All that pneumatoses is not NEC

OK, I know pneumatose is not a verb, but I thought it was a cute title.

What is NEC, anyway? Necrotizing Enterocolitis, of course, you might reply. But it’s not as simple as that. The very preterm baby who deteriorates after being stable (usually after introduction of feeds), with abdominal distension, ileus, intestinal dilatation, obvious pneumatosis on x-ray, air in the portal venous system, who progresses to perforation and on laparotomy has skip lesions of necrotic bowel, such a baby is a clear case of classical NEC; but may be in a minority.

I have seen babies who present clinically exactly like that but on laparotomy had a strangulated internal hernia or other diagnoses. Full term babies also develop similar clinical and radiologic findings, but they almost always have other major risk factors. Infants with spontaneous perforation would have been classified as NEC in the past, but are now clearly recognized as a separate group.

Even among those with apparent ‘premie NEC’ there are major problems in diagnosis. Previous studies have shown that the radiologic diagnosis of pneumatosis is very uncertain, with inter-observer variability very high. A new study has looked at whether diagnosis of NEC made by local investigators can be supported when the files are reviewed by other experts.

Challis P, et al. Validation of the diagnosis of necrotising enterocolitis in a Swedish population-based observational study. Acta Paediatr. 2018.

This is a publication from the EXPRESS cohort that we have covered here on several occasions. Over a 3 year period all the babies of less than 26 weeks probable gestation born in Sweden were followed; and for many publications, they also followed stillbirths and counted mothers who were admitted with threatened extremely preterm delivery.

For this publication the data from the 707 live born babies was examined, and the 602 who survived more than 24 hours were included. All babies with a diagnosis of NEC in the database were reviewed, in addition any baby who had a sudden reduction in their feeding intake, to less than 10% of total fluid intake for more than a day (or if they never exceeded 10% in the first 10 days). The hospital records were obtained of these babies to see if independent neonatologists would confirm the diagnosis or not.

There were 39 babies identified in the database as being cases of NEC of which 16 after review were not definite cases of NEC, even 5 of the babies who had surgery were re-classified as no-NEC, 3 spontaneous perforations, one volvulus, and one meconium ileus.  Two babies were classified as no clinical suspicion of NEC, and 11 as possible NEC (referred to as Bell’s stage 1) which didn’t fit the case definition.

Among the 74 babies who had an episode of feeding reduction/interruption there were 4 with definite NEC, 2 had surgery and had reported findings consistent with NEC, 1 had NEC at autopsy, and 1 had clear x-ray findings. Another 7 babies were thought to have possible, stage 1, NEC and were therefore classified as no NEC.

This, to me, points out 2 things; firstly, sometimes data in clinical databases is unreliable, if a baby with findings on autopsy of NEC can be in the database as a case of ‘no NEC’, and a baby with volvulus is a case of ‘NEC’ then we have to be very careful to interpret our databases. Precise definitions, quality control of data entry, secondary verification of critical diagnoses, are important to improve reliability. Secondly, even for cases that are not clearly errors, in a diagnosis such as NEC there is a lot of inter-rater variability (or you might call it subjectivity) in deciding whether an x-ray shows pneumatosis, or other findings consistent with stage 2 NEC. One of the things that has changed (relatively) recently is the appearance of abdominal ultrasound to try to help in management of the condition. We have had cases which never had pneumatosis on x-ray, but an abdominal ultrasound was reported as showing “pneumatosis”, they were then entered into our database as cases of NEC, despite the fact that strict application of case definitions in use at the time did not include ultrasound findings.  The newer version of the definitions we use  now states “or other imaging modality” which I think is a mistake.

