Is benign neglect for the PDA the right move?

Is benign neglect for the PDA the right move?

I don’t think you can be a Neonatal blogger without writing about the patent ductus arteriosus from time to time. It’s been a little while so when something floats past my desk that I find interesting I share it with you. When that article is Canadian and written by someone I collaborate with on the Canadian Pediatric Society Fetus and Newborn Committee I am even more apt to do so. In the last few years the idea of letting nature take its course with respect to the PDA has been growing. The evidence is lacking that treatment for most infants in the first two weeks of life makes a difference to important pulmonary outcomes ie. BPD. There is a growing movement asking whether treatment at all really makes a difference to these infants or whether we should just be managing the medical complications of increased pulmonary bloodflow with diastolic steal from the kidneys and intestine. The alternative of course is to treat these infants most commonly with NSAIDs and hope that side effects such as renal impairment and spontaneous intestinal perforation don’t happen. Full disclosure, I was raised to find the PDA and if hemodynamically significant treat it, so that has been my general approach. I am open to suggestion though so without further adieu let’s talk about a recent Quebec study on the topic.

University of McGill in Montreal

Anchored by Dr. Altit with the lead author being De Carvalho Nunes the experience at this hospital was recently published as Natural evolution of the patent ductus arteriosus in the
extremely premature newborn and respiratory outcomes
. The authors looked a specific population of infants born at <29 weeks gestational age (214 infants in total) and importantly had a reasonable number of small infants >26 weeks at birth (84) to see what happened to their PDAs in the long run. Many years ago the unit adopted a non-intervention policy with respect to treatment of PDAs and since 2015 were in a new hospital. This afforded them the opportunity to look retrospectively at a modern cohort of infants all cared for in the same environment from Feb 2015 – Sept 2019 and see what happened to respiratory morbidity over time. While this was retrospective and lacks a control group the concept here was that one could look at the rate of BPD over time and see if it was static, rising or falling and in turn you could also compare to the Canadian Neonatal Network (not done in this study) to see if your approach was leading to all sorts of morbidity.

What did they find?

The authors chose to standardize the definition of BPD:

by Higgins et al from 2018

Grade I (nasal flow cannula <1 L/min with FiO2 ≤ 70%; nasal cannula with flow of 1 to 3 L/min and FiO2 between 22 and 29%; CPAP, noninvasive positive pressure ventilation [NIPPV] or nasal cannula with flow >3 L/min with FiO2 of 21%),

Grade II (nasal flow cannula <1 L/min with FiO2 > 70%; nasal cannula with flow of 1 to 3 L/min and FiO2 ≥ 30%;
CPAP, NIPPV or nasal cannula with flow >3 L/min with FiO2 between 22
and 29%; invasive mechanical ventilation [IMV] with FiO2 of 21%)

Grade III
(NIMV, NIPPV or nasal cannula with flow >3 L/min with FiO2 ≥ 30%, IMV
with FiO2 > 21%).

When looking at the total population including after discharge 91% of all babies greater than or equal to 26 weeks experienced ductal closure without intervention. Secondly, if you look under 26 weeks the results were hardly any different with 90% closing. Before discharge from the hospital 66% of the larger infants experienced closure prior to discharge and 76% of those under 26 weeks. Interesting finding that more infants under 26 weeks by percentage had closure.

Looking at the respiratory outcomes a total of 77% had BPD under 26 weeks of varying severity compared to 40% in the larger infants. Other morbidities were not different.

Interestingly the authors also noted a decline in Grade 2 BPD over the 5 year study.

Thoughts on the results

It’s important to look at the overall results from the Canadian Neonatal Network to see how this group compares to the rest of the country. What follows is not perfect but its a start for a discussion.

This includes all babies in the CNN under 1500g. If we use <1250g as a rough cutoff for under 29 weeks you can see that by weight the rate of chronic lung disease ranges from 30 – 100%. At 77% under 26 weeks which corresponds to babies around 750g or less (some are a little more) then the rate should be somewhere between 60 – 80% if you count babies 500 – 750g. I would say the rate of 77% overall is not bad in terms of comparison. Secondly if you look at the distribution of CLD for this group it was at their centre it was 47, 24 and 7% for Grade 1 – 3 respectively. This is particularly interesting as when you look at mild, moderate and severe in the bars above it would suggest their babies on average with a “benign neglect” approach are more mild. This approach is looking up!

One thing that I note though is that the rate of postnatal steroid use in this group was 75% under 26 weeks and 22% for those from 26-28 weeks. This represents a large increase over the mean in the CNN back in 2019 of 11.9% for postnatal steroid use. The babies under 26 weeks were also ventilated invasively for a median of 29 days. That seems a little long to me but there are no comparisons with the CNN to know for sure.

I can’t help but wonder if you are trading short term pain for long term gain. It’s hard to argue with the long term results in terms of a shift towards better rates of lower grade BPD. I do wonder though if the eventual closure of the PDA is being helped along with use of more postnatal dexamethasone. There is some data suggesting increased rates of closure with use of dexamethasone so maybe what is going on here is that rather than using NSAIDs there is a shift to long durations of ventilation and increased rates of dexamethasone use. Something for the authors to look at though.

With everything there are trade offs so maybe less NSAID use means longer ventilation and more postnatal steroids but in the end the pulmonary outcome is better? I see a prospective RCT coming to eventually settle this debate!

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?