Reducing the incidence of prematurity is a goal that we have had little success with. The incidence differs greatly around the world, which leads me to think that there are probably underlying mechanisms that could be attacked to reduce the incidence in high-risk populations. If the rate is 14% in Malawi and 5% in Sweden, there should be something anything we can do in Malawi (as one example) to reduce this enormously high rate?
But, most of the variation around the world (and between Sweden and Malawi) seems to be linked to maternal health and socio-economic status, which are rather difficult to address. One thing I hadn’t realized was that there is prior evidence that vaccination against HPV might reduce some adverse pregnancy outcomes, in particular preterm labour and premature delivery, but intra-uterine growth restriction also.
A new population-based case-control study from Sweden, (Zhang Z, et al. Quadrivalent human papillomavirus vaccination before pregnancy and pregnancy outcomes: nationwide, population based case-control study. BMJ. 2026;395:e100739) shows a measurable reduction is preterm birth among women vaccinated against HPV, compared to the non-vaccinated. Over the years of the study (2006-2023) there have been several changes in the program “From 2007 subsidised human papillomavirus vaccination was offered to girls aged 13-17 years, and in 2012 a free school based programme for girls aged 10-12 years was introduced alongside catch-up vaccination for girls born in 1993-98” Since 2020 boys and girls have been vaccinated. These progressive changes introduce a potential bias in the data, if there were some other reason for a progressive reduction in prematurity, it could appear to be due to the vaccine, but the authors have performed covariate adjustments for many variables, including year of birth.
There is, after all adjustment, a measurably lower rate of prematurity among vaccinated women, and in addition a lower rate of IUGR and pPROM
Vaccination at an earlier age (<17 yrs) seems more effective than 17 years or older for reduction of preterm and very preterm delivery, and for pPROM.
There is already excellent evidence that routine vaccination dramatically decreases cervical cancer, to the extent that elimination of the disease is being discussed. With 90% vaccination, and changing the screening standards, an incidence below 4/100,000 is expected.
I can understand why not having HPV in the cervix could decrease preterm delivery and pPROM, but I don’t really understand why there would be an impact on IUGR. Whatever the mechanism, this adds another excellent reason for routine universal vaccination in the early teen years.
Many publications and some guidelines about the use of probiotics for NEC prevention in the preterm make the claim that the evidence is more reliable for the moderately preterm than for the extreme preterm.
Other RCTs which have been restricted to, or have reported subgroups of, extremely low birth weight infants are all quite small, except for the Australian Proprems trial, which used a preparation that included a B infantis, and had about 460 babies <28 wks. That study had a low incidence of NEC in the controls in the <28 wk GA subgroup, of 5.8%, which was reduced to 4.2% in the probiotic group, a relative risk of 0.73, but with wide confidence margins (0.33-1.6) in that subgroup. Overall the reduction in NEC in that trial was unlikely to be due to chance, RR 0.46 (0.23-0.93) and there was no significant interaction between treatment effect and birth weight.
Most of the trials, on the other hand have included very immature and extremely low birth weight infants, they have just not reported subgroup results, meaning that Systematic reviews have little power to determine efficacy specifically in that subgroup.
A recent Norwegian observational study, reports a national cohort of extremely preterm infants (<28 weeks or <1000g) covering the period, 2014-2021 (Hapnes NC, et al. Probiotics for extremely preterm infants: a Norwegian population-based study. Arch Dis Child Fetal Neonatal Ed. 2026). This period started when the Norwegians issued a recommendation to give probiotics to this group, but uptake was far from universal. It also covers a period when the commonly used preparation Infloran was available, then withdrawn from use, leading to a drop in utilisation for a year, then another preparation was used, Labinic droplets, and more recently, another preparation, Proprems which is the one used in Sweden that I discussed in my previous post, was starting to be used. All 3 preparations include a B infantis.
The outcomes of interest were mortality, late-onset sepsis, and surgical NEC; like some other databases, the concerns about the subjectivity of the diagnosis of medical NEC are such that they concentrate on surgical NEC, and all of the cases were reviewed to ensure they met diagnostic criteria. The vast majority of these babies received maternal or donor breast milk, fortified as a routine with bovine based fortifier, until 32 to 34 weeks PMA. Of note, the babies receiving probiotics had a lower birthweight average, by 100 g, and were less mature, with worse CRIB scores, meaning they had a higher baseline risk, so the adjusted analyses are important. The associations with all cause mortality and surgical NEC are shown below.
There is lower mortality, lower surgical NEC, less “death or surgical NEC”, and, importantly, very similar late-onset sepsis (LOS), even though they did have 5 cases of probiotic sepsis among the over 600 babies who received them.
Like many SRs, the single strains are grouped by genus, even though there are major differences between the different species within a genus, but it seems to hold true that a mixture of strains are probably the most effective for reducing LOS, and mixture containing a B infantis seems to hold the best chance of both LOS and NEC reduction.
Indeed that decision has had serious negative impacts on our babies, this analysis (Tolia VN, et al. Probiotics and necrotizing enterocolitis in preterm infants after the food and drug administration warning actions. J Perinatol. 2026) used data from the Pediatrix data warehouse. It analyses NEC incidence by NICU rather than by baby, and divided NICUs according to whether they were giving more or less than 80% of their 23 to 29 week preterm babies probiotics, before the FDA warning.
