Should we give up on nebulised surfactant?

Posted on 17 March 2022 by Keith Barrington

A new RCT of curosurf given by nebulisation was published shortly after a systematic review of the previous data. The RCT showed no real benefit, whereas the SR suggested efficacy.

The RCT first, this international trial (Dani C, et al. A Randomized, Controlled Trial to Investigate the Efficacy of Nebulized Poractant Alfa in Premature Babies with Respiratory Distress Syndrome. J Pediatr. 2022) randomized 129 babies (28 to <33 weeks GA) into 3 groups, 2 received different doses of Curosurf nebulised by a special device that could be attached to the nasal prongs (either 200 or 400 mg/kg). Eligible babies were those with HMD who needed between 25 and 40% oxygen on CPAP 5 to 8 cmH2O.

The babies in the 3rd group stayed on regular CPAP. The primary outcome variable was needing intubation; for surfactant therapy (over 40% oxygen need) or becoming hypercapnic (pCO2>60 with pH<7.2) or having lots of apneas.

The study was stopped for futility after just over 40 babies per group, which, as always, is disappointing. The relative numbers of babies who had primary outcome criteria in the higher dose surfactant group (49%) was less than the controls (58%). The 95% confidence intervals for the relative risk of “respiratory failure” (the primary outcome criteria) was 0.56-1.26 for the 400 mg/kg dose and 0.68-1.42 for the 200 mg/kg dose.

It took about 30 minutes to nebulise the higher dose (and half that for the lower dose) and the babies tolerated it well. Post-hoc subgroup analyses suggest that the nebulised surfactant was more effective in the more mature babies.

The systematic review (Gaertner VD, et al. Surfactant Nebulization to Prevent Intubation in Preterm Infants: A Systematic Review and Meta-analysis. Pediatrics. 2021;148) included the results of that trial (called Curoneb), the numbers are a little different, which seems to be because the SR mixed the results of the pilot and the full trial, so instead of the 129 babies in Curoneb, they report the 152 babies in the combined trials. As you can see from the following Forest plot, the SR overall suggests that nebulised surfactant decreases intubation within the 1st 72 hours of life, but the results are really completely dependent on the Cummings trial, which showed a major decrease by 48% in need for intubation, without Cummings there seems very little there. The I2 shows lot of heterogeneity, but nevertheless, the 95% compatibility limits of the RR from the results of Curoneb overlap with the summary Relative risk, and there is some overlap with Cummings trial.

If we examine the Cummings trial in detail, (Cummings JJ, et al. Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial. Pediatrics. 2020) it was a strange study, which included babies from 23 to 41 weeks gestation, who were on any mode of non-invasive support between 1 and 12 hours of age, needing, at first, 25 to 40% oxygen, but then later on in the trial that was changed and babies in 21% oxygen were enrolled. There were no objective criteria in the trial design for intubation, or for failure of treatment, even though intubation for surfactant administration within the first 4 days was the primary outcome and the trial was unblinded.

There were actually more late term/posterm babies in the trial than babies under 27 weeks, and there were as many early term babies as those born at 27 or 28 weeks. The following figure, which shows that information, includes 20 babies (which is what the “combined cohorts” means) who were randomized after extubation having already received surfactant while intubated. As you can see most of the babies were more mature infants, over 30 weeks gestation. The babies received 210 mg/kg of Infasurf, via a modified nebuliser via an oral airway.

The major problem with this trial, of course, is the use of a subjective outcome criterion in an unblinded study. In addition, the inclusion of full term babies, makes it difficult to generalize the results.

Overall then, it seems that there might be clinical effects of nebulised surfactant, a proportion of the administered dose is deposited in the lungs, and gas exchange tends to improve. In larger preterm babies, this probably somewhat reduces the need for more invasive surfactant administration, but any other benefits (reduced chronic lung disease, improved pulmonary health in infancy, less nosocomial pneumonia or sepsis, improved family interactions or satisfaction) have not been shown.

The implications of all this are that nebulised surfactant has an efficacy which seems limited, and many babies will still need either MIST/LISA or intubation for surfactant therapy. If you take the group that seems to have the best response, between 30 to 34 weeks, a baby that has HMD and is on CPAP with 25 to 40% oxygen in the first few hours, will progress around about half of the time and need surfactant by direct intra-tracheal administration, but if given nebulised surfactant that decreases to between a quarter and a third.