A recent systematic review of the diagnostic accuracy of abdominal ultrasound for diagnosis of NEC has been published. (Cuna AC, et al. Bowel Ultrasound for the Diagnosis of Necrotizing Enterocolitis: A Meta-analysis. Ultrasound Q. 2018;34(3):113-8). As all systematic reviews/meta-analyses it suffers from the limitations of the primary publications, but it does give some guidance as to the likely usefulness of the technique. The systematic review found 6 prospective cohort studies, with 462  infants with suspected NEC who had both radiographs and ultrasound studies. For such studies you have to decide what is the “gold standard” which is of course staging as Bell’s stage 2 or more using radiography. I can’t think of  a way of getting around this at present, but the “gold standard” is more like a tarnished silvery coloured metal. The review showed that among infants with confirmed NEC, ultrasound was relatively insensitive for most findings (portal venous gas, pneumatosis, free air, bowel wall thickening, bowel wall thinning, absent peristalsis, ascites and focal fluid collection) but was reasonably specific, mostly over 95%. The exceptions being pneumatosis at about 90%, and for bowel wall thickening at 67%.

So among the babies in these studies, even when there was a clinical suspicion of possible NEC, 10% of the time when the ultrasound showed “pneumatosis” the baby did not have a final diagnosis of Bell’s stage 2 NEC. 1/3 of the babies with bowel thickening did not have NEC.  I have seen kids having an abdominal ultrasound for other reasons, and having no symptoms, being reported as showing pneumatosis. In contrast I am sure there are babies where pneumatosis is not clearly seen on radiography, but ultrasound suggests that it is there, who do really have NEC. What is the place of ultrasound then? I think there are data that show that many more babies with NEC will have portal venous gas on ultrasound than on x-ray, and I think that finding is probably a very good indicator that they really do have the disease. Free air is a pretty definite indication that something serious is wrong(!) but is obviously not restricted to NEC; ascites with lots of junk in the liquid (to use the technical terminology) is usually not a good thing to find. Colour doppler investigation of bowel perfusion might help in decision making, but you really need to be a bit sceptical, I have seen more than 1 infant have a laparotomy, partly based on analysis of bowel perfusion, who had healthy looking bowel when the surgeons opened, and closed again, his/her abdomen.  Of course that can also happen without ultrasound/doppler, knowing when the bowel is necrotic, and needs to be resected, is notoriously difficult.

A much better way of clinically confirming mucosal injury, and its severity, would be great. Unfortunately all the biomarkers that I have seen investigated (from memory that includes calprotectin, PAF-1, fatty acid binding proteins, various interleukins, neutrophil surface markers, and Something About Amyloid called SAA) have been of very limited value. A recent review article about calprotectin suggests that one reason for that is that NEC is not one single disease, it may also be that, in my humble opinion, most biomarkers are a waste of time, if they are sensitive enough to be useful they are not specific, and if they are specific enough to rule out other diseases they are not sensitive! (a much more thoughtful review of biomarkers for NEC is available) A prospective study from Groningen looking at the usefulness of serial calprotectin for predicting NEC showed that levels are very high in preterm babies just after birth, and then vary widely, not being useful for prediction of NEC.

And of course all of these studies suffer from almost never being sure that a baby actually has NEC! The closest we really get to a gold standard diagnosis is in those babies who have laparotomy and bowel resection with pathology. In less severe cases the diagnosis will often be surrounded by question marks. The study from Sweden confirms this again.

There are only a few ways an immature bowel, with highly abnormal microbiome, limited circulatory reserve and underdeveloped Paneth cells (to name a few issues) can respond to an insult. Blood in the stools, ileus, and pneumatosis can occur in other conditions than classical premie NEC, and other associated conditions must be eliminated. The baby with a strangulated internal hernia did very well after the surprise finding on surgery, followed by resection and repair. In contrast babies with severe NEC requiring surgery continue to have a very high mortality, with about 5% in many series never going to surgery and dying, and 20% to 40% dying after surgery.

Those numbers are one of the reasons this subject comes up so often on this blog, and that doesn’t even touch on the adverse effects of the serious inflammatory insult and the associated nutritional difficulties on brain development.

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Richard Ehrenkranz 1946-2018

I am very fortunate in many ways in my life, including having met, and become friends with, many of the greats of neonatology.