Probiotic use dropped from 86% to 7% in the high use centres, and from 13% to 0.1% in the low use centres. Both medical and surgical NEC increased when probiotics were stopped, LOS did not change.
There are several observational studies, therefore, restricted to extremely preterm infants (either <28 or <29 weeks GA) which show the same impacts of probiotic therapy on NEC as are seen among more mature preterm infants.
It seems to me that there is no good evidence to exclude the most immature babies from the benefits of routine probiotic supplementation. Putting everything together, a multistrain preparation containing a B infantis probably has the greatest benefit for preventing NEC, and likely has a modest impact on overall LOS also.
Many of you will know that I have been convinced for some time that probiotics can reduce the frequency of NEC. Once the data became strong enough, and safety seemed to be assured, we were, I think, the first Canadian centre to routinely administer probiotics to our very preterm babies.
Until recently we were using a mixture, which included several bifidobacteria, and a lactobacillus, called “Florababy”, but there were some corporate changes, which led to the new owners deciding that they no longer wanted to help our babies. We sought a commercial mixture containing the best strains, and have settled on a new preparation, which, has a Bifidobacterium animalis, and a Lacticaseibacillus rhamnosus, it is not, I think, optimal, but was the best available to us.
There are clearly differences between the different preparations in impacts on NEC; most vital are the quality control to ensure that the bugs are viable, and more importantly that there are no pathogens in the mix. The identity of the strains is important, and probably the single most important strain in Bifidobacterium longum subspecies infantis (which I will call B infantis for simplicity). Some of the systematic reviews suggest strongly that a mixture of strains is preferable, rather than a single strain, but they did not include any RCT with a single strain B infantis. It is uncertain if you need a mixture if you have B infantis, or not. The reason this germ might be the most important is that it is the only strain that can digest all the HMOs.
For those who are new to this subject, HMOs (Human Milk Oligosaccharides) are the third most important component of breast milk, after lactose and fat. And humans cannot digest them, they exist only to feed the intestinal microbiome. Historically B infantis was the most prevalent probiotic organism in the infant intestinal microbiome, but that has changed in modern industrialised societies.
The fact that B infantis alone, of all the organisms tested, is the only one that can digest every HMO suggests that it has co-evolved with us to colonise the infant gut. B infantis, and other probiotic organisms, interact with Toll-like Receptors TLRs, of various types, to reduce inflammation and protect the GI tract. There may be other actions, such as the metabolism of breast milk amino acids to anti-inflammatory mediators.
Probiotic preparations (single strains or mixtures) that did not contain B infantis were less effective, and although the calculated I2 was still zero, you can see looking at the results of all 48 (!) studies that some showed no impact, and others, especially some very small studies, had a large effect.
The next Forest plot shows the impact on mortality, which is substantial with preparations containing B infantis, RR 0.65…
but less evident with other preparations. The top line of the next Forest plot showing the impact of probiotic preparations without B infantis, and the lower part is the overall impact of all probiotic preparations.
Probiotics are very safe, live organisms given to preterm infants with their limited immune development require surveillance, of course, and we have shown that the incidence of sepsis caused by these organisms is about 0.6% of treated infants. Sepsis was more common among the more immature infants, but was uniformly mild, and no infant died of sepsis. Other recent publications have calculated even lower risks.
The balance between this risk, and the benefits of NEC reduction is extremely important. The FDA in the USA published an advisory, warning against routine probiotic use, in which they made no mention of any analysis of the risk-benefit balance, and indeed no mention of the benefits at all.
You can see the immediate, dramatic fall in NEC with the use of a daily dose of the probiotic, which was a mixture containing B infantis Bb-02, B lactis BB-12, and S thermophilus TH-04. As you can see, the reduction was most marked among the group at highest risk, the most immature babies.
Another publication, this time from a national database, in Sweden, where use is variable, but has been increasing. This study only addresses babies between 28 and <33 weeks, who were recommended, by the Swedish neonatal group to receive probiotics. The received the same preparation as in the Ducth study above.
you can see the dramatic increase in uptake after 2019, to over 70% of this group in 2024. The figures for NEC death and sepsis in this graph are for the entire population, with and without probiotics. When comparing between those 2 groups of babies, who almost all received with maternal or donor breast milk, the results are below, with 3124 babies without probiotics, and over 1500 who received them.
Mortality, NEC and surgical NEC were all strongly associated with probiotic use, and sepsis was unchanged. The combined, competing outcomes of death or NEC (medical or surgical) were also therefore dramatically lower. Death or sepsis was also reduced, because of the reduction in mortality, but this was less clearly significant.
More immature babies in Sweden are eligible for the ongoing PEPS trial, evaluating the same probiotic mixture.
EVC001 is, of course, the name of the strain strain of the B infantis that was used. Although this is retrospective data, it is hard to think of any other reasonable explanation than a causative one. There was a similar decrease in stage 2 and in surgical NEC, and the data remained equally significant when corrected for known risk factors, such as SGA and antenatal steroids. All cause mortality was lower during the probiotic epoch, 4% vs 6.5%, but the confidence limits overlap.
