Badly performed, badly presented, unethical published research; what to do?

Posted on 29 October 2024 by Keith Barrington

Since at least 2013 the World Medical Association Declaration of Helsinki has mandated registration of clinical trials prior to enrolment of the first subject. Since 2005 the International Committee of Medical Journal Editors has required trial registration as a condition of publication, before the onset of patient enrolment.

This principle is reiterated in the new version of the declaration of Helsinki, just published and discussed in many places, including JAMA.

Nonetheless, retrospectively registered trials are still being accepted by journals, most of whom should know better, as well as publications with no mention of registration at all. It has been a recurrent problem in some neonatal studies, and some large recent neonatal trials were retrospectively registered after being completed, and after all the data were collected. The fact that prominent journals will still sometimes accept such research gives the publications a credibility which is not deserved.

This has a significant impact on how we analyse the literature and make therapeutic decisions. To take one example, the use of Erythropoietin in preterm infants. Let’s analyse the literature to determine if Epo prophylaxis decreases NEC, a major health issue in these babies. A recent high-quality systematic review was published by Ananthan et al, Ananthan A, et al. Early erythropoietin for preventing necrotizing enterocolitis in preterm neonates – an updated meta-analysis. Eur J Pediatr. 2022;181(5):1821-33. This SR found 22 studies with over 5000 patients enrolled, and a clinically significant reduction in “definite” NEC, RR 0.77 0.61-0.98. However, of the 4 largest trials in that review 2 were registered after completion of enrolment (Song 2016, n=743, Wang 2020, n=1285), one was registered in 2006, shortly after the first patients were enrolled in 2005 but prior to completion (Natalucci 2016, n=365) and one was registered prospectively (Juul 2020, n=936). If we re-analyze the data excluding the retrospectively registered data, and the older non-registered trials, the effect of Epo on NEC no longer reaches classical statistical significance

It does still look like there might be an effect, doesn’t it? Adding Natalucci back in (the absolute requirement for prior registration dates to around the time the study was started, so it is much less of an issue) makes little difference, as they had only 3 cases with Epo and 4 in the controls. Which points out how desperately important this is. Are we failing to provide an effective therapy for our babies? Are we at risk of dosing thousands of babies with a prophylactic intervention which is ineffective?

One characteristic of many of these retrospectively registered trials is they are not published in the typical neonatal/pediatric literature, Wang 2020, for example was published in the Journal of Translation Research. Song 2016 was published in Annals of Neurology, which claims to follow the ICMJE guidelines and the declaration of Helsinki, but clearly failed to do so for this article.

I’m not sure what to do about this on-going problem. If it was bench research we could just refuse to publish, but when babies have been subjected to research procedures and parents to the stress of having a baby in an NICU and in a trial, it seems unfair to those research subjects to categorically refuse to publish. But, unless there is some sort of sanction, this will continue, and indeed it does continue. Perhaps there should be a separate journal: “The Journal of Unregistered Research”, or a separate section in some journals: “Unreliable Information”. We can’t ascribe ignorance to the authors, Song et al, who retrospectively registered the first trial in 2016 are the same authors as Wang et al, who retrospectively registered that later trial in 2020! There are numerous other problems with these 2 projects, they were unmasked trials but the controls still received placebo injections, why on earth would you do that?

The importance of trial registration is discussed in many different places, including by the WHO, one thing that the WHO don’t discuss, but which is vitally important, is that prior trial registration makes it clear if primary outcomes have been changed, or if outcome definitions have been “adjusted”. Even better is full publication of the trial protocol, in addition to registration, which makes those things even clearer, and less liable to fudging the results.

The problem is not, it seems, going away. Which may, in part, be because of the proliferation of biomedical journals, some of which have very loose standards it seems. The journal “Biotechnology and Genetic Engineering Reviews” of the Taylor and Francis group, has just published what appears to be a clinical trial of caffeine in preterm infants. (I won’t add to the hit count of the journal by providing a direct link, but the article is listed on PubMed if you want to read the abstract: Jiang Q, Wu X. Effect of early preventive use of caffeine citrate on prevention together with treatment of BPD within premature infants and its influence on inflammatory factors. Biotechnol Genet Eng Rev. 2024;40(3):2730-44). A clinical trial in newborn infants is way outside of the apparent aims of the journal, which you can read on the website. I wonder if the journal was picked at random, or because it was known to have lax editorial standards, and/or if the article was refused in other places first. None of the named editorial board members has a medical background, (it also takes on average 209 days from submission to first decision, so stay away!) As it is not a medical journal, there is no mention of the ICMJE in the descriptions I found. It is an open-access, pay to publish journal, maybe it was cheaper than other alternatives.

Not only is this the wrong place to have published this article, it is written in very bizarre English, and has very questionable features to its design. Infants were “chosen and segregated within control and observation groups through random number table protocol” which led to two groups with “no significant difference in perioperative data” and then received caffeine by “intravenous pumping” or saline.

According to the methods, apparently “Doctors and nurses should show enough patience and love in the face of children, speak gently, smile and communicate with children, try to calm the children’s mood, so that the treatment can proceed smoothly”. Who can disagree with that?!

There is no mention of ethical review board approval.

The study was apparently performed without any funding, even though there was blood work, lab analyses, respiratory mechanics equipment and procedures, and repeated neurodevelopment testing. Several inflammatory markers (MMP-9, TNF-alpha, TLR-4) were measured prior to and after therapy. TLR-4 is of course a transmembrane receptor, so I have no idea if measuring circulating concentrations is of any interest, and the results they report are 10 fold higher than any others I have found in the literature. Also it required multiple blood samples, with the pain involved.

The authors give data for respiratory mechanics, which are almost certainly fictional, as they describe no methodology for measuring mechanics (resistance, compliance and work of breathing), which is extremely difficult in any case in spontaneously breathing newborn infants. The company that they claim made the equipment they used for lung mechanics lists no such equipment on their website.

Even more bizarrely, they report the neurodevelopment of the babies which was “evaluated by Child Development Center of China (CDCC), including Psychomotor development index (PDI) and Mental development index (MDI), with scorings ranging across 0–100 points for each part”. They give results at baseline before treatment as well as after treatment (age not specified). No actual results are given, just a p-value claiming that the caffeine group had better MDI and PDI after therapy, but not the controls. The figure of these results, figure 3, is actually the same as the figure for growth, figure 4, and shows length, head circumference and weight gain.

The desperately bad research described here makes me hope it is actually a work of fantasy, as the idea of subjecting real babies to such an awful protocol horrifies me.

A huge concern is how an apparently legitimate publisher and the editorial board of this journal can allow this garbage to pollute the medical literature. I have written to the company, Taylor and Francis, (there is apparently not currently a chief editor of the journal) and left a comment on PubPeer. If any of my gentle readers have a link with Taylor and Francis, maybe you could try to trigger a response, and hopefully a retraction, before these data get incorporated into Systematic Reviews.

I started writing this post because I wanted to discuss the new version of the Declaration of Helsinki. You will have to wait for the next issue!

Posted in Neonatal Research | Tagged , , , | 4 Comments

Too much antibiotics, part 2

Posted on 28 October 2024 by Keith Barrington

The multicentre project, that I started the last post with, has just published a new important article, which addresses the duration of antibiotic treatment (Dimopoulou V, et al. Antibiotic exposure for culture-negative early-onset sepsis in late-preterm and term newborns: an international study. Pediatr Res. 2024) and is particularly focused on those babies with negative blood and/or CSF cultures. They divided the babies who received antibiotics without ever having a positive culture into those which were treated for less than 5 days, or for at least 5 days.

