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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Oxygen for preterm infants, what dose of this toxic drug is the right dose? #NeoEBM

The NeoProm primary publication is the result of a prolonged gestation; I remember meetings over 15 years ago when Cynthia Cole from Boston was suggesting the idea, and although she was not, I think, finally an author on any of the major trials or the Prospective Meta-Analysis, she was quite persuasive and helped to get the ball rolling.

Askie LM, et al. Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis Collaboration. JAMA. 2018;319(21):2190-201. I am actually a little surprised that the title of this article starts with the word “association”; surely prospective randomized controlled trials are designed to investigate causation, rather than association?

What is NeoProm, and what is a prospective meta-analysis (PMA)? The idea behind PMA is that, to prove small, but clinically important, differences in outcomes we need to perform very large trials. In neonatology we look after about 10% of all human beings, but only for the first few days, or occasionally weeks, of life. When we are looking at an even smaller proportion of those live births, around 1%, that is, those born extremely preterm, then large international collaborations become essential for many of the important questions in the NICU.

Costs for such very large trials can become prohibitive for a single funding agency, even if, like NIH (USA), CIHR (Canada), NHMRC (Australia), and the MRC (UK), many large national bodies are willing to fund participants in other countries, if you need to fund a trial in 5000 intensive care patients, requiring extensive data collection, it gets very expensive. One alternative is to perform a number of co-ordinated trials, funded by different agencies, with the intention of performing an Individual Patient Data meta-analysis. You facilitate the IPD, by agreeing beforehand on what data will be collected, and how, and what the definitions of certain outcomes will be. It is also important, of course, to pre-define the primary outcome and the important secondary outcomes. These restrictions on trial design are what makes a PMA different to a post-hoc IPD meta-analysis.

A PMA is not as powerful as an individual trial with the same number of participants, because you have to use some of the statistical power to account for possible differences between trials. You also have to be careful that all the originally planned trials are truly committed to the PMA, otherwise you might end up with fragmentary publications, which might artificially inflate the apparent “significance” of the results.

The NeoProm collaboration is, I think, the first PMA in neonatology. Bravo to all the PI’s, the steering committees, the local investigators (including me!) and in particular to Lisa Askie, who seems to still be sane (or at least as sane as she ever was) following the successful completion of this megaproject.

The Collaboration included SUPPORT, which was started and finished first with dates that overlapped the others, the BOOST-2 trials in Australia and in NZ, BOOST2-UK, and COT. In total there were indeed almost 5000 extremely preterm babies in the trials.

The primary outcome, agreed before the collaboration proceeded, was a composite of either death or “major disability” at 18 to 24 months corrected age: major disability was any of the following: Bayley Scales Development version 3 cognitive or language score of less than 85; severe visual loss (cannot fixate or is legally blind with visual acuity <6/60 in both eyes); cerebral palsy with the GMFCS 2 or higher; or deafness requiring hearing aids.

Basically there was no impact of the different saturation targets (high 80’s vs low 90’s) on the primary outcome.

I guess I could stop there, but you know me!

I have serious concerns about how this result might be interpreted, and about the relevance of this primary outcome.

A Bayley-3 score of under 85 at 2 years of age is NOT A DISABILITY. The Bayley test is a somewhat useful, over-sensitive, screening test (over-sensitive as most screening tests should be) for developmental delay, the MAJORITY of infants with a Bayley under 85 at 24 months do not have any long-term impairment. Very few of them have a disability, and even fewer have a handicap. It is certainly not equivalent to being dead.

The major part of the “disability” outcome was a low Bayley score, of the 1429 babies with “major disability” 1319 had a low Bayley score, 213 had cerebral palsy, 120 were deaf and 48 had serious visual problems; and there were 896 deaths in total by 2 years of age. (In the supplemental information you can find that the Bayley-3 language or cognitive composite scores were under 70 for 443 of the infants).

I understand the problem of competing outcomes, that a baby who is dead cannot have a developmental delay at 24 months, but there are other ways of dealing with competing outcomes that do not imply equivalence. Including: hierarchical outcome evaluations, for example, which evaluate the most important first.

What should the primary outcome be for large neonatal studies? Almost all of our survivors have acceptable quality of life, so I think that survival should be the primary outcome of any of these studies. There might be some reasonable disagreement, however, about the place of very profound disability with inability to communicate, although rare, there are reasonable people, and parents of extremely preterm babies, who find such an outcome to be equivalent to death, in terms of the value to them and the infant. Perhaps the first outcome to evaluate could be a composite of death and very profound impairment (inability to communicate). I also think that the decision regarding primary, and other, outcomes should be made in collaboration with parent partners, and former preterm infants.

Following this, evaluation of other aspects of longer term outcomes could follow.

As profound impairment with inability to communicate is so rare among our extreme preterm babies, the primary outcome of this PMA would likely be unchanged if death or profound disability was used as the primary outcome, compared to death alone. The PMA shows an absolute decrease in mortality before discharge of 2.4%, and a relative decrease of 17% when the higher saturation targets are used, compared to lower targets. The 95% confidence intervals for that outcome do not include ‘no difference’, so the difference is unlikely to be due to chance alone. As the article in JAMA is (too) ready to point out, that is a secondary outcome; the components of a primary outcome are strictly always secondary outcomes, but I think they have a different status to other outcomes, which are not directly related to the primary, such as, for this study, bronchopulmonary dysplasia for example. Many years ago when we started on this adventure I thought that BPD would probably be less frequent in the low saturation group, as you would need less oxygen and lower mean airway pressures during ventilation, and less non-invasive ventilation afterwards; but there really is no signal at all for BPD. There are of course more babies in the high saturation target group receiving oxygen at 36 weeks gestation, but other indicators of lung injury severity, such as the proportoin going home on oxygen (supplemental appendix), when home oxygen babies came out of their oxygen, and hospital readmissions in the first years of life, were the same between groups. One think I hadn’t particularly been expecting was that the lower saturation group would have more severe Necrotising Enterocolitis (that is needing surgery or dying), but that does seem to be the case, with 9% in the low saturation group, and 7% in the high saturation group.

The implication of this for clinical practice is that NeoProm confirms that the only target SpO2 range which is evidence-based is between 90 and 95%. Anything else (such as 88 to 92% for example) is speculative and would require other studies of many thousands of babies. I don’t think that is likely to happen in the near future.

The main adverse outcome of higher saturations is worse retinopathy, leading to an increase in the need for treatment, from 11% to 15%. As noted in the individual trials, even though treatment was more frequent, visual outcomes at 2 years of age were not different. We need to find other ways of decreasing retinopathy, in particular improving nutritional standards and growth outcomes.

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