These 3, admittedly observational, studies add the overwhelming evidence of the benefits of probiotic supplementation, and tend to confirm the probable importance of B infantis as a component of that therapy. Not just NEC, but mortality is reduced by probiotic supplementation. An occasional case, of usually mild and easily treatable bacteraemia is surely not a reason to stop probiotic supplementation. It is a reason to continue to investigate the most preferable strain, and combinations with other interventions.
The risk benefit balance is clearly in favour of the routine use of probiotic preparations in the very preterm infant.
Some previous observational data suggested a possible benefit, and the authors also quote a “supportive” animal study, that I think is of highly questionable relevance. In that study newborn mice had systemic dexamethasone during the hyperoxic insult, starting on day 7, and they had less new vessel formation. Other data suggest an inflammatory component to the progression of RoP, which might, therefore, be responsive to local glucocorticoids.
This was the study protocol, all exams were recorded by RetCam and evaluated centrally.
100 babies were randomized 50:50, and they had very similar RoP stages at baseline, dosing was 1 drop per eye every other day for stage 1 or 2 ROP, and 1 drop per eye daily for stage 3 ROP. The primary outcome was progression to “type 1” RoP, that is need for immediate treatment, which could be either laser or antiVEGf injections.
The results showed that 38% of placebo infants, and 20% of dexamethasone-treated progressed to type 1. There appears to be a major error in the labelling of the figure A, as it shows about 65% compared to 37% had type 1.
There was some minor evidence of systemic absorption, with salivary cortisol being lower during treatment, and a possible minor impact on length growth. There was no evidence of intra-ocular hypertension or other adverse local effects.
Although a well-done study, unfortunately there were 7 infants who had invasive treatment despite not satisfying the pre-agreed criteria for therapy. Obviously we don’t know what would have happened to those babies had they been followed without intervention. An analysis of the results without those babies gives a similar relative risk of RoP, of almost exactly 0.5, with 95% CIs of 0.26 and 1.0 (that is my own calculation using Medcalc online, and obviously unadjusted).
The visual abstract accompanying the article is really designed for dummies, it is very stripped down, and includes an infantile cartoon of a retina. Do we really need 2 cartoons of droppers, one filled in in a grey shade and the other white? Surely a visual abstract could be a useful adjunct to an article without being so reductive. That visual abstract states “there was no statistically significant reduction in incidence of type 1 ROP” between groups.
The actual abstract of the article is more reasonable and nuanced “Timely administration of topical dexamethasone numerically reduced the risk of prethreshold ROP progressing to treatment-requiring type 1 ROP. Although the analysis did not reach statistical significance, these findings suggest that topical dexamethasone may be a safe, noninvasive strategy to reduce the need for invasive treatment.”
That is quite appropriate, although the use of the word “may” could apply to almost any intervention. What do we do with these results? Do we need more studies?
I am in 2 minds, I think that if my own baby had pre-threshold RoP and I saw these results, I would be very tempted to ask for the drops. There seems to be a likely benefit, and little risk. But widespread use of dexamethasone eyedrops in large numbers of babies will inevitably lead to more complications, so it would be nice to be somewhat more certain about the benefit. The 95% CI do, just, include the possibility of no effect, the adjusted Odds Ratio is probably between 0.17 and 1.12. Although it would be nice to have more stringently positive data, it might be difficult to convince many parents in a future trial to have the risk of receiving a placebo, and perhaps an increased risk of their infant being subjected to retinal laser ablation. It might, on the other hand, be more reasonable to randomize infants in whom the intervention, in case of progression to Type 1 disease, would be antiVEGf injection.
Laser treatment destroys the peripheral retina and leads to an extremely high incidence of high myopia, avoiding it is a worthwhile outcome. Anti VEGf treatment, in contrast, is relatively benign, despite some stated concerns about systemic effects, it appears to be extremely safe.
The next baby in my practice? I think if a baby has Type 2 disease, then a discussion with the parents and the ophthalmologists will be essential. Despite the evidence not being “iron clad”, the DROPROP regime seems reasonable, especially if the anticipated intervention is laser ablation.
Edit added 13 August.
Ann Hellstrom just sent a comment about this post, which you can read in the comments section. I must say, I had not read all the references in detail, and I didn’t realize that there was another animal study in the reference list which is much more relevant to this intervention. (Yagi H, et al. Timed topical dexamethasone eye drops improve mitochondrial function to prevent severe retinopathy of prematurity. Angiogenesis. 27: 2024. p. 903–17). This publication is a report of a prospective observational study of 5 preterm infants with off-label dexamethasone drops given for type 2 RoP, (all of them were stage 3, zone 2) all of whom regressed. It also reports studies in mouse oxygen-induced retinopathy with local dexamethasone application. The mouse disease has some similarities to human RoP, the immature retina is avascular, and undergoes vasoconstriction during hyperoxia, and when the mice are returned to normoxia, they develop new vessels (at least if you have exactly the right strain of mice!) Of note, the mice are exposed to hyperoxia along with their mothers who are lactating, the mothers sometimes die of hyperoxic lung damage, they usually become sterile, and they sometimes even cannabilise their pups!(Kim CB, et al. Revisiting the mouse model of oxygen-induced retinopathy. Eye Brain. 82016. p. 67–79). I also haven’t seen any evidence that the pups’ retinas develop fibrosis leading to retinal detachment, and there are, in addition, some differences in the vaso-occlusion phase, which is more central in mice, and more peripheral in humans. Nevertheless, that study by Yagi showed that giving the dexa drops to the mice during the avascular phase didn’t do much, and giving them after new vessels started to regress was ineffective. However, there was a significant reduction in neovascularization when given in the middle group, prior to peak new vessel formation.