I think that 4 days of treatment, for a well baby with risk factors who has negative cultures, is already far too long, the optimal duration for such a baby would be 0 days! But, given that there was enough concern to perform a blood culture, then antibiotics can be stopped after 36 hours, with only a tiny possibility that a true-positive blood culture will become positive after 48 hours, and then very rarely for organisms treated with our usual empiric antibiotics.

But what about those babies who are thought to have “culture-negative sepsis”? In this new study, babies treated with antibiotics for 5 days or more, one extant definition among many, were 20 times more frequent than true EOS. There were 8000 babies with negative cultures who received treatment for >4 days, compared to 375 with a proven EOS.

What are we treating, when we continue antibiotics despite negative cultures? I well remember some twins (more than 1 pair) where one twin was sick with sepsis and positive cultures, and the other was similarly sick, but with negative cultures. To me, those cases have been the best proof that culture-negative sepsis does indeed exist. But what is it? Many such infants do not have an active bacterial infection. Many have circulatory and respiratory illness caused by the inflammatory cascade following a bacterial infection. Some cytokines have been shown to cross the placenta, such as IL6, for example, so the infant could become passively ill as a result. In other cases the infection may already have been effectively treated, such as when a mother had chorioamnionitis, and has received antibiotics. In such a case the infant is affected by the cytokines and other inflammatory mediators released by the mother or by the infant themselves. In the example I gave at the beginning of this paragraph it may be that a truly infected co-twin sets up enough of an inflammatory response that their sibling is symptomatic.

In such an infant, blood cultures will be negative, but also they will not benefit from antibiotics. The sensitivity of current culture techniques are such that, down to about 1 CFU/m, over 98% of cultures are positive, and any concentration of bugs higher than this will rapidly make the culture machine alarm ring.

For a more complete discussion of the issues in “culture-negative sepsis” you could do no better than to read Joseph Cantey’s article from the Journal of Pediatrics in 2022. I can’t tell if it is open access, but if you have difficulty getting it, I am sure we could find a way to get a copy to you.

I mentioned, in the part 1 post, another recent publication, with probably some overlap in the data, from a national Swedish database (Gyllensvard J, et al. Antibiotic Use in Late Preterm and Full-Term Newborns. JAMA Netw Open. 2024;7(3):e243362). In that publication the incidence of EOS had fallen over time up to 2020, and treatment of culture negative infants had decreased also, but the gap had actually widened. Also, in that study, the median duration of antibiotic treatment among all infants with negative cultures was 5 days, IQR 3-8 d, 97% of infants who received antibiotics had negative cultures. It is clear that not all infants who have a culture taken and are started on antibiotics have sepsis, culture-positive or -negative. Although there do not appear to be national Swedish guidelines for when to screen for and treat neonatal sepsis, there are guidelines about when to stop them (again translated by Microsoft Word)

Full-term child with suspected early onset sepsis (illness before 72h): discontinue antibiotics after 48-72h and do not diagnose as neonatal infection:
• Never required ventilator care or had septic shock
• Mother not diagnosed with obstetric infection
• Blood culture negative, growth of contamination or not yet responded to
• Well-being at 48-72h age
• CRP peaks below 60 mg/L, and CRP decreases during antibiotic withdrawal
• CRP peak between 60-100 mg/L, and CRP in decreasing consider discontinuing antibiotics

The way I understand it, you need all of those in order to stop the antibiotics; thus, ongoing treatment of increased CRP concentration without other signs of infection is recommended by this guide, a practice which has no evidence-base, and leads to major over-treatment of uninfected babies. Previous publications have shown that you can stop measuring CRP, and routine CBCs, without any adverse impact, only a reduction in unnecessary antibiotics. Although the Swedes are doing much better than most of us in reducing the number of antibiotic courses administered, they are still treating 50 babies with antibiotics for every truly infected infant, and as noted, they treat for a median of 5 days. If they just stopped doing CRPs, but still used the other criteria in that national standard, they could do even better, and there is no evidence that there would be any risk involved. It is well known that CRP concentrations increase several hours after the initiation of inflammation, so they are usually ignored if they are low during the initial sepsis evaluation. They also increase easily and are very non-specific, so they should also be ignored in later analysis of whether an infant has “culture-negative sepsis” or not.

There has been a lot of woolly thinking about this. Infants are defined as having “culture-negative sepsis” if they are treated with 5 days or more of antibiotics. Studies have then shown that infants with “culture-negative sepsis” have higher CRP concentrations, and this is published as evidence that CRP concentrations are useful in the diagnosis of the phenomenon. But, it is often the high CRP which leads to the prolonged antibiotic use. Circular reasoning anyone?

One early study of the neonatal use of CRP, for example, showed that 9% of the babies who were considered “definitely not infected” had raised CRP. Infants delivered vaginally have higher CRP than those delivered by Cesarean, especially CS without labour. Infants with a final diagnosis of TTN have higher CRP, as do those with Meconium Aspiration, who are often treated with prolonged antibiotics in the absence of other risk factors for sepsis. In part, this is probably because CRP increases to a mean of over 40 at 48 h in such babies, despite negative cultures and no evidence of any benefit from antibiotic use.

As this figure from the new article shows, the babies who clearly do need antibiotics, in red, are vastly outnumbered by the others, both the group with <5 days antibiotics, and those with 5 or more days. And there is enormous variation between networks.

Routine stopping orders for antibiotics after 36 hours, and requiring a conscious decision to continue if cultures are negative, could immediately have a big impact on exposure. A re-evaluation of each case, and a thoughtful answer to the questions “does this baby really have “culture-negative” sepsis?” and, “is this baby likely to benefit from continued antibiotic therapy?”, which are linked but not identical questions, could further reduce the unnecessary overuse of antibiotics. It would help to preserve their usefulness for the future, as well as reducing adverse impacts on that individual.

Posted in Neonatal Research | Tagged , | 3 Comments

Too much antibiotics, part 1.

Posted on 25 October 2024 by Keith Barrington

An important multi-centre observational study examines how many newborn infants, term or late-preterm are receiving antibiotics, for how long, and the responses to negative cultures. Centres from Europe, Australia and North America are represented. Data collection differs between the participants which are all regional networks (or in the case of Norway, national), but all provided data on babies who received antibiotics for any reason within the first week of life.

The first publication from the study (Giannoni E, et al. Analysis of Antibiotic Exposure and Early-Onset Neonatal Sepsis in Europe, North America, and Australia. JAMA Netw Open. 2022;5(11):e2243691) showed that 2.86% of the babies in the networks (total births over 750,000) received antibiotics, but the variability was enormous between networks, from 1.18% to over 12%.

The overall incidence of culture positive sepsis was less than 0.05%, if the coagulase negative staph are eliminated (they were not automatically considered to be contaminants in this study, but I think it is very rare that EOS in term and late preterm infants is really caused by CoNS) the incidence was 0.041%.

One thing I really appreciated in this publication is the openness of the investigators to identify themselves. As you can see below, the centre with the highest exposure of babies to antibiotics was Perth. As you can also see, from panel B, they, and Rhode Island, are the sites with the shortest duration of treatment of culture negative babies. As you can also see, panel D, Perth dramatically reduced antibiotic exposure between 2014 to 2018.