One of the those greats was Richard Ehrenkranz, a neonatologist who spent most of his professional life at Yale, and who was extremely productive. As a junior faculty, he worked with Laura Ment in the Yale neonatal neurology lab, and he became very interested in long term neurological and developmental outcomes of preterm infants.

He was a major part of the NICHD neonatal network, and helped the network become the force that it now is.

For the last 30 years or so he became the person to go to for evidence about the influence of nutrition of outcomes of extremely preterm babies. He used the NICHD neonatal database to show that nutrition in the first few weeks of life of the extremely preterm infant has lifelong impacts on how their brains develop.

He died this August, an obituary is here. His enormous contributions to the wellbeing of preterm babies can be seen here : https://www.ncbi.nlm.nih.gov/pubmed/?term=ehrenkanz+r

Thank you, Richard.

Good Bye.

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Mother’s milk is best, but how best to use it?

A survey of practices in Germany, Austria, and Switzerland (the German speaking part) demonstrates the range of practices for handling mother’s own breast milk in very preterm babies. Klotz D, et al. Handling of Breast Milk by Neonatal Units: Large Differences in Current Practices and Beliefs. Front Pediatr. 2018;6:235.

The authors wanted to know what the units did for CMV surveillance and inactivation, bacterial cultures and responses to cultures, and how they managed fortification. About half of the 300 or so units replied.

Most units performed some sort of maternal CMV screening, but 66% fed raw colostrum from sero-positive mothers for at least a couple of days. After that 58% performed some sort of CMV inactivation for milk from sero-positive mothers, either standard Holder pasteurization, high temperature short duration pasteurization, or freezing and thawing the milk, usually until about 32 weeks.

Nearly half of the units cultured the breast milk, and then either pasteurized it or threw it out based on bacteria found and bacterial counts; there were 30 different thresholds for those actions in the different units.

Fortification was individualized using breast milk analysis in only 16 units (5 of those in a trial, only 6 did it as a routine, the remainder in selected cases). Fortification was usually with commercial multi-component fortifiers, but additional use of protein was common, additional lipids and carbohydrates were also sometimes used.

Units started putting babies to the breast mostly at 32 weeks, sometimes at 33 or 34 weeks.

Practices in different parts of the world might well be very different to those in this survey, but the study pointed out to me how little we know about what we should really do about these issues. In some countries the national recommendation is to pasteurize all maternal breast milk before giving it to the most immature babies. Pasteurization inactivates CMV, and profoundly decreases bacterial counts, but has negative effects on several large proteins, including some of those which may be responsible for the advantages of maternal breast milk. Two trials comparing raw mothers milk to pasteurized mother’s milk (Stock K, et al. Pasteurization of breastmilk decreases the rate of postnatally acquired cytomegalovirus infections, but shows a nonsignificant trend to an increased rate of necrotizing enterocolitis in very preterm infants–a preliminary study. Breastfeeding medicine. 2015;10(2):113-7. A “before and after” study and Cossey V, et al. Pasteurization of Mother’s Own Milk for Preterm Infants Does Not Reduce the Incidence of Late-Onset Sepsis. Neonatology. 2012;103(3):170-6, a Randomized Controlled Trial) both show a trend to more complications if mothers’ breast milk is pasteurized.

Using mother’s own milk is an important factor in improving outcomes for very preterm babies, I think it is about time we knew how to do it.

What are the indications for pasteurizing mother’s own milk? How is it best done to be effective and have the fewest adverse impacts? For which babies do we need to adjust fortification, and is individual breast milk analysis significantly better than just adding more protein (or protein and fat, or…)? Does adding prebiotics improve outcomes? How can we normalize the development of the intestinal microbiome in addition to mother’s milk?

And,just as important:

How can we increase the percentage of mothers who commence breast milk production for their very preterm baby? How can we increase breast milk production over the long term? How can we increase the proportion of babies who go home receiving exclusively mother’s milk?