In addition, I agree with Dr Hellstrom that antiVEGf injections are not completely benign, and shouldn’t be considered banal, but they are much less damaging to the eyes than laser retinal ablation. Avoiding laser with dexa drops is more of an advantage than avoiding antiVEGf treatment, but the long term outcome really needs to be investigated,
As frequent readers of the blog will know, there are major concerns about using the classical dichotomous composite outcomes for trials. One of the outcomes included is usually death, as it “competes” with many other outcomes, and the other components in the composite may range from the extremely important such as ‘NEC requiring surgery’ or ‘profound disability’ to the less important, such as culture-negative sepsis, or oxygen requirement at 36 weeks.
Among the problems with dichotomous composite outcomes are that if different parts of the composite change in different directions, then the overall analysis may be null, which might hide an important benefit, or adverse effect. The best example of this in neonatology is the SUPPORT trial, which showed a reduction in RoP (which was expected) but an increase in mortality (which was a surprise, but has been confirmed by other trials), when babies received oxygen targeting a lower saturation of 85-90% rather than a higher 91-95%. The primary outcome was not different between groups, even though most people would agree that dying is a worse outcome than “threshold retinopathy or retinal surgery or bevacizumab injection” (the definition of severe RoP used).
One way to address these problems is to use Hierarchical Composites, where the various parts of the composite are placed in ascending order of seriousness. The analysis requires either that the patients are entered as pairs, and each is compared to the paired patient in the other group, or, now more commonly, every individual in group 1 is compared to every individual in group 2. For each paired comparison, if one survives and the other dies then the survivor is declared the winner. If both die, then the outcome is a draw. If they both survive, then the second outcome in severity is compared, and a winner (if there is one) is then declared, and so on through the list of outcomes of diminishing importance. Eventually a winner or a draw is determined.
The analysis of such outcomes is still being developed, the simplest, I think, is the “win ratio” (Cunningham JM, et al. Win Ratio Method for Hierarchical Composite Outcomes in Randomized Clinical Trials. JAMA. 2026) that I have written about a few times. There are several examples of trials where the primary analysis of the outcome as being dichotomous has shown a null result, but the analysis using win ratio has been significant, demonstrating a real clinically important difference in the results between 2 interventions, missed by conventional methods. Several trials have more recently been designed to primarily use Win Ratio, or other hierarchical endpoint analyses.
That article by Cunningham discusses the analysis of a recent cardiovascular therapy trial (where these types of endpoints have been most widely used), and points out that the significant difference between results that the trial found (comparing 2 different treatments in Chagas’ disease cardiomyopathy) was not in mortality, or hospitalisation, as you can see from the figure below, but in the results of a blood test, measuring the change in NT-proBNP. The figure shows the number of wins for each group, the number of ties, and the overall difference between groups, which was almost entirely due to changes in the serum marker.
This points out a limitation of this kind of trial analysis, it is important to include items which are of clinical significance, that is, they are of significance to patients. I doubt that many people care too much about the relative changes in their NT-proBNP. Perhaps how far they could walk without being breathless, or something else of importance to the patient, should have been measured.
Our family vacation this year was to Costa Rica. One week just Annie and me, then another 2 weeks with Annie’s mother and 2 of our children. Costa Rica has a well-deserved reputation as a destination for holidays with abundant easy access to wildlife. 30% of Costa Rica is protected land, and vigorous laws have ensured the survival of endangered species, and the return of some that were previously endangered, such as the Costa Rican population of Scarlet Macaws.
There were many great experiences on the trip, hikes and spectacular scenery, as well as other opportunities to photograph the wildlife
Including this Mantled Howler Monkey carrying a baby who was peeking out of mom’s fur.
A tiny Volcano Hummingbird, only found at high altitude along the Talamanca Cordillera.
This Golden-browed Chlorophonia is also restricted to that range.
For those interested, I posted a few other photos on my other blog keithbarrington.com, including this iconic Costa Rican bird, the Resplendent Quetzal
This is still a fairly rare phenomenon in my hospital, but it does seem to increasing slightly here, as it is just about everywhere else.
The science is settled, transplacental transfer of vitamin K is extremely limited, hepatic stores at birth are very low, and human milk contains extremely low concentrations of vitamin K. In later life, most of our vitamin K2 is produced by intestinal microbiota, including by our friends the Bifidobacteria, as well as Bacteroides and Prevotella, but we don’t have many of those present at birth or over the first few days. Routine supplementation with intramuscular vitamin K is an intervention with amazingly positive risk/benefit balance, which has proven its worth over decades. Like many other preventive interventions, the success of routine vitamin K prophylaxis is probably part of the reason for the current situation. In addition, the relative rarity of what is now called Vitamin K Deficiency Bleeding (VKDB, which I think is a better name than Haemorrhagic Disease of the Newborn) means that most families will never have heard of a case.