To really prove that you can avoid intra-tracheal surfactant administration in that proportion of such babies really needs another trial, probably with a non-inferiority design. It would be expensive to do this as a masked trial, with a separate team to care for the baby during nebulisation, so I would think an unmasked trial is more likely to be possible, failure criteria should be objective, and it should really be limited to preterm infants.

Is it actually worth doing such a trial? I’m not sure that sometimes avoiding intra-tracheal surfactant administration by nebulising it instead is an outcome that matters enough in larger preterm babies. Laryngoscopy and endotracheal intubation, or passing a catheter through the cords, isn’t much fun for the baby, but the GA group of babies where there seems to be most efficacy have little in the way of serious complications. I think if you could reduce intubations in babies under 28 weeks, then that is a whole different issue, but there doesn’t seem much preliminary evidence that that would work.

Looking at the minor difference in outcomes in the group of 27-28 week babies in the above graph, and that is despite the potential biases in study design, you would need a huge trial to confirm a similar reduction in intra-tracheal surfactant need in the babies for whom it might make a clinically important difference. Unless there are better ways of ensuring that an effective surfactant can be quickly deposited in sufficient quantities in the terminal air sacs, I think we might have to say goodbye to nebulised surfactant as a great idea that didn’t live up to its promise.

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Hypoglycaemia, symptomatic or non-?

Posted on 15 March 2022 by Keith Barrington

Many algorithms for detection and treatment of hypoglycaemia make a big deal of whether the hypoglycaemia is symptomatic or not. Symptomatic hypoglycaemia is supposed to be more dangerous in the long term, and requires more aggressive treatment. But symptoms accredited to hypoglycaemia also occur in non-hypoglycaemic infants, and many infants with low blood sugars look and act just like their normoglycaemic peers.

So bravo to a group of German investigators who have tried to determine whether clinical signs really discriminate between babies with and without low blood sugars. (Hoermann H, et al. Reliability and Observer Dependence of Signs of Neonatal Hypoglycemia. J Pediatr. 2022)

They video monitored 145 term and late preterm babies, some considered to be at-risk of hypoglycaemia (SGA, LGA, diabetic mothers, late preterm, and respiratory distress), and others at standard risk. 430 videos were taken just before the blood sample, which was analyzed by a bedside “Stat-strip” glucose analyzer. This is, I think, the main limitation of the study, as such monitors are known to be inaccurate, they produce results which tend to be lower than reference methods, when in the hypoglycaemic range. But if we assume that the hypoglycaemic babies were truly hypoglycaemic, which would often be true, then clinical signs, as detected by the 8 nurses and 2 neonatologists who reviewed all the videos, are completely unreliable.

The sensitivity and specificity of any of the clinical signs were poor, with tachypnoea being the clinical sign which was most different between babies with blood sugars above and below 2.5 mM/L (45 mg/dl).

Apart from the very rare baby with blood sugar of zero who is convulsing, clinical signs are really not much use in detecting hypoglycaemia, and there really is no reliable evidence that an infant with a low blood sugar who has some of these clinical signs has any worse prognosis than a baby with a similar blood sugar who is not thought to be symptomatic.

I really question the division of hypoglycaemia into “symptomatic” and “asymptomatic”; as these authors note, there is no good previous data that shows reliably that symptoms of hypoglycaemia are reproducible or readily detected, and nor is there good data that babies with what are considered to be signs of their low blood sugar are worse off in the long term than those without such clinical signs.

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Skin to skin contact reduces pain… in mothers!

Posted on 8 March 2022 by Keith Barrington

Some neonatal interventions for pain relief don’t seem to work in older subjects, sucrose for example doesn’t seem effective out of the neonatal period, a study from our Emergency Room showed no benefit of sucrose for bladder catheterisation in infants (Desjardins MP, et al. A randomized double-blind trial comparing the effect on pain of an oral sucrose solution versus placebo in children 1-3 months old needing bladder catheterization. CJEM. 2021;23(5):655-62).

A new publication, however, shows that skin-to-skin care of mother with her baby reduced the pain of perinatal repair after vaginal delivery (Zou Y, et al. Effect of early skin-to-skin contact after vaginal delivery on pain during perineal wound suturing: A randomized controlled trial. J Obstet Gynaecol Res. 2022;48(3):729-38). New mothers were randomized to have the baby in their arms during perineal repair or to have “standard care” where the infant was on an overhead heater during the repair.

The mothers’ pain scores were substantially lower in the skin-to-skin care group than the controls.

I’m sure the babies were happier too.

Image from UNICEF
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Should we feed insulin to preterm babies?