Figure 3 in that publication shows a vague correlation between actual sepsis incidence and antibiotic use. In the supplement there is a version without CoNS

I find it hard to believe that individual decision making about sepsis evaluations and antibiotic treatment are affected by a difference in true EOS rate between just over 1 per 1000 compared to 0.3 per 1000. But, perhaps, the local choice of which guidelines to follow is affected by sepsis rates?

In terms of the consequences of sepsis, EOS mortality was very low, at 3.2% of the true EOS cases, or 12 deaths among 750,000 babies. As you can see from the figures, Stockholm county has an average incidence of EOS, but consistently has the lowest rate of antibiotic treatment. They do this, it appears, by not using the Kaiser Permanente sepsis calculator. That calculator has reduced antibiotic use in centres where it has been introduced, but the lowest antibiotic use reported after introduction of the sepsis calculator is 3%. In Stockholm the rate is less than half of that. How do they do it, without an increase in sepsis mortality? As far as I can tell, there are no published guidelines in Sweden regarding when to screen and/or treat the term and late preterm infant for sepsis. I downloaded and translated the national recommendations, but they only discuss the antibiotics available, the importance of blood cultures, a statement that culture negative sepsis is a possibility, and a vague discussion of epidemiology. This is the automated translation (Microsoft Word) of the section about screening and diagnosis:

Underdiagnosis of severe neonatal infection can quickly lead to a worsening situation of septic shock and even death, while overdiagnosis can lead to unnecessary antibiotic use. Fatigue, poor skin color, episodes of apnea, and bradycardia are common symptoms of sepsis.

Using hands, eyes, ears and stethoscopes to examine the patient and interpret these symptoms is and remains the basis of all diagnostics. In addition to this, the doctor has a number of diagnostic methods available, each with its different strengths and weaknesses (Table III). There is currently no method that has optimal speed, sensitivity and specificity. CRP is the most commonly used diagnostic test.

Another recent publication of national data from Sweden, which includes over 1 million babies and extends until 2020, shows a continuing low frequency of antibiotic exposure, with a decreasing incidence of EOS. Again, in that publication there is no mention of any general guidelines for when to screen and treat for suspected sepsis.

Other jurisdictions have adopted the “Serial Physical Examination” approach, but the details of such an approach vary, it generally requires hourly structured physical examination by a nurse, following a written and agreed protocol, of at-risk infants. This article from Stavanger, Norway, for example, (Vatne A, et al. Reduced Antibiotic Exposure by Serial Physical Examinations in Term Neonates at Risk of Early-onset Sepsis. Pediatr Infect Dis J. 2020;39(5):438-43) is rather vague on which infants qualified as “at-risk”; it seems to be any infants born after chorioamnionitis (undefined) or with a previous sibling with GBS, and “neonates who during the first 72 hours of life developed clinical symptoms indicating a possible sepsis”. All such babies were admitted to the NICU for an hourly structured physical exam.

we accepted mild symptoms (heart rate >160/min, grunting or respiratory rate >60/min, poor feeding and decreased activity) of <2–4 hours duration. We only started antibiotics if these mild symptoms persisted (>2–4 hours) despite corrective actions, if additional alarming symptoms occurred (Table 1) or if the neonate became clinically ill as judged by the attending neonatologist.

This is the Table 1 referred to:

That study was limited to babies of at least 37 weeks, and was able to decrease antibiotic exposure from about 3% to about 1.3%; the incidence of “culture-negative sepsis” also declined dramatically, but remained, supposedly, 50 times more frequent than culture-positive sepsis.

One factor which has probably reduced the incidence of “culture-negative sepsis” is the reduction in CRP measurements! As you will see in part 2, many babies receive prolonged antibiotics to treat their CRPs.

Antibiotic treatment rates much lower than those which follow use of the current EOS calculators can be achieved without any increase in sepsis mortality. Of course the consequences of EOS are not just mortality, untreated, or late-treated EOS may lead to more severe acute illness and long term disability. Such outcomes are very difficult to capture in studies such as these, all-cause mortality is one outcome to be followed, in case babies present with severe illness not recognized as being sepsis, and, in these studies, lower antibiotic use is not associated with increased all-cause mortality.

Decreasing antibiotic exposure in uninfected infants is an issue which is important individually, as it leads to major disturbances of the intestinal microbiome, which are very prolonged, pain caused by IV access, cost, interference with parent-infant interaction, vulnerable child syndrome, and perhaps long term health impacts such as obesity, allergic predisposition, asthma, diabetes, juvenile idiopathic arthritis, celiac and inflammatory bowel disease. To the health care system as a whole, the exposure of a significant proportion of the population to antibiotics must contribute to antibiotic resistance.

Posted in Neonatal Research | Tagged , , | 2 Comments

Does preterm formula cause NEC?

Posted on 23 October 2024 by Keith Barrington

The question in the title was recently adjudicated in US courtrooms, with an enormous award of damages to the family of a premature infant who developed Necrotising Enterocolitis, and survived, but has, apparently, major neurodevelopmental issues. In July, the jury awarded the infant’s mother $95 million in compensatory damages and another $400 million in punitive damages against Abbott who produce the preterm formula that the baby had received. A previous case against Mead-Johnson (the only other preterm formula producing company in the US) was also decided against that company in favour of a family whose baby died of NEC, they were awarded $60 million. As far as I can tell, the basis for the awards is that the companies failed to warn the families of the risks of their formulas. I don’t know how the companies are supposed to warn the families, or how neonatal programs across the USA are responding to this situation, but there are apparently hundreds of other lawsuits that have been, or are in the process of being, launched.

I just did a Google search for Necrotizing Enterocolitis, lawsuit, and breast milk, 15 of the first 16 results were web pages of US law firms touting for business, some of them being hidden as pretend legal news sites. The sites rapidly open active chat windows, trying to get you to communicate with them to find out how much money you could win. The other one was a real US news station.

No company could possibly run the risk that each baby who receives their formula and then develops NEC will cost them millions of dollars. There is a real chance that the 2 companies that currently make artificial formula for preterm infants will pull out of the market, and what then?

There are also apparently parents in NICUs (in the USA) currently who are refusing preterm formula, as they have heard about these lawsuits, or have heard from lawyers that preterm formulas are dangerous, and cause NEC. Fortunately, this has not yet arrived in Canada, but such things have a tendency to osmotically pass through the semi-permeable membrane which is the longest border in the world separating us from the madness.

Without the preterm formulas, when feeding preterms with artificial formula we would have to return to supplementing term formula with additional protein, calories (probably mostly fat) and minerals (especially phosphorus, but also calcium and others). With no reason to think that this would be preferable in terms of NEC risk, indeed almost certainly this would not reduce NEC, but would introduce other risks: of errors, of contamination, or of excessive osmolarity.

The courts are clearly not the best place to determine scientific causality. So what does the science say? There are no RCTs comparing mother’s own milk (MoM) to artificial formula, for reasons which I hope are obvious, nor are there any trials comparing MoM to donor human milk (DHM) for the same reasons.

There appear to be 12 RCTs which have compared artificial formulas, all of those tested being based on cows’ milk, to DHM for preterm infants. As the most recent Cochrane review notes, there are multiple differences between the trials

The 4 oldest trials, published 1976 to 1983 used standard term formula, and only one of them (Gross 1983) reported NEC, which was nearly 5 times more frequent with term formula than with DHM! However, the trial was small and the numbers with NEC were tiny; so the difference in incidence of NEC, 3/26 babies receiving term formula compared to only 1/41 who got DHM, is not statistically significant (RR 4.73 95%CI 0.52-43.09). I don’t think statistical significance matters to law courts, however, so maybe that finding could be used in court to show that term formula is associated with the same risks of NEC as preterm formula.

In some ways, this is a philosophical question of the meaning of causation. NEC is more common in very preterm babies receiving artificial formula than in those receiving MoM, with an intermediate risk with DHM. Does that mean that MoM is protective, or does this mean that DHM causes NEC? And that formula is even more dangerous?

Or does it mean that the pathogenesis of NEC is very complex, that there are some components of human milk that are protective, and that there is an advantage of MoM over DHM. The advantage of MoM over DHM is, I think, in part because it is not pasteurized, and perhaps also because there are some differences in the composition of the milk of mothers who deliver preterm. Also, babies getting MoM are more likely to get maternal colostrum, which is not available from milk banks, and may be especially protective, perhaps maternal colostrum is part of the explanation why babies receiving MoM have lower NEC rates than DHM.

Preterm milk composition differences from term milk, which is the majority of what is supplied by almost all milk banks in the world, include higher concentrations of protein and some minerals. There is also probably some impact of PT birth on the oligosaccharide composition of milk (Human Milk Oligosaccharides HMOs). Bifidobacteria and Lactobacilli are present in most unpasteurized human milk, and are able to metabolise HMOs, which humans are not able to digest. Preterm milk has higher concentrations of HMOs, but they apparently are less diverse. I have previously posted about the potential role of DSLNT Di-Sialyl-Lacto-N-Tetraose (a specifically human HMO), which has now been shown in 4 studies to be present in lower concentrations in the breast milk of mothers whose babies develop NEC despite receiving MoM, Autran, Hassinger, Masi, Van Niekerk. It also protects against NEC in Lars Bode’s rat model. Apparently it is difficult to synthesize, but hopefully we will eventually get trials to see if NEC can be prevented by adding DSLNT to MoM, DHM or preterm formula.

This graphic is from a recent Chinese study (Zhang W, et al. Causative role of mast cell and mast cell-regulatory function of disialyllacto-N-tetraose in necrotizing enterocolitis. Int Immunopharmacol. 2021;96:107597), which examined the role of DSLNT in a rat model of NEC, which reproduced the protective effect in rats. It also showed that human intestinal specimens from NEC resections demonstrated Mast Cell activation compared to specimens without NEC, and also that an enzyme (chymase) produced by Mast Cells caused epithelial loss; and that in a human foreskin cell model DSLNT protected against this. Which is apparently a new potential mechanism for the beneficial effects of DSLNT.

In the current climate I cannot imagine any business putting money into trying to develop a preterm formula with DSLNT to try to reduce NEC risks, however. I suppose it will be up to public funding agencies to do so, and then hopefully for public organisations to profit, if it can be shown to be protective.

For the present, all very preterm babies at increased risk of NEC should have access to DHM when mother is unable or does not wish to provide enough MoM, which means all babies born at less than 33 weeks. From 33 weeks onward, the risk of NEC appears to be, currently, very close to the baseline risk in term babies, although very good recent data are difficult to find.

All of the discussion in this post has made some very questionable assumptions, which include (1. that NEC can be diagnosed reliably, and (2. that NEC is a single disease in the very preterm. I know that neither point #1, nor point #2 are actually reliably true. But I also know that NEC can be a devastating disease, with a high mortality and long term consequences, despite these considerations.

NEC in full term infants, including those with cardiac malformations, post-asphyxia, and after gastroschisis repair, is probably even more pathophysiologically variable, and not clearly impacted by breast milk use. Among late preterm infants the protective impact of breast milk is also unclear, they have been excluded from most trials. One of the earliest trials to show a benefit of breast milk in prevention of NEC, by Lucas and Cole, included babies of under 1850g birth weight, some of whom were over 32 weeks. They had 4 cases of NEC among 34 to 36 week infants who only received formula, compared to 0 in the breast milk groups. One very interesting finding in that early study was that babies who received breast milk AND formula had the same risk of NEC as those who received 100% human milk. Here is the table of results from that study including all gestational age groups:

Which, if I was a lawyer/expert witness, I would quote as good evidence that it is not formula that causes NEC, but breast milk that is protective.

Posted in Neonatal Research | 4 Comments

Long-term outcomes after preterm birth; the next step

Posted on 9 October 2024 by Keith Barrington

I usually try to avoid buzz-words and phrases like “paradigm shift” but it applies well, I think, to what is happening in the world of neonatal follow-up, and more broadly, I hope, to neonatal research as a whole.

Neonatologists were pioneers in the development of outcome research (Barrington KJ, Saigal S. Long-term caring for neonates. Paediatr Child Health. 2006;11(5):265-6), when we started saving babies who would have universally died in the past, we wanted to know how they would turn out, and what kinds of lives they would have. Follow-up clinics developed with a dual mandate, to ensure that ex-preterm infants were evaluated and to co-ordinate any care they required, and to measure and collate their outcomes for quality control and research.

We used measures that were available, and we have gradually developed an almost universal approach, focusing primarily on brain injury, with standardized screening for developmental problems, neurologic exams to identify motor dysfunction, and hearing and vision screening. Other domains which have an impact on families after discharge have been less well evaluated, such as behaviour, feeding issues, sleep, pulmonary symptoms.

Developmental screening tests of various types have been used, and in, most of the world, the Bayley Scales of Infant Development (BSID) have become the default developmental screening exam. Despite what you might think, if you have read these blogs for a while, I actually think that developmental screening is a good thing! Some sort of universal screening for developmental issues is important to identify infants having difficulties, and ensure that they can receive any intervention that they need. What I am very opposed to is the simplistic dichotomising of outcomes into “impaired” if the score is less than 85 (and severely impaired if it is less than 70), and “non-impaired” if the infant gets 85 or more! Even worse is compounding low developmental screening test results with death, to give the dichotomous outcome of “death or NDI”.

I am now not even sure what to call a low BSID score. I have frequently referred to this as “developmental delay”, however, I have heard that some parents dislike this term as it implies that the infant will catch up. While this is true for large numbers of infants, it is not universally the case. We showed in the CAP cohort that only 18% of babies with a 2 years BSID score more than 2 SD below the mean had a 5 year IQ >2 SD below the mean. (Schmidt B, et al. Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA. 2012;307(3):275-82.Manley BJ, et al. Social variables predict gains in cognitive scores across the preschool years in children with birth weights 500 to 1250 grams. J Pediatr. 2015;166(4):870-6 e1-2).

This figure is from the first of those publications, with the red parallelogram I added to include all the babies who had an 18 month BSID <70, but had a 5 year IQ >70, the differences between the 2 scores we referred to as “cognitive gain”. As you can see, many babies with BSID version2 MDI scores considered to be impaired had normal IQ, or even above average IQ, once they reached 5 years. Only the few beneath the red shape still had IQ >2SD below the mean. Perhaps we should just call a low BSID, or other similar test, score “LDSTS” a low developmental screening test score, that, I think would emphasize the ridiculousness of equating death with low BSID scores, and cerebral palsy and visual or hearing problems. It doesn’t lend itself to a snappy acronym however, “NILDSTS” (neurological impairment or low score on developmental screening test) hardly trips off the tongue.

When I review the literature about the predictive ability of the BSID (whichever version) for later outcomes, many publications have reported that the BSID have a statistically significant correlation with later outcomes, but few have really evaluated the predictive value of the BSID for later outcomes. It is hardly surprising that a screen for developmental problems will be statistically correlated with later IQ tests. But whether the developmental screen is individually useful as a predictor of the likelihood of intellectual impairment is a totally different question! Publications often include statements such as, in this interesting publication among preterm infants, “there was a highly significant correlation between language scores at 2 years and later literacy skills”, but they usually do not continue with what this study showed “language development at 2 years explained 14% to 28% of the variance in literacy skills 5 years later”.

To make sure that is clear, there was a significant correlation between scores on the developmental screening test and later abilities, but that correlation explained only a very small part of the later outcome. The same has been shown with other domains of the screening tests, especially cognitive. Motor development scores tend to be more predictive of later motor outcomes.

I think of this as a similar issue to the value of pre-discharge MRI in preterm infants. Overall, in large groups of babies, more MRI-visible brain injury is correlated with poorer developmental and later intellectual outcomes. Which is not the same thing as showing that a pre-discharge MRI is of value to the individual. The individual predictive ability of almost any finding on an imaging study (MRI or ultrasound) for the outcomes we usually measure is between low and very low. Of course, there are exceptions, extensive bilateral cystic PVL is very highly predictive of Cerebral Palsy, for example, but most other findings have very limited predictive value. (Chevallier M, et al. Decision-making for extremely preterm infants with severe hemorrhages on head ultrasound: Science, values, and communication skills. Semin Fetal Neonatal Med. 2023;28(3):101444).

To get back to the “Paradigm Shift” I mentioned, all of the previous discussion in this post has been about outcomes that we currently measure, BSID, Cerebral Palsy, etc. which, as the Parents’ Voice Project has shown are of limited interest to parents (Jaworski M, et al. Parental perspective on important health outcomes of extremely preterm infants. Arch Dis Child Fetal Neonatal Ed. 2022;107(5):495-500). We are shifting, perhaps all too slowly, to a new paradigm, an emphasis on outcomes that are of importance to families.

A national group of investigators and parents have been working together in Canada to develop both a catalogue of outcomes that are important to parents, and to decide how best to measure and collect the data. That process is described in a new article just published in Pediatrics, with a parent and a physician investigator as co-first authors! Pearce R, et al. Partnering With Parents to Change Measurement and Reporting of Preterm Birth Outcomes. Pediatrics. 2024. (Although I was not an author of this article, you will see I am named as a member of the Network).

The publication is a clear description of the needs, and challenges, in preterm follow up, and how the network is addressing them. We really need better data about outcomes of preterm infants, measuring things that matter to families, in order to be able to intervene, research, and counsel parents.

Let’s shift that paradigm!

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What should saturation targets be in established chronic lung disease with pulmonary hypertension?

Posted on 4 October 2024 by Keith Barrington

This question has been puzzling me recently, as we are trying to evaluate our current approach, and whether it needs to be changed.

My bias has been that oxygen is toxic, and we should only give the minimum needed to maintain adequate saturation. But that, of course, begs the question “what is adequate saturation”? I take my approach partly from the results of BOOST, this was the trial with which Lisa Askie burst onto the scene of neonatal clinical research, (Askie LM, et al. Oxygen-saturation targets and outcomes in extremely preterm infants. N Engl J Med. 2003;349(10):959-67) with a multi-centre trial in 350-odd babies (<30 weeks GA) who were still needing oxygen at 32 weeks. They were randomized to have SpO2 targets of 91-94% or 95-98%. There were no advantages shown of higher saturations, but far more high sat group babies needed oxygen at home, 30% vs 17%, and more babies died of pulmonary causes (6 vs 1, p=NS).

The STOP-ROP trial was also cautionary. In that trial, very preterm infants with pre-threshold RoP, who needed O2 to keep their saturation >94%, were randomized (average PMA 35.4 weeks) to a target of 91-94% or 96-99%. There was no difference in terms of progression of their eye disease, but the higher saturation target group had “increased risk of adverse pulmonary events including pneumonia and/or exacerbations of chronic lung disease and the need for oxygen, diuretics, and hospitalization at 3 months of corrected age“.

I haven’t found any study directly addressing the clinical outcomes of different saturation targets specifically for the group of preterm infants with BPD who also have proven pulmonary hypertension.

The AHA/ATS guidelines state “Supplemental oxygen therapy is reasonable to avoid episodic or sustained hypoxemia and with the goal of maintaining O2 saturations between 92% and 95% in patients with established BPD and PH (Class IIa; Level of Evidence C)” Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015 Nov 24;132(21):2037-99.

Similarly the PPHNnet guidelines have :”Supplemental oxygen therapy should be used to avoid episodic or sustained hypoxemia and with the goal of maintaining oxygen (O2) saturations between 92%-95% in patients with established BPD and PH. (class 1, LOE B)” Pediatric Pulmonary Hypertension Network (PPHNet). Evaluation and Management of Pulmonary Hypertension in Children with Bronchopulmonary Dysplasia. J Pediatr. 2017 Sep;188:24-34.e1

Indeed there are experimental data that show that once adequate saturation has been obtained, further increases in FiO2 do not decrease pulmonary vascular resistance, in normal lungs or those with PPHN.This graphic for example, from one of Satyan Lakshminrusimha’s animal studies, shows a decrease in PVR with increasing PO2 with a maximal effect at either 50 (control) or 60 (PPHN). Further increases in FiO2 had no significant impact on PVR, but do generate oxygen free radicals, and impede NO-dependent arteriolar vasodilatation.

The same group, in another model, showed that the minimal PVR was achieved with an SpO2 of 93-97%, which in this model required an FiO2 of 50%. Further increasing the FiO2 led to much higher PaO2, and SpO2 of 98-100%, but increased the PVR.

Given this, I found it strange to note that a publication supposedly presenting the European guidelines from the EPPVD (Hansmann G, et al. Pulmonary hypertension in bronchopulmonary dysplasia. Pediatr Res. 2021;89(3):446-55) suggests an SpO2 target of >95%, with no high limit. I tried to find the source of the data from this recommendation, and the only reference they give is to the 2019 consensus statement, which doesn’t actually recommend such high targets. Indeed that statement just states “The term or preterm newborn infant should receive oxygen, ventilatory support and/or surfactant if needed to achieve a pre-ductal SpO2 between 91% and 95% when PH is suspected or established. It is useful to avoid lung hyperinflation and atelectasis, or lung collapse and intermittent desaturations below 85%, or hyperoxia with pre-ductal SpO2 above 97%. (S9-1)—(S9-3)“, the SP-1 etc seem to refer to publications which aren’t actually very relevant. There are no other SpO2 recommendations in that statement. There don’t seem to be any data to support the recommendation of >95%.

In other words, despite a major lack of good quality data to show that different SpO2 targets in infants with chronic lung disease and pulmonary hypertension have an effect on important clinical outcomes, the consensus seems to be that 92-95% is probably best. Higher targets have no known benefits, and may increase pulmonary toxicity and adverse outcomes.

Avoiding intermittent hypoxia is probably important, for which prolonged caffeine therapy appears to be effective. The ICAF trial, presented at PAS this year, but not yet published, showed much less intermittent hypoxaemia in convalescing very preterm infants who were randomized to caffeine or placebo after about 34 weeks (about 80 per group). Of course these were not babies with BPD-PH, but if the same reduction in intermittent hypoxia occurs in that subgroup, which I have no reason to doubt, then there could also be an impact on pulmonary vascular resistance.

Infants with chronic lung injury and pulmonary hypertension are a very high risk group, good quality trials to inform the best therapy for them are urgently needed.

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Making decisions for extreme preterms, do parents regret their choices?

Posted on 2 October 2024 by Keith Barrington

In 2022 we published an article addressing the question in the title. As part of the Parents’ Voices Project, we questioned families of very preterm infants at follow up about their experiences prior to, during, and after the NICU. 98% of families attending responded, the extremely high response rate being partly because they were given multiple different potential ways of participating (on-line, on paper, in person); about 30% of respondents were fathers. We published a qualitative analysis of the responses to an open-ended question “knowing what you know now, is there anything that you would have done differently?” (Thivierge E, et al. Guilt and Regret Experienced by Parents of Children Born Extremely Preterm. J Pediatr. 2022;257:113268). None of the parents reported regret about life-and-death decisions that they participated in. Of course this was a “biased” sample, of only parents of surviving babies. Many parents did express regret, but it was usually because they regretted not looking after themselves during the NICU period, or they felt guilty about the preterm delivery and regretted the things they had done that they believed had triggered that delivery.

Of importance there was no difference in regret or guilt between parents whose children were considered to have “impairments”, using standard definitions, and those without impairments. Also, as we have also shown, parents often don’t agree with the medical classification of their infant as being impaired or not (new publication to come soon in ‘Pediatrics’); and, using parents own classification of their infants as having challenges or not, didn’t change the fact that they were not more likely to express guilt or regret if they thought their child had limitations.

A new publication from 2 US centres (in Portland OR and Newark NJ) has used a published scale to survey mothers of infants who delivered between 22 and <26 weeks GA, from 2004 to 2019. 56% of them were contacted and 54% participated. Of the respondents, 137 of them stated that they had chosen active intensive care, 43 comfort care, and 23 “other”. Unfortunately, with the very long delay between delivery and being surveyed for some mothers, the authors found some discrepancies between what was reported in the charts, what was actually done, survival, and the mothers’ reports of their decisions. They used a published scale to evaluate decision regret.

The scale is constructed from responses to 5 statements, each on a Likert scale of 1= ‘strongly agree’, 2= ‘agree’ etc to 5= ‘strongly disagree’. Here are the 5 statements:

1) It was the right decision.
2) I regret the choice that was made.
3) I would go for the same choice if I had to do it all over again.
4) The choice did me a lot of harm.
5) The decision was a wise one

As you can see, statements 2 and 4 were expressed as negatives, in order to account for some people who tend to just agree to everything, so the Likert scores for those items are reversed.

The responses are then averaged, 1 is subtracted, then the result multiplied by 25. If someone answered ‘strongly agree’ to all except one, and ‘agree’ to one of the statements, they would score 5; and if someone responded ‘agree’ to all the statements they would score 25. What I don’t understand, in the way these are interpreted in this publication, is that a score of 5 to 25 is considered an “elevated decision regret score”; which is bizarre. If I am comfortable with the decisions that were made, and I tick agree with every statement, rather than strongly agree, the authors report that as elevated decision regret, whereas I think it is the opposite, showing very little decision regret.

There were differences between mothers who reported an active care decision to those remembering other decisions. As you can see here, the 75%le for the score in the ‘active care’ group shows very little decision regret, with substantially more showing regret among the other 2 groups.

Also, one of the determinants of a higher decision regret score was that the infant died; either after comfort care, or in the DR, NICU, or at home, after active care, whatever the decision was made.

As the authors note, there is little other direct research of decisional regret in neonatology. Guertzen et al have published 2 studies, the first, from 2017, (Geurtzen R, et al. Prenatal (non)treatment decisions in extreme prematurity: evaluation of Decisional Conflict and Regret among parents. J Perinatol. 2017;37(9):999-1002) with unfortunately very low response rates (27%), the sample was restricted to parents who actually delivered at 24 weeks. At the time that study was done, optional care at 24 weeks had recently been recommended by the Dutch guidelines (previously being limited to 25 weeks and above) the low response rate and total n of 61, meant that there were only 5 who opted for comfort care among the respondents. Although the authors did show low decision regret scores (using the same scale as the new publication), the small numbers in some groups make interpretation difficult. Decision regret was very low among parents of survivors, and higher among parents of babies that died despite active care, but the scores were still very low (median 7.5). Among the 5 who opted for comfort care decision regret was higher, but the tiny numbers and low response rate make it impossible to extrapolate, it is possible that those with regret, or those who opted for comfort care were less likely to respond. The second publication from the group from 2021 (Geurtzen R, et al. Decision-making in imminent extreme premature births: perceived shared decision-making, parental decisional conflict and decision regret. J Perinatol. 2021;41(9):2201-7), studied parents who underwent counselling between 23 and <25 weeks, they were questioned 1 month later. There were only 20 respondents to this part of the study, most of whom actually delivered after 25 weeks. There was little decision regret.

Another study I found included some newborns, as well as other infants under 1 year of age with “neurological conditions” who had a “goals of care” discussion, defined as being a discussion about continuing life-sustaining interventions or instituting long-term medical technology. (Barlet MH, et al. Decisional Satisfaction, Regret, and Conflict Among Parents of Infants with Neurologic Conditions. J Pediatr. 2022). It is a mixed bag of patients, whose parents were questioned about decisional regret one week after discharge. The study included just over 60 parents, They used the same scale as in those other studies, and, in addition, a scale of decisional satisfaction and another designed to measure uncertainty in decision making, which they refer to as “decisional conflict”. They showed fairly frequent decisional conflict (perhaps not the best term as many answers just show a lack of certainty rather tha conflict) but very little decisional regret, and most parents were satisfied with their decisions. I don’t see an analysis of whether there is any difference in scores depending on the outcomes, survival, death or impairment.

I have had a brief scan through other studies about decision regret, including a systematic review from 2016, which found 59 articles, covering many different aspects of medical decision making, from individuals having cosmetic surgery, through parents making decisions about hypospadias surgery, to surrogates who made decisions about life-sustaining measures in the adult ICU. In general, looking at the more critical decisions, the majority of respondents have little regret regarding their decisions, whatever the decision, and whatever the outcome.

When patients survive without long term consequences, there is very little decision regret (as you might expect). When the patient dies, those who made decisions for limitation of active care seem more likely to experience regret than those who decided for active intervention. The feeling that “at least we tried” seems to lead to less regret than “what if we had tried?) And what about those whose loved one survives after a decision to continue active care, but has major long-term consequences? Among families who have made such decisions, regret still seems to be quite uncommon.

In terms of my personal history, I have spoken on occasion about the decisions we made about starting intensive care for my daughter, born at 24 weeks and 3 days in May 2005, and about the crisis a couple of weeks later when she was critically ill and comatose with septic shock. We came very close, within minutes, of redirecting care, but with the support of my mentor Neil Finer, and following some minimal signs of improvement thanks to the excellent care of the NICU team, we decided to continue full intensive care. I am very proud to tell you that Violette has just started in the Bachelor of Science in Nursing program at the Université de Montréal! Here she is modelling her first set of scrubs.

We obviously haven’t the slightest hint of regret for our decisions, but I am trying to imagine how I would have felt about our decision now, 19 years later, if she had died. I honestly think that if we had continued with our decision for comfort care, and she had died, I would be heart-broken, but probably not feeling regret for the decision. I would not, of course, know how she might have ended up, and would, I imagine, be comfortable that we had made the right decision for the right reasons. If she had died despite changing our minds, and continuing intensive care, then I would still probably be comfortable that at least we had given her a chance. I am less sure how I would feel about the other possibilities, such as her surviving, but with major limitations. Most parents do not regret decisions that they made for their children, even if they have serious challenges, and most parents with challenged kids report both good and bad impacts of their preterm baby on their family. (Milette AA, et al. Parental perspectives of outcomes following very preterm birth: Seeing the good, not just the bad. Acta Paediatr. 2022;112(3):398-408). Indeed my lit review seems to confirm that parents of children living with even very severe impairments rarely regret intensive care or life and death decisions that they made.

Do we sometimes worry that parents who decide to continue active intensive care in life-threatening situations might regret such decisions if their infant survives with major limitations? If so, that worry seems to be unfounded. Regret appears to be more common (even if still a minority) among parents who decide for comfort care.

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Improving human milk for preterm infants.

Posted on 12 September 2024 by Keith Barrington

Mother’s own milk (MoM) is clearly preferable for the enteral nutrition of all infants, with major advantages demonstrated among the preterm. Despite one bizarre, flawed, and seriously biased article, that I have criticized on this blog, the next best substrate is, also very clearly, donor human milk (DHM).

Most DHM around the world is provided by altruistic volunteers who provide milk to their local milk bank after expression into sterile containers. But how do they actually do it? I scanned the on-line information provided by several milk banks, and there was little instruction to prospective donors about how exactly to express their milk.

The Ontario milk bank has a video which suggests pumping 1, 2 or 3 times a day, or pumping when first waking in the morning if the mother wakes with breast fullness, or pumping from one breast while their infant suckles from the other, if the baby seems to have a preference. Information for bereaved mothers suggests pumping for 15-20 minutes every 3 to 4 hours.

The Vancouver milk bank recommends pumping once a day, but in their video they also mention pumping from a contralateral breast, or after feeding the mother’s own baby. A few organisations (such as NICE in the UK) counsel against the use of “drip” milk, that is, milk that is spontaneously secreted from the contralateral breast during a breast feed (such drip milk has been shown to have much lower macronutrient content, especially low fat). Most have no other specific instructions. NICE also encourages hand expression, rather than using a pump; this is not explained. In the document detailing the evidence supporting the guideline, they don’t really explain why manual expression is preferred over an electric pump.

Composition of breast milk changes with gestational age at delivery, postnatal age (Mimouni FB, et al. Preterm Human Milk Macronutrient and Energy Composition: A Systematic Review and Meta-Analysis. Clin Perinatol. 2017;44(1):165-72), and even time of day (a relatively minor effect, Paulaviciene IJ, et al. Circadian changes in the composition of human milk macronutrients depending on pregnancy duration: a cross-sectional study. Int Breastfeed J. 2020;15(1):49). Importantly though, composition changes with timing during a feed (with foremilk having lower, and hindmilk higher, fat content, Bishara R, et al. Nutrient composition of hindmilk produced by mothers of very low birth weight infants born at less than 28 weeks’ gestation. J Hum Lact. 2008;24(2):159-67), As for protein content, published research is somewhat contradictory, some showing that hindmilk also has more protein than foremilk, while others seem to show them as being similar. There are some minor problems with the literature, mostly that the definition of when foremilk becomes hindmilk is unclear, it is usually defined after a specific time interval.

Since the development of the human milk bank in Québec, which is organised by the blood transfusion service (Héma-Québec), the program has had stringent quality control, follows HMBANA guidelines, and has been evaluating the macronutrient content of the milk provided. Donor milk received by our milk bank varies in calorie density between 58 and 72 kcal/100mL, and a typical pooled donor milk sample shows a total calorie content of well below 67 kcal/100mL (the classic 20 kcal/fl.ounce). Thus what we give as DHM usually averages close to 60 kcal/100 mL (18 kcal/oz) so we routinely calculate our donor breast milk fortification on this basis, adding 50% more fortifier to DHM than to MoM to achieve our standard 81 kcal/100ml (24 kcal/oz).

Our nutrition committee and the Héma-Québec milk bank personnel wondered if it would be possible to provide DHM with higher fat, and therefore calorie density, by informing mothers of the potential advantages of hindmilk, and assisting them to provide it. But it was realized, as a preliminary, that we didn’t actually know how mothers were expressing their milk. We have just published the results of a questionnaire, surveying donors to our bank, asking them exactly how they were expressing their milk, and if they would be prepared to change their practices in order to produce hindmilk DHM with higher fat content. (Girard M, et al. Donor Milk Expression Habits: Can we Favor Hindmilk Banking for Extremely Preterm Infants? Breastfeed Med. 2024) 126 of 170 mothers completed the questionnaire, 57% reported expressing donated milk between breastfeeds; 15% reported simultaneously breastfeeding while expressing from the other breast; 12% reported breastfeeding their baby on each breast, then expressing (in other words, providing hindmilk). Most mother/donors were willing to consider changing practice to donate hindmilk, even though this is somewhat more onerous. It entails stopping the breast feed, then washing the breast, then expressing into the sterilized container. Some mothers thought they might not have enough milk left after breastfeeding, or that they were already exhausted after a breast feed, nevertheless 89% were willing to provide hindmilk at least some of the time, and 2/3 could envisage doing so exclusively.

The comments from many respondents (which you can read in the article) were quite touching, and show the dedication of the donors to providing the best start possible for preterm infants. The next stage is to identify exactly how we will identify, and keep separate during preparation, hindmilk, and to ensure that there are no negative impacts on overall donation volumes. Then proving that nutritional outcomes are improved, if possible, although there are already a couple of published studies that we mention in our article and refer to in our bibliography that show such an effect.

Another potential application of this data is for mothers expressing milk for their own baby, would it be possible to provide MoM with more hindmilk? I am sure many mothers would be willing to do so, if we can figure out the logistics.

I don’t suppose there are many breast milk donor who read this blog, but if there are: “Thank You!”, your selfless act benefits many babies who you will never meet.

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Sending home preterm babies with Inguinal Hernias

Posted on 22 August 2024 by Keith Barrington

It has been dogma for quite some time that newborn preterm infants with Inguinal Hernias (I will resist the temptation to latinise the plural, although I was brought up hearing about ‘herniae’) should have them surgically fixed prior to discharge home because the risks of incarceration were so much higher in the young infant.

This practice has been widely followed wherever I have worked; discharge has sometimes been delayed, depending on logistics and clinical status of the baby, and just about all of them have been surgically repaired prior to going home.

Anesthesia and surgery are not without risks, and the preterm infant at risk for such hernias is also at risk of cardiorespiratory instability during and after hernia repair. Delaying surgery might allow a more stable clinical status of the infant, if it can be safely done without increasing complications, in particular incarceration, with its risks of strangulation and intestinal obstruction.

This pivotal multicentre RCT was performed to answer the practical question “is repairing an Inguinal Hernia in a former preterm infant safer if it is performed before discharge home from the NICU, or if done post-discharge at more than 55 weeks PMA?”(HIP Trial Investigators. Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial. JAMA. 2024;331(12):1035-44)

So the primary outcome was “safety” which was defined as the absence of any serious adverse event. These “included pulmonary events (apnea requiring intervention, prolonged intubation, unplanned reintubation, stridor, pneumonia), cardiac events (bradycardia requiring intervention, cardiopulmonary resuscitation, cardiac arrest), surgical events (intraoperative injury, wound disruption, surgical site infection), events related to the hernia (incarceration, recurrence, reoperation), and death”. Babies were eligible if born preterm (<37 weeks) and had an Inguinal Hernia. They were enrolled and randomized when thought to be 2 weeks from being discharged.

Clearly some of those outcomes are much more important than others, and this is one issue that we could have with the trial. If there had been more deaths in one group, but more apneas in the other group, then the overall number of SAEs might be identical, but clearly one outcome is worse than the other! Indeed, the main real difference in outcomes was many more apneas in the early repair group.

There was, overall, at least one adverse event in 28% of the early and 18% of the late group.

As you can see, all the other components of the primary outcome were uncommon, including, most importantly, incarceration, for which the absolute risk difference was 2.7%.

One other outcome of interest were the reasons for non-repair in the 2 groups, among the early repair group, 7 had the hernia resolve spontaneously between enrolment into the trial and the date for the surgery. In the late group 17 babies had resolution of their hernia. I think this is a major advantage of delaying surgery, another 8% of the infants will never need to have the surgery if it is delayed!

As a practical trial, there were many babies who had early repair despite being in the late group,

including due to parent or clinician preference (one could argue that such babies should not have been randomized) and 11 because “concerned about incarceration”, which isn’t really explained, does that mean that there were some signs of incarceration? or someone was just worried?

The analysis was Bayesian, so the results are presented as the likelihood that late repair is preferable to early repair, in terms of numbers of adverse events. For the group as a whole, using a neutral prior (meaning there was no previous good evidence that one approach led to fewer SAEs than the other) the posterior probability of an advantage of the late group was 97%. On subgroup analysis, the major difference in SAEs was among the more immature babies (more than 99% probability of benefit of delaying), compared to 28 weeks GA or more; and among those with BPD.

This is presumably because it is the very immature baby who has a major risk of peri-operative apneas, babies over 28 weeks rarely have such events, so will not have much of that particular benefit, which was the only large difference between groups. The other large benefit of late repair, in relative terms, was avoidance of prolonged assisted ventilation post-op, this occurred in 6 early and 0 late repaired babies, which is presumably related to why late repair was more beneficial in babies with BPD than those without.

I think this trial should have an immediate impact on practice. If safe surveillance can be ensured, then infants at high risk of perioperative apnea, that is, those <28 weeks, have a benefit from late repair, after 55 weeks. Where I live and work, some families come from hundreds, or even thousands of kilometers away, and may have difficulty being transferred back for surgery, especially if it is urgent; they could continue to have pre-discharge repair, because the major increase in risk is for apnea, which is a short-term complication that we can monitor for.

For those who live on or close to the island of Montreal, they can be discharged a little earlier (mean of 5 days sooner in this trial) and the hospitalisation for the hernia repair is usually very brief (mean 0.5 days).

As a more theoretical, study design, consideration, future trials should construct ordinal outcomes, which take into account the relative importance of the outcome variables. As it happens, in this trial I think the relative rarity of all outcomes other than apnea, and the lack of any big difference between groups, means that a DOOR type analysis would almost certainly have given the same results.

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Colostrum and feeding preterm babies

Posted on 14 August 2024 by Keith Barrington

Forgive me if you are already convinced, but I remain somewhat sceptical of the benefits of routinely painting the inside of the preterm infant’s mouth with colostrum. Even though I have supported the introduction of the practice on our NICU, it seems to me to be a bit flaky, to use the scientific term. Can this intervention really have the enormous benefits for the outcomes of our babies that are claimed? I have read the theoretical justifications, and the small mechanistic studies showing impacts on IgA, and maybe on lactoferrin, but the practice has become widely promoted, with catchy names (Oral Immune Therapy) and 3 letter abbreviations- OIT, without good evidence to support it.

What is the evidence of clinical benefit? Does it only work with Mother’s own Colostrum? Does it have to be fresh? Is there a dose response?

There is a Cochrane review, which dates from 2018, they found 6 studies with 335 infants included, and no clear benefit of anything. There are several more recent Systematic Reviews, of varying quality. One of the better very recent ones seems to have been performed following the appropriate standards (Kumar J, et al. Oropharyngeal application of colostrum or mother’s own milk in preterm infants: a systematic review and meta-analysis. Nutr Rev. 2023;81(10):1254-66). This includes 17 RCTs, of varying quality, and I did a quick search and was unable to find anything newer that wasn’t in this SR. Of note, in many of the trials they included, the enteral feeding schedules of the included babies were far from being standard-of-care; large numbers of the babies received artificial formula and some were kept npo during the first days of life. The intervention is also somewhat variable, although 0.2mL of colostrum q3h for 2 to 3 days is the most frequent, some have used greater volumes, or much longer durations, switching to Mother’s own Milk as time went on.

Despite all the hype, there is little evidence of benefit, but the small numbers, and poor quality, mean there remains a real possibility of a major impact on NEC, the RR of stage 2/3 NEC was 0.65 (95% CI 0.36-1.2, n=1089), and of late-onset sepsis was 0.72 (0.56-0.92, n=1482), the latter being very-low quality evidence by GRADE.

Even that NEC result is almost entirely dependent on a single study from China (n=252), which was retrospectively registered, and was terminated early because of an early apparent advantage of the colostrum group, who had much less NEC. The overall incidence of NEC in the controls (<33 weeks gestation, mean GA 30 weeks in each group) was over 10%, they do not appear to have had donor milk available, and it is really difficult to understand some of the data. The late-onset-sepsis result is also largely dependent on this single study.

I do not understand why so many trials from China are retrospectively registered, everyone knows that it is essential to register trials, but doing so retrospectively makes a mockery of the system. It means we can have no confidence that the primary outcome has not been changed, or that the analysis is what was planned. Systematic reviews should always consider this to be a huge red flag, and note it in Risk of Bias evaluations.

This SR illustrates the difficulty in doing trials to prevent NEC; babies in future trials should have optimal evidence-based NEC prevention already in place, with early human milk feeds, standardised protocols and multi-component probiotics; with such approaches NEC becomes less frequent, so very large numbers of subjects are required. Perhaps the only way to do such trials in the future will be performing registry trials with cluster-randomisation. Oro-pharyngeal colostrum administration is, on the other hand, almost certainly quite safe, and, other than the logistic difficulties in ensuring early colostrum expression, and tracking the stuff from mother to baby, quite inexpensive. Perhaps we should all do it anyway, and accept that we will never really know if it is making a difference to NEC or to late-onset sepsis?

I hate to suggest that, but perhaps we can all agree that OIT (!) is almost certainly harmless and just might have measurable benefits. Introducing frequent oropharyngeal painting with uninfected fresh maternal colostrum as a routine practice would have the additional benefit of strengthening efforts to support mothers in the very early expression of their breast milk. For which there is a great deal of observational evidence (such as this very recent publication) that it helps to ensure good milk production over the first weeks of NICU hospitalisation.

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