A new publication from Sweden (Simatou E, et al. Vitamin K Prophylaxis in Newborns and Bleeding in Infancy. JAMA Pediatr 2026) has the usual limitations of all large database studies, uncertainty about the accuracy of each individual data entry, diagnostic standards etc. But it points out that infants (>35 weeks GA) without a record of neonatal IM vitamin K prophylaxis (checkbox left empty) had a much higher rate of having an ICD-10 diagnosis of “any bleeding episode” prior to 6 months of age. They also had a much higher risk of having intracranial bleeding, or the combined outcome “death or bleeding”. When the analysis was restricted to the first 28 days of life the associations were even stronger. The greatest difference between groups with and without IM vitamin K administration documented was in “death or intracranial bleeding” in the 1st 28 days of life: 0.1% in infants with VitK, 1.5% in those without. Of course, most of those deaths would have nothing to do with vitamin K, but they should be equal in the 2 groups. However, when I look at these new Swedish data in detail, there are very many more deaths among the infants without a record of Vitamin K administration: 1300/100,000 compared to those who received vitamin K, 50/100,000, before 28 days of age (calculated by subtracting ICH from “death or ICH”) which I don’t fully understand.
That review article on refusal rates (Loyal et al) also reviewed the published reasons parents gave for not wanting prophylaxis. they broke them into 3 categories. 1. Concern of harm from the injection (from the preservatives or from pain, or because the dose is too high, or it causes cancer). 2. Desire to be natural, often assuming that being “natural” meant that vitamin K insufficiency is not a problem. 3. Belief in alternative prophylaxis, either oral, or maternal or something else.
I just did a quick search on Facebook about Vitamin K in babies, fortunately the very first result (maybe that’s just my algorithm) was from the excellent Jessica Knurick, whose clear evidence-based videos are always spot-on. The remainder range from clear support for the science to fear-mongering nonsense, including one from a prominent physician fear-monger who claims that God wouldn’t make babies short of vitamin K, I don’t know how he explains any congenital anomalies. Other posts frequently talk about how blood should be “thinner” at birth, often stating that vitamin K increases viscosity preventing the good cells from doing their work. Like a lot of medical pseudoscience on the internet, the nonsense is frequently repeated by other “influencers” who are usually selling something, even if its only subscriptions to their channel. They also often claim that physicians are making the vitamin K recommendation because of a personal gain. How we are supposed to be making money from recommending universal IM vitamin K prophylaxis, I don’t know.
One hospital in Tennessee, where there was a cluster of cases, introduced a mandatory information sheet detailing the risks of IM vitamin K refusal, and required signing an opt-out form, which is entered into the infants chart. Intramuscular vitamin K administration should be automatic, and require an opt-out for reluctant parents, whether requiring that parents read a document and sign a form will help, I am unsure. It has been proposed that parents should not even have the right to opt out (Isennock SM. The Legal Limits of Parental Autonomy: Do Parents Have the Right to Refuse Intramuscular Vitamin K for Their Newborn? HCA Healthc J Med. 42023. p. 5–11), as vitamin K is safe and effective and we need to protect newborns against badly informed parents; even though I have a little sympathy for that attitude, I don’t think its likely to get very far.
I am really at a loss to know how to approach the uncertainties of certain parents, the few who are rabidly anti-science, and the many who are just confused and hesitant. Requiring social media companies to reign in the misinformation would be a good idea, but is not likely to get very far with extreme right wing conspiracy theorists being responsible for the most potent communication vehicles that humanity has ever known.
The first step for an individual case of vitamin K refusal has to be to recognise that all parents want the best for their babies, and that most of them will have no idea about the devastating consequences of VKDB. They will not understand the deaths and the brain injuries that can occur, or that they can be almost entirely prevented by a brief painful injection of a vitamin.
Bedside echocardiography has been used to try and define characteristics of the baby and the ductus that might benefit from treatment, but the difficulties in interpretation mean that most of the trials have either just confirmed patency, or have just measured ductus diameter (which isn’t much above the limits of resolution of the devices) as a criterion for entry into the trial.
Studies of the natural history of the PDA in the very immature infant confirm that, sometimes, large diameter PDAs close spontaneously, whereas other PDAs of similar size may have large shunts and tend to remain open. If we could be smarter about this, maybe we could define criteria for a study which would only include those where the shunt is causing problems, the PDA will tend to stay open, and it really is contributing to the adverse outcomes of the baby.
The trial was performed in 4 Canadian and 3 US NICUs with functional echocardiography programs. It only included infants with a GA of <26 weeks. Of note, the trial lasted until day 7 of life. after which open label treatment of control group (or indeed active treatment group) infants was permitted.
Eligibility for the trial required an open PDA, documented prior to 72 hours of age, after which treatment in the active treatment arm followed an algorithm, requiring at least a “moderate” shunt, with “moderate” or severe clinical signs, or a “severe” shunt as defined in the right-hand column below, regardless of clinical status.