There are, fortunately, now many investigators around the world researching some of these issues (you can see a list of a selection of recent publications below; sorry I haven’t got time to put a URL attached to each one, but they are all listed in PubMed), but many important questions remain to be answered.

Parker LA, et al. Facilitating Early Breast Milk Expression in Mothers of Very Low Birth Weight Infants. MCN Am J Matern Child Nurs. 2018;43(2):105-10.
Romaine A, et al. Predictors of Prolonged Breast Milk Provision to Very Low Birth Weight Infants. The Journal of pediatrics. 2018.
Cuttini M, et al. Breastfeeding outcomes in European NICUs: impact of parental visiting policies. Archives of disease in childhood Fetal and neonatal edition. 2018.
Tshamala D, et al. Factors associated with infants receiving their mother’s own breast milk on discharge from hospital in a unit where pasteurised donor human milk is available. J Paediatr Child Health. 2018;54(9):1016-22.
Grzeskowiak LE, et al. Domperidone for increasing breast milk volume in mothers expressing breast milk for their preterm infants: a systematic review and meta-analysis. BJOG : an international journal of obstetrics and gynaecology. 2018;0(0).
Haiden N, et al. Comparison of bacterial counts in expressed breast milk following standard or strict infection control regimens in neonatal intensive care units: compliance of mothers does matter. J Hosp Infect. 2016;92(3):226-8.
Hannan KE, et al. Impact of NICU admission on Colorado-born late preterm infants: breastfeeding initiation, continuation and in-hospital breastfeeding practices. J Perinatol. 2018.
Kaya V, Aytekin A. Effects of pacifier use on transition to full breastfeeding and sucking skills in preterm infants: a randomised controlled trial. J Clin Nurs. 2017;26(13-14):2055-63.
Pannaraj PS, et al. Association Between Breast Milk Bacterial Communities and Establishment and Development of the Infant Gut Microbiome. JAMA Pediatr. 2017.
Heon M, et al. An Intervention to Promote Breast Milk Production in Mothers of Preterm Infants. West J Nurs Res. 2016;38(5):529-52.
Tully KP, et al. A Test of Kangaroo Care on Preterm Infant Breastfeeding. Journal of Obstetric, Gynecologic & Neonatal Nursing. 2016;45(1):45-61.
Peters MD, et al. Safe management of expressed breast milk: A systematic review. Women Birth. 2016;29(6):473-81.
da Cunha RDeS, et al. Breast milk supplementation and preterm infant development after hospital discharge: a randomized clinical trial. Jornal de Pediatria. 2016;92(2):136-42.
Belfort MB, et al. Breast Milk Feeding, Brain Development, and Neurocognitive Outcomes: A 7-Year Longitudinal Study in Infants Born at Less Than 30 Weeks’ Gestation. The Journal of pediatrics. 2016.
Kreissl A, et al. Human Milk Analyser shows that the lactation period affects protein levels in preterm breastmilk. Acta Paediatr. 2016;105(6):635-40.
Healy DB, et al. Structured promotion of breastmilk expression is associated with shortened hospitalisation for very preterm infants. Acta Paediatr. 2016;105(6):e252-6.
Post ED, et al. Milk production after preterm, late preterm and term delivery; effects of different breast pump suction patterns. J Perinatol. 2015.
Mörelius E, et al. A randomised trial of continuous skin-to-skin contact after preterm birth and the effects on salivary cortisol, parental stress, depression, and breastfeeding. Early Human Development. 2015;91(1):63-70.

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Surfactant by nebulisation

After the PAS meeting I blogged about a presented abstract of nebulized lucinactant, which showed a possible reduction in needing intubation among babies on CPAP who received the surfactant, compared to controls.

