just asking.

Kelleher J, et al, et al, et al. Prophylactic Indomethacin and Intestinal Perforation in Extremely Low Birth Weight Infants. Pediatrics. 2014. This prospective cohort comparison used the generic database to examine the incidence of SIP in babies who received prophylactic indomethacin or  not, and subdivided each group as to whether they had early feeding or not. Early feeding was defined as receiving any feeds in the first 3 days of life. My European readers might laugh at that as a definition of early feeding, but there were plenty of these babies, 400 to 1000 g birth weight, who were npo for at least 3 days, indeed there were 11,000 of the 15,000 who got no enteral feeding during the first 3 days (between 1999 and 2010).

As for the results, there was no evidence that prophylactic indomethacin increased SIP, and early feeding is associated with a lower rate (there may be some confounding here, as babies who have abdominal signs and maybe early signs of SIP might have feeds held as a result). Babies who had early feeding had less developmental delay at 20 months, (or, as the NICHD persists in calling it, ‘neurodevelopmental impairment’: if I have to say it again, a low Bayley score is not an impairment!) and the association of early feeding with better Bayley scores, was seen whether or not the babies got prophylactic indomethacin.

The prophylactic indomethacin babies also did not have more NEC, and they had fewer PDA ligations. They also had much less frequent treatment with indomethacin or ibuprofen later in their hospital course, but the RR is reported as being over 1, and significant, which I don’t understand.

The early enteral feeds groups also had much quicker advancement to full feeds, and many fewer days of parenteral nutrition.

This confirms the RCT results, with a lot more babies but an observational study design, indomethacin doesn’t seem to increase SIP (despite our case-control findings) decreases PDA ligations, and adds very positive data about early feeds, at least starting feeds before 3 days of age. I think you should have a very good reason for not feeding a very preterm baby, such as shock requiring inotropes perhaps.