This trial was designed and powered as a pilot, with the primary outcome being the feasibility of a future adequately powered trial, feasibility being determined by the following “The proportion of eligible infants recruited during the study period, (2) the proportion of treatment outside of protocol-mandated therapy among randomised infants and (3) the proportion of infants in the control group meeting pre-defined safety criteria.” Sample size was also determined by feasibility considerations and required 100 randomized infants.
The usual clinical outcomes were collected and analyzed using Bayesian methods, and a WinRatio hierarchical composite was constructed (not mentioned in the protocol).
As a moderately sized trial there were some small imbalances in baseline characteristics, more of the controls were 24 weeks or less, more controls had normal antegrade descending aortic flow, etc. but generally speaking the groups were quite balanced.
The feasibility outcomes all demonstrated that a future trial is entirely feasible, with a high recruitment rate, and only 1 control was a protocol violation and was treated to close the PDA before 7 days of age.
In terms of clinical outcomes there were 2 differences that stand out, the most striking being the reduction in pulmonary haemorrhage in the active treatment arm, 0/51 compared to 6/53, 11%; also NEC was 6% compared to 15%.
These data were also analyzed using a Win Ratio approach, with the outcomes of Death, Pulmonary haemorrhage, sepsis, NEC or RoP. If you don’t recall what that means, basically every individual baby in the SMART group was compared with every individual in the CONTROL group, and for each comparison a decision is made whether the SMART group infant is a winner (has better outcomes) or a loser, or if there is a tie. So for example if baby 1SMART and baby 52CONTROL both survive and neither have a pulmonary haemorrhage, but baby 52CONTROL has sepsis and baby 1SMART does not, then baby 1SMART is the winner. Finally you add up all the wins and the losses, and the ratio of wins to losses is calculated. The analysis in this paper then applies a Bayesian approach, which shows that SMART has a higher likelihood of being preferable than control.
This is a much better approach than just “death or complications” as a binary outcome, as it immediately gives survival a higher importance than the other outcomes, unlike “death or BPD” (for example) which gives them equal weight. It does require some partially subjective decisions, for example I would probably put the outcomes in the following decreasing severity order : septic shock, NEC grade 3, NEC grade 2, culture-positive sepsis without shock. Pulmonary haemorrhage, I certainly agree, is a very important complication, especially as defined here, associated with increased oxygen requirements leading to an MAP >12 and an FiO2 >60%. Putting it as the second most important adverse outcome seems reasonable.
Of note, 16 (/53, 30%) control infants had a “predefined safety event”, which seems to be either a severe pulmonary haemorrhage or persistent hypotension, 4 of them received PDA medications before 7 days to treat those events; a further 29 of the control infants received PDA medications after the 7 days, for a total of 64% of the controls receiving treatment. 35% of the SMART group didn’t satisfy the treatment criteria during the 7 day trial period.
This pilot gives adequate justification for a larger trial, it does not, I think, provide strong enough justification for routine implementation of the SMART protocol. The only significant benefit, an important one, was one of many secondary clinical outcomes, the reduction in pulmonary haemorrhage. Other trials of early PDA closure have also shown fewer pulmonary haemorrhages, in particular Martin Kluckow’s trial of early indomethacin (Kluckow M, et al. A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus. Arch Dis Child Fetal Neonatal Ed. 2014;99(2):F99–F104). In that trial of infants <29 weeks GA, echocardiographic screening was much earlier, 3 to 12 hours of age, and infants were eligible for treatment on the basis of simply PDA diameter, and the absence of bidirectional shunting (diameter limits being >1.8 mm at postnatal age 3–5 h, >1.6 mm at post- natal age 6–8 h and >1.3 mm at postnatal age 9–12 h). The study was stopped early because Indomethacin was no longer available. Early pulmonary haemorrhage was much less frequent with early intervention among those with a large PDA, 1/44 va 10/48. But the primary outcomes, for which that trial was designed, were no different between groups.
As you can see from this Forest plot from the latest Cochrane review of early PDA treatment, there is an increase in mortality with very early ibuprofen, overall. Any future trial of very early treatment has to be adequately powered to ensure that there is no increase in death with treatment. This new trial had about 18% mortality in each group, so, to be fairly sure there wasn’t an increase in mortality, of about the amount shown in this SR, (about a 36% increase) with reasonable power (80%), a trial of over 400 patients per group is needed.
The risks of serious pulmonary haemorrhage start quite soon after birth, and I understand the logistical problems with randomizing and enrolling infants after a qualifying echocardiogram before the 72 hour limit in SMART-PDA. But to have the most benefit in reducing pulmonary haemorrhage, randomization before 36 hours would be preferable. It is easy for me to say that, as I don’t do functional echocardiography, so I wouldn’t be on the call schedule for urgent echos over the weekend!
This high quality pilot trial points the way to designing a definitive trial of smarter treatment of the PDA in extremely immature infants. Early screening, eligibility based on criteria which show a large shunt and which predict persistent patency of the PDA seems to be the way to go to answer some of the many questions that remain.
Neonatal Opioid Withdrawal is a major public health problem in the world. Large numbers of infants born after fetal exposure to opioids experience unpleasant symptoms, requiring non-pharmacologic and pharmacologic intervention.
Studies of different approaches for symptom control have the potential to improve outcomes for this fragile population.