A new publication from Perth (Minocchieri S, et al. Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial. Archives of disease in childhood Fetal and neonatal edition. 2018) reports a similar study, but using poractant and a different type of nebulizer. The authors randomized 64 babies, between 29 and 33 weeks gestation with HMD, to CPAP or to CPAP with the nebulizer placed between the bubble CPAP circuit and the face mask. Infants were eligible if less than 4 hours old, on CPAP of 5 to 8 cmH2O and needed some oxygen, but less than 30%. Treated infants received 200 mg/kg via nebulization, and 100mg/kg if they needed re-treating.

Despite the difficulties, this was done as a masked trial with the surfactant team behind a screen during the administration of surfactant (or equivalent period for the controls).

Failure of assigned treatment was determined by an increase in FiO2 to more than 35% for over 30 minutes, or over 40%, or a respiratory acidosis (CO2>65 and pH<7.2) or multiple apneas or if the physician got fed up (intubation “deemed necessary” but without the other criteria).

The need for intubation within 72 hours was reduced from 22/32 controls to 11/32 surfactant nebulizer babies. This was a short term pilot study, but seems again to show the potential benefit of this intervention, at least for the larger babies; among the babies in this trial, a subgroup analysis suggested benefit only in the more mature babies, but the study was underpowered for such analyses.

The only weird thing about the study is that is was performed between 2010 and 2012, it isn’t clear why it took 6 years to publish it after the end of the trial. I don’t know if that could be related to the fact that the first author has a patent with PARI pharma for the nebulizer.

Many of the intubations, especially of the smaller babies, were because of physician preference. With many of us now being more comfortable having babies on CPAP despite moderate respiratory distress (especially the 29 to 30 week gestation babies) physician preference might well be different if a similar study was redone.

None of the babies developed BPD or IVH or NEC, which makes one wonder, what is the benefit to the infants of avoiding intubation? If our outcomes for such babies are already excellent, is reducing the number or duration of intubation a significant advantage? I would say that in the short term there are advantages, to the baby and the family; intubation is associated with serious physiologic disturbance (and major pain unless you use good analgesia), multiple attempts are often required with increased risks, not likely to show up in a small pilot trial. Seeing a baby intubated rather than on CPAP is probably more stressful for the parents.

Also if we can prove efficacy in the larger early preterm babies, testing the intervention in the more immature babies, and intervening very early, would really be worth doing and may produce further benefits.

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Does phototherapy cause epilepsy?

A previous Danish study suggested an association between phototherapy in the neonatal period and a seizure diagnosis in childhood. Like many such studies the analysis was not adjusted for the bilirubin concentration, so if the association is true it might be because of confounding by severity, that is babies with higher bilirubins being more likely to get phototherapy, and potentially the link to seizures being higher bilirubins, rather than the phototherapy itself.

Other suggested associations of phototherapy, including childhood cancers, have also been made, but that association largely disappears after controlling for bilirubin concentrations.

In this new publication (Newman TB, et al. Childhood Seizures After Phototherapy. Pediatrics. 2018;142) the Kaiser Permanente Epidemiology group have used administrative databases and the electronic health records to compare diagnoses of epilepsy and prescriptions of anti-epileptic drugs between infants with and without phototherapy, after correcting for the serum bilirubin concentration. This analysis shows a statistically significant association even after correction. The increased risk of seizures in association with phototherapy was small, between 2 and 7 per 1,000 babies treated, but as they note, in situations where there is no evidence of benefit, i.e. a probability of exchange transfusion that is extremely low, then even a small increase in risk is better to avoid.

They also point to a new guideline promoted by a consensus group from the Northern California Neonatal Consortium. Because of the rarity of kernicterus, and the potential small risks of phototherapy, they took the AAP guidelines (this would apply to the very similar CPS guidelines, of which I was one author) divided them up by individual weeks of completed gestational age, and by whether there were neurotoxicity risk factors or not (that is hemolysis, sepsis, acidosis, hypoalbuminemia or “clinical instability”), and then added between 0 and 3 mg/dl (that is 0 to 51 micromol/L in modern units) to create new curves. You can access their on-line calculator here, or you could print out the new curves here or you can read the whole document (as a downloadable Microsoft Word file) www.phototherapyguidelines.com/NeoHyperbilirubinemiaGuidelineFINAL_2018-0209.docx.

