Stubborn PDAs despite prophylactic indomethacin!

Stubborn PDAs despite prophylactic indomethacin!

As time goes by, I find myself gravitating to reviews of Canadian research more and more.  We have a lot of great research happening in this country of ours and especially when I see an author or two I know personally I find it compelling to review such papers.  Today is one of those days as the lead author for a paper is my colleague Dr. Louis here in Winnipeg.  Let me put his mind at ease in case he reads this by saying that what follows is not a skewering of the paper he just published using Canadian Neonatal Network data (CNN).  Over the last twenty years that I have had the privilege of working in the field of Neonatology we continue to discuss the same things when it comes to the PDA.  Does it really cause problems or is it an association for many outcomes? Does treatment make a difference?  If you treat then what should you use (ibuprofen, indomethacin, paracetamol)? When should you treat and if you treat early should it be in the first few days or right after birth using a prophylactic approach (provided within 12 hours of delivery)?  It is the prophylactic approach which is the subject of this post!

Why treat prophylactically?

The TIPP trial reported the results in 2001 of the study whose goal was to determine if prophylactic indomethacin use could improve neurosensory impairment at 18 months by reducing rates of severe IVH.  The results of the study are well known and showed that while the rates of severe IVH and PDA ligations were reduced through this approach, there was no actual effect on long term outcome.  The use of this approach fell off after that for many years but recently resurfaced as some units in Canada opted to start the practice again as the two benefits seen above appeared to be worth using the approach.  The thought from a family centred approach, was that eliminating the stress for families of informing them their tiny preterm infant had a serious intracranial bleed and potentially avoiding a surgical ligation with probably vocal cord impairment afterwards were good enough outcomes to warrant this practice.  Having used this approach myself I have to admit one consequence is that indomethacin was so effective at closing the PDA most of the time that over time one begins to assume the PDA is in fact closed and is less likely to go hunting for one when the baby is misbehaving later on in their course.  What if it didn’t close though?  Are there any predictors that can increase our index of suspicion?

Answering the question

The CNN provides a large database to look retrospectively to answer such a question.  In this article, the authors looked at a period from 2010 to 2015 including all infants < 28 weeks gestational age at birth yielding a very large sample of 7397 infants.  Of these 843 or 12% received prophylactic indomethacin and from there a little over half (465) still had a PDA.  From there, 367 received treatment with eventually 283 needing only medical, 11 having a PDA ligation and 73 having both medical and surgical closure.  From this analysis so far I can tell you that providing prophylactic indomethacin certainly does not guarantee closure!

When a myriad of risk factors were put into logistic regression a number of interesting risk factors arose accounting for more of less risk of a PDA that needed surgical ligation despite prophylactic treatment.  Much like all infants in the NICU, the risk for a persistent PDA was highest with declining GA.  The combination of outborn status and short interval of ruptured membranes predicted higher risk.  No doubt this is reflective of less frequent antenatal steroid use and even if provided time for it to work.  Looking at medical or surgical treatment, surfactant therapy increased risk which may be explained by an improvement in oxygenation contributing to increased left to right shunting as PVR drops.  Maternal hypertension and longer duration of rupture of membranes again play a role in reducing risk likely through the mechanism of the former increasing endogenous steroid production and the latter again allowing for steroids to be provided.

What can we learn from this paper?

I suppose the biggest benefit here is the realization that even with prophylactic indomethacin we are not assured of closure.  In particular if there is a lack of antenatal steroid use or a stressed fetus one should be vigilant for the PDA.  Interestingly, all of the risks seem to point towards antenatal steroid use.  The bottom line then is that this reinforces what is already known and should be the focus of improvement strategies for centres.  Increase the rate of antenatal steroid use and you will reduce the risk of a PDA even in the baby receives prophylactic indomethacin.  I am happy to report that our centre has taken one step towards this goal by reinforcing to our Obstetrical colleagues that when they receive a call from a referring centre and have a woman who might be in labour it is better to err on the side of caution and just give the steroid course.  If they are wrong on arrival then one can always repeat a course later on as we do although repeated courses of steroids are in and of themselves a contentious issue.  What can your centre do to improve your results when it comes to antenatal steroid coverage?