To go back in the history a bit, the Finnegan scale was developed as a research tool, it is fairly cumbersome, with 21 items, several of which are rather subjective, and some are frequent in babies without opioid exposure. The threshold for treatment, of a score of 8, was entirely arbitrary, and has never been adequately tested or compared to other thresholds. It was developed in 1975, when the standards now required for development of such tools were not in place.
A big advance in the management of NOWS was the development of a different system; the ESC system, rather than being a “score” is a method of evaluation of an infants ability to function normally . Babies are assessed on their ability to breastfeed successfully, or eat at least 30 mL per feed, to sleep uninterrupted for at least 1 h, and to be consoled within 10 min. If any of these conditions are not met, non-pharmacological soothing methods are instituted, and eventually medications may be introduced. Rather than regular timed Finnegan scoring, the ESC system is a continuous longitudinal evaluation allowing intervention as soon as an infant is unconsolable, or feeds poorly, or has sleep interruption.
Infants managed with ESC have much lower opioid exposure in the neonatal period, and nevertheless have no increase in adverse outcomes in the short or medium term.
One of the questions about the ESC approach was exactly when drug therapy is indicated, and how to manage it. This RCT compared 2 different approaches, shown diagrammatically below. This was a cluster randomized trial, with individual centres being the clusters, they were randomized to start with the symptom-based dosing approach to pharmacologic therapy, and then switch after 5 months to the scheduled opioid taper approach for a second 5-month period; or to commence with approach B and then switch to approach A.
As you can see the initial evaluation and intervention is the same in both groups. In the standard tapering, “B”, group, once the infant had symptoms which breached the threshold for pharmacologic treatment, they were immediately started on regular drug dosing, which was then adjusted and weaned progressively. In the A group, the symptom-based dosing group, an infant who was over the treatment threshold would receive a single dose of whichever was the hospitals usual approach for such an infant (morphine, buprenorphine or methadone) and then, if their symptoms improved, they would go back to monitoring without routine repeated doses. If they needed more than 2 consecutive doses at either 2, 3 or 4 hour intervals, they were started on regular dosing and then weaned after they were stabilised.
At least I think that was the protocol, because the figure has a note which states “Infants were eligible if they received less than 3 doses in the preceding 24-hour period and fewer than 2 consecutive short-interval doses” But fewer than 2 means 1, and I don’t know how you can have 1 consecutive dose? Similarly less than 3 doses means either 1 or 2 doses, which is actually not what is in the protocol.
The protocol, attached as a supplement, states that the infants were allowed up to 3 doses (not less than 3) in a 24 hour period, and if they needed a 4th dose, then they switched to regular dosing and weaning. The precise wording in the protocol is “if a 4th dose is required within any 24 hour period, the study site will move to scheduled opioid treatment per the algorithm used at the study site…”.
I think the note by the figure should say “less than or equal to 3 doses in the preceding 24-hour period, and less than or equal to 2 consecutive short-interval doses”. That would be then consistent with the text of the article which states “Each time the threshold for treatment was met, an as-needed dose was given as long as the infant had not already received 3 opioid doses in the preceding 24-hour period or 2 consecutive short-interval doses”.
In other words, I think what that means is that if an infant was not eating, or sleeping, or consolable, they would receive a dose of morphine (or an alternative). If 2 hours later they were still in that state, they would receive another morphine dose; but if they needed another one 2 hours later they were started on regular morphine, with a progressive wean once the symptoms were under control.
The primary outcome for the trial was the time until medical readiness for discharge, which meant more than 96 hours of age and more than 48 hours since the last opioid dose, or when the medical provider discharged them, whichever was first. This primary was only used for the babies cared for with the ESC approach, which was used in 15 hospitals, with 8 using the Finnegan score.
This is my first question “why on earth would any centre still be using the Finnegan for term babies with NOWS?” Especially a centre with enough babies, and enough academic interest, to get involved with this trial? None of the reviews I have read, or the studies that have been performed, show any advantage to the Finnegan based system. Infants treated using the Finnegan system receive more opioids, and stay in hospital much longer, with no decrease in adverse outcomes.
In the ESC centres there were a total of around 190 infants treated by each approach. The length of hospitalisation was 2.5 days shorter in the symptom-based group. The same proportion of infants received at least one dose of medication (40% in each group), but, among that subgroup, the number of doses was much less, duration of opioid treatment was 3 days shorter, and many fewer received secondary medications (which could be either phenobarbital or clonidine)
The results in the Finnegan hospitals confirm the much longer hospitalisation with the out-dated approach, the Symptom-based approach led to 1.5 days shorter hospitalisation, but stay was more variable, and the difference may have just been a random effect.
Just getting these babies home (or at least discharged from hospital) earlier isn’t, of course, the only important outcome. Safety outcomes were similar between groups, with the rare primary, critical safety adverse outcomes occurring only in the scheduled taper group, n=3, not significant. Hospital re-admissions and ER visits were also similar, but numerically less frequent in the symptom-based group.
This seems to me to be another major step forward in treatment of this condition. Infants with NOWS should clearly be managed with the ESC approach, and if they cannot E or S or C, then intermittent opioid dosing can be used without immediately starting a regular regime.