I am not convinced about the risk of seizures from these data, but they certainly support a possible link, and safe ways to reduce phototherapy use are probably in the best interest of families and babies.

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Back to blogging

A long break from blogging this summer, with a trip to Vietnam, and other great experiences over the last few weeks. I will put up some of my Vietnamese wildlife photos on a page very soon (mostly birds).

I thought I would start with a series of short posts about recent publications, before getting back into my usual prolonged dissection of studies.

To start off, a study that I already discussed after the PAS meeting has now been published in full, that is the randomized trial designed to protect noses during CPAP. Imbulana DI, et al. A Randomized Controlled Trial of a Barrier Dressing to Reduce Nasal Injury in Preterm Infants Receiving Binasal Noninvasive Respiratory Support. The Journal of pediatrics. 2018;201:34-9 e3. A clinically important intervention with a clearly positive result, hydrocolloid dressings should be the standard of care unless someone can develop something better..

Secondly I discussed the Family Integrated Care study by Karel O’Brien and colleagues previously, and noted that I couldn’t understand the primary outcome, that it seemed to have been miscalculated. The paper stated that the babies had a z-score for their body weight that had changed by about +1.5 in each group, but the data didn’t seem to make sense as the babies appeared to have dropped off the growth centiles a little, over the 4 weeks of the study period, and I thought they should have had somewhat negative z-score changes. The authors have now published a correction to their article, the correction notice states that the primary outcome was actually a z-score change of −0·071 [SD 0·42] vs −0·155 [0·42]; p<0·0002. The adjusted difference in z-scores between groups was also corrected to a difference of 0·095 (95% CI 0·0–0·14), p<0·0001. I now don’t understand how a difference between groups, for which the 95% confidence intervals reach 0.0, can be significant at p<0.0001; even if there is a rounding issue, and the 95% confidence limit is in reality a little more than 0.0, it seems unlikely that this could translate into a p-value which is so tiny. Anyway, the on-line version has apparently been corrected (I have asked for a new copy of the pdf from the inter-library loan system) and the abstract, which now appears in PubMed because the journal is now indexed, has also been corrected, you can follow the link above to the entry in PubMed. What the new result means of course is that both groups of babies grew less than the Fenton percentile curves, and lost about 1 tenth of a standard deviation of their weight in comparison to standardized growth percentiles, losing less in the FICare group than the controls.

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Does inhaling Nitric Oxide cause cancer?

How would you answer the question posed in this title? Given the relative rarity of infant cancers, I guess you would have to follow thousands of babies treated with iNO, and compare with thousands of babies who were equally sick but not treated with iNO. You could only do that with national databases I would guess. Here is a new study that has done exactly that: (Dixon F, et al. Treatment with nitric oxide in the neonatal intensive care unit is associated with increased risk of childhood cancer. Acta Paediatr. 2018). There are previous studies showing an increase in hepatoblastomas amongst very preterm babies, and apparently there are also some studies showing an increase in malignancies among larger than average babies.

This new publication suggests that, as a new potential risk factor, or marker of risk, inhaled nitric oxide use in the neonatal period is associated with an increased risk of neonatal cancers, and specifically liver tumours.

The birth database that the authors used included just over 1 million births between 2000 and 2011, with the outcome of interest being malignant disease diagnosed at any time, so the average follow up was about 6.5 years. There were just over 1000 cancers diagnosed, so about 0.1% of live born babies.

2.2% of the total birth cohort of babies were in the NICU database, whereas nearly 6% of the cancers were among NICU patients (or ex-NICU patients). They looked at demographics, especially gestational age and birth weight. And found 2 associations, being preterm or being high birthweight, between the occurrence of any cancer and the characteristic. Being born before 37 weeks gave an increased Odds Ratio of cancer of 1.3 (95% CI 1.0-1.6) and, for being over 4 kg the OR was 1.4 (1.2-1.6).