Posted on 8 March 2022 by Keith Barrington

This was an idea I had not heard about prior to seeing this newly published trial (Mank E, et al. Efficacy and Safety of Enteral Recombinant Human Insulin in Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2022). The introduction is very limited on the prior justification for the trial, but the beginning of the discussion gives a lot more background.

The discussion section notes that, in previous animal studies “the small intestinal weight and intestinal disaccharidase activity (ie, lactase, sucrase, maltase) were significantly higher in both piglets and rats treated with either enteral rh (recombinant human) insulin or enteral recombinant porcine insulin relative to controls, suggesting that insulin has a key role in promoting intestinal maturation. The effect of enteral insulin on the intestine seems to be mediated by insulin receptors, which have been observed on both the apical and basolateral enterocyte membrane of various animals” and apparently insulin receptors have been seen in human foetuses up to 19 weeks, but only on the basolateral membrane of the enterocytes, not apically. There is apparently also quite a lot of insulin in human milk in the first few days after delivery, and an interesting prior study from Deborah O’Connor’s group in Toronto showed that standard Holder pasteurization decreases human milk insulin concentrations by about half.

They therefore performed this study to see if adding a new powdered insulin preparation to human milk feeds would improve GI function, as measured by time to tolerating full enteral feeds, among preterm infants <32 weeks gestation.

The first disappointment I had with this trial was that the investigators excluded infants less than 26 weeks gestation. I can’t see any good reason why more immature babies should have been excluded from the trial, more immature babies are more likely to have feeding intolerance, and including higher risk patients improves study power. Also, if it works overall, then surely you would want some evidence that it works in the highest risk patients. Excluding higher risk, more immature, patients from trials means that we cannot develop the evidence base needed to improve their care (Barrington KJ. The most immature infants: Is evidence-based practice possible? Semin Perinatol. 2021:151543). There were several exclusion criteria, including infants significantly SGA, needing more than 60% oxygen, having a blood count suggestive of infection, etc. Babies were eligible within the first 5 days of life if they had started enteral feeds. Babies were randomized to receive either 400 micro-units of insulin per mL of milk, or 2000 micro-units/mL or placebo, in a masked fashion.

The next disappointment is that most of the attached protocol is redacted. Which is truly weird. The study procedures part of the protocol from section 9.1, screening and eligibility procedures to 9.5 discontinuation/withdrawal of infants are blacked out, the 10 pages with the important details of the study protocol look like something from Trump’s White House or a report into parties at 10 Downing Street. I wanted to read the protocol because I wasn’t clear about one part of the published article, where it states that, in babies receiving exclusively maternal milk, treatment was not initiated until 72 hours post-partum. It wasn’t clear to me what that meant for the other infants, and what would happen if the mother wanted to breast feed, but baby received partially banked human milk, which is why I wanted to read the protocol… I have no idea what they are trying to hide.

I think the delay in maternal breast milk fed babies is because there is a lot of insulin in human milk in the first 3 days, so they wanted to avoid an overdose in those babies. Presumably the intervention was started immediately after randomization in the other babies.

The primary outcome of the trial was the time to full enteral feeds, defined reasonably as 3 consecutive days of at least 150 mL/kg/d of milk. The sample size was calculated based on a reduction from 8 days to 6.6 days, as shown in a pilot study. I find that outcome a bit problematic, it isn’t a terrible idea, but really, who cares? I think the reason for caring about time to full feeds is that more prolonged feeding intolerance is associated with increased other complications, such as late-onset sepsis, cholestasis and increased costs. 1.5 days less of partial parenteral nutrition is really only of clinical significance if it is, firstly, clearly very safe, and secondly leads to reduced other complications. I understand that powering a trial for those other complications is going to lead to very much larger sample sizes, but that is also the only way to be sure that the intervention is safe. If even a small proportion of babies have an adverse secondary effect of enteral insulin, then a reduction of 1.5 days of time to full feeds becomes irrelevant. I think at this stage of investigation, time to full feeds was a reasonable compromise, but doesn’t give me a strong reason to consider introducing a new intervention.

The sample size calculation arrived at 150 babies per group, in a multicentre design, with 2 gestational age strata. After 225 babies were randomized, an interim analysis showed that the calculated power for finding a reduction of 1.5 days in time to full feeds was <35%, so the DSMC proposed stopping the trial. By the time the trial was actually stopped 303 babies had been randomized. In another move which is not fully explained, babies who were in the trial, but had not yet reached full feeds had the intervention stopped, in addition, there were some babies who had the intervention stopped because they were transferred to non-study centres. As a result there are only data about the primary outcome for 261 infants.