I don’t understand why phenobarbital is still being used as a secondary medication, it has numerous secondary effects, and even the sedation is short lived, with longer treatment leading to hyperactivity. Clonidine makes much more sense. I don’t know if we even need an RCT of phenobarbital, as its use doesn’t seem to have a rational basis. But trials of the appropriate threshold for introduction of clonidine could be valuable.
Pineda R, et al. Language and sound exposure across neonatal intensive care hospitalization and relationships with early outcome. J Perinatol 2026. In this short term outcome study, 64 very preterm infants <29 weeks GA were evaluated at near-term age with the Neonatal Neurobehavioural Score (NNNS). They had previously had a recording of the ambient noise for 4 separate 16 hour periods during their NICU stay, which was analysed to determine the exposure to any noise, including electronic sounds (which I guess means alarms, and monitors beeping), or meaningful language or distant voices.
The NNNS scores on the multiple various scales are shown below, with the “Comparator Value” being the average scores of full term infants, with the SD.
The statistically significant correlations with sound exposure and NNNS scores are shown below
Exposure to speech was associated with less stress, exposure to louder noise with more hypertonia, and so on.
In terms of statistics, this might be a bit questionable, as there were 5 sound characteristics and 13 different scales compared, leading to 65 possible associations, and a high risk of a type 1 error Nevertheless, the importance of human voices and the adverse impact of electronic sounds, especially loud sounds is consistent with everything else we know.
Take Home Message : Please get your parents, and everyone else, to talk calmly to the babies, and reduce as far as possible background noise and electronic sounds. Supplying books to parents, so that they can read to their infants while in kangaroo care, rather than scrolling on their phones, can only be a good thing.
In this multicentre observational study, infants with uncomplicated CoNS sepsis were compared between those with >96 hours of antibiotics. Cases were defined by “Presence of clinical signs of infection more than 72 hours after birth, a positive blood culture showing CoNS, and an increased C-reactive protein (CRP) level >10 mg/L within 24–36 hours after the onset of sepsis” and uncomplicated sepsis meant “clinical recovery within 24–48 hours, no central venous line in place or removed after the onset of sepsis, no signs of necrotizing enterocolitis or infected thrombus, and no Staphylococcus lugdunensis bacteremia”. (Apparently S. lugdunensis is particularly virulent). Most were treated initially with flucloxacillin and an aminoglycoside.
The primary outcome was the incidence of relapse of infection, and it was performed as a non-inferiority retrospective observational study.
There was one relapse in the short treatment group of 172 infants, and 0/218 in the long treatment group; short treatment satisfied the non-inferiority criterion.
Take Home Message : 4 days of adequate antibiotic treatment might well be enough for uncomplicated CoNS sepsis.
In the PREMOD2 trial, of delayed clamping vs cord milking for preterm infants at birth, some centres allowed waiver of consent and others did not. This study examines the differences in patient characteristics and the impact of the trial intervention between those 2 groups of centres.
When the study was designed and started, there was no evidence that one approach was preferable to the other, and some centres were doing DCC, others cord milking. If you remember, the trial found an increase in severe IVH with cord milking, leading to premature termination of the trial. There were 475 babies in total in the trial, 99 of them in hospitals that required pre-randomisation consent, the remainder in hospitals allowing waivers. “At hospitals permitting initial waiver, 3% of parents who were approached after the delivery intervention declined postnatal consent for data collection. At hospitals without initial waiver, 75% of deliveries were approached for participation. Among those approached, 49% of parents declined consent (range 39–61%)”.
In hospitals with a waiver, enrolled infants were more likely exposed to maternal chorioamnionitis (35% vs. 22%), less likely to have complete antenatal steroids (75% vs. 85%), and less likely to have received antenatal MgSO4 (79% vs 97%) compared to the others. Antenatal steroids and chorioamnionitis impacted the risk of having a severe IVH, mostly in the Cord Milking (UCM) group.
As you can see, in the cord milking group, antenatal steroids reduced the risk of severe IVH to 7%, compared to 14% without completed antenatal steroids, and Chorioamnionitis increased the risk from 3% to 22%.
Not having a waiver of consent therefore impacted the apparent difference between UCM and DCC, with waiver centres showing a decrease, and non-waiver centres showing no difference. This is probably because of the different risk profile among babies born in the different groups.
Our results highlight the importance of methods to enroll representative samples of the populations, to whom the studied interventions will ultimately be applied. Infants born to mothers that can be approached antenatally may have different comorbidities and co- treatments than the infants for whom the evidence will ultimately be applied… Relevant regulatory frameworks in countries including the USA and Australia have been previously described to support ethically appropriate modifications of the consent process for research on the safety and efficacy of common delivery room interventions. Based on the experience of PREMOD2, such methods may prevent false reassurances about safety or efficacy when unwarranted
There are previous data which confirm that parents questioned after the fact were supportive of this kind of waiver of consent. Even though 50% of those approached prospectively (in this trial) refused consent. I think that says something about how difficult it is in the midst of the stress of a threatened preterm delivery to explain comparative trials of differing approaches in common clinical use, which are both considered acceptable interventions.
Take Home Message : Waivers of consent, when ethically appropriate, allow randomization of subjects that more closely reflect the entire population. They may reveal effects of interventions which would otherwise be missed.