The authors then examined the various subgroups of cancers, for the preterm group, the risk appears to only be increased for hepatic tumours. The OR being over 12 for the babies between 23 and 31 weeks and 2.0 for the 32 to 36 week group. Although the impact of being very preterm was “statistically significant” this group only included 3 babies with liver tumours, similarly in the 32 to 36 week group there were another 3 babies, compared to 20 in the full term group.

The authors don’t identify the type of liver cancers in their study, but the majority of pediatric liver cancers are hepatoblastomas, those are embryonal tumours that are thought to often have their origin in the prenatal period. I have seen 3 or 4 hepatoblastomas diagnosed in the late fetal, or neonatal period. The association with preterm birth has been postulated to be due to exposure to numerous oncogenic or potentially oncogenic phenomena, such as x-rays, phthalates and other drugs.

In this study the authors excluded babies with a diagnosis in the first 4 weeks of life, so one of my first thoughts, which was that maybe the babies were sick because they already had complications of their cancer (although rare that could happen often enough to change the imbalance by a couple of kids or so).

Among the neonatal therapies they examined, from the NICU database were surfactant, indomethacin, postnatal steroids, and inhaled nitric oxide. There were 8 babies who received nitric oxide who developed a cancer, of a total of nearly 800 NO treated patients. In the abstract they note that the 8 who developed cancer 4 months to 5 years after inhaled NO treatment were between 30 and 41 weeks gestation. That information doesn’t seem to be anywhere else in the manuscript.

All observational studies are at risk of residual confounding, even when you do your best to correct for everything that you can think of. That is why RCTs are so powerful! So what are the risks for confounding in these data? Infants who receive inhaled NO are often acutely sick, have multiple infusions of multiple different drugs, may have TPN for prolonged periods, have multiple x-rays.

Is it biologically feasible that inhaled NO could increase the risk of hepatic tumours? There is some evidence, that the authors quote, of involvement of nitric oxide in oncogenesis, but the articles that the authors quote are all about intra and intercellular signalling by endogenously produced NO. That is very different to potential roles of inhaled NO, which has largely been degraded to nitrates and nitrites before it gets anywhere else in the body than the lung. Nitric oxide has oxidant and anti-oxidant and nitrosylating actions in the lungs of treated animals, but it might be a stretch to suggest that the same effects might occur in the liver or the brain.

If you take hepatic tumours out of the equation, is there any other signal in these data? That is hard to say as the numbers start to get too small, I would guess, if you break down different tumours by intervention type. But I would also guess that if all the 8 NO treated babies had the same kind of weird tumour (or the same kind of less weird tumour like Hodgkins Lymphoma for example) they would have said so.

I think that, as with all well-performed large observational studies, we are left with associations, that could potentially be causative, but might also be related to other risks that the babies have in common. It would be nice to see a case control study, or one using propensity score matching, comparing sick NICU babies who received NO and those who didn’t but who had a similar duration of intensive care treatment, assisted ventilation, exposure to phthalates, numbers of chest x-rays etc, to see if the risk remains when well matched for other interventions. Other studies to see if there is a dose-response relationship might confirm the possibility that the effect is causative.

Given that there is no good evidence that inhaled NO improves clinically important outcomes in preterm babies, this new data suggest that we should avoid iNO in the preterm patient unless you have a good reason for supposing it will be helpful. In full term babies inhaled NO may be life-saving, and the possibility of an absolute 1% risk increase in cancer risk should be taken into account, but would not often change my mind. On the other hand, less of most things is likely to be less toxic, so weaning nitric oxide as soon as it isn’t helping anymore is probably a good thing to do, and not only for the possible cancer risk.

We should now perform more epidemiologic studies in unrelated populations to see if we can confirm this worrying association, and that it is robust after correcting for other potential confounders.

 

 

 

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