Although the trial was stopped early for futility, the final results actually show what is potentially a valuable reduction in time to full feeds in the insulin groups. Median time to full feeds was 10 days in each of the insulin groups compared to 14 days in the controls. Which was twice as great as the hypothesized difference. The difference looks unlikely to be due to random effects, the 95% compatibility intervals were 1 to 8 days shorter time to full feeds. Other outcomes were not much different between groups, if you put the 2 insulin groups together, mortality was about the same 3% insulin vs 4% control, late-onset sepsis was slightly lower with insulin 12% vs 15% and NEC was lower, a difference which, if confirmed in future larger trials, might be a clinically important difference, 5% vs 10%. My back of the envelope calculation shows that difference to be compatible with no real impact of insulin on NEC, or, obviously, with a major reduction.

Early stopping of trials for futility is a common occurrence which seems to be getting more frequent. There are scientific and ethical reasons for questioning the practice, which are illustrated by this trial. Scientifically speaking, the risk of stopping early for predicted probable futility is exactly what this trial has shown, that the trial, when fully analyzed, may show a real difference between treatments, even a difference greater than hypothesized, but being stopped early, of course, reduces the power of the trial. It is easy to imagine situations in which a similar trial may be stopped and show a difference which is not quite convincing, and reported as “not statistically significant” but if it had been continued, and accrued the expected number of participants would have been a positive trial.

Other trials have had similar occurrences, the following figure, for example, is from a cancer trial (for which futility analyses are common) The calculated power of the trial to produce a significant result is plotted over time, which shows that it varied substantially as the results accumulated, the point at which the power dropped was when the pre-planned futility analysis was performed which led to stopping the trial. The lower graph shows the actual primary outcome (for PFS, progression free survival) at the end of data collection, which was better with the new regimen than the old one.

In our current trial there were no safety issues identified at all, no evidence of harm. Also it is hard to believe that oral insulin powder is a hugely expensive intervention, which might be an issue with continuing some cancer trials, especially industry sponsored trials where the medication might be extremely costly and potentially toxic.

Ongoing monitoring of trial outcomes to reduce risks of the trial to participants is very important. But where there are no identified risks of the intervention, and where being in the trial does not prevent the participant from receiving other interventions, (I can imagine in cancer trials that some of the considerations are different), then the threshold for stopping a trial should be much higher.

From an ethical point of view, I think we have a responsibility to families that participate to ensure the trial is as useful as possible to the community. To expose families to the stress and potential risks of an intervention, and then stop a trial before you have any reliable answers is very questionable. In particular, I think it was wrong in this trial to stop the intervention in babies who had already been randomized and started the intervention. Those families had already consented to be part of the trial, and had started the intervention (insulin or placebo) but then had the intervention stopped part way through, meaning they were exposed to the stress and to the risks of an RCT but were not permitted to contribute to the final results. Surely, once babies are randomized they should have continued in their randomized group until they reached primary outcome criteria, and for the 28 day intervention period.

I think if the DSMC had found increased risks for the insulin group, that would have been an entirely different situation. Also, if the primary outcome results were clearly going in the wrong direction, with an increase, rather than the expected decrease, in time to full feeds with the insulin, then I think the decision to stop for futility would make more sense. Instead we are left with a trial which did not reach planned sample size, in which 42 of the 303 enrolled babies did not even contribute to the primary outcome. A trial which is, therefore, only suggestive of a benefit.

Imagine if the trial had continued to the planned sample size, it is quite possible that an important reduction in NEC might have been found, as well as a potential reduction in late-onset sepsis. At least we would have had more reliable data to proceed with more investigations.

The next disappointment is that the study finished in 2018, and only short term outcomes are reported. Why did it take 4 years to get this in press? It seems an unnecessarily long delay.

The final disappointment is that many of the babies did not receive milk from optimal sources. Although the study started in 2016, and human milk banks were not as widely available as they are now, there were several babies who received formula alone, and many who received a combination of milk sources; the “mixed” category in the results includes babies who received both maternal and banked milk, as well as those who received both human and artificial milk, and it is not clear how many received artificial milk. As the standard of care is now maternal milk feeding, and banked human donor milk when sufficient maternal milk is not available, for preterm babies at risk of NEC (such as all the babies in this study) it is important to know if these potential advantages of enteral insulin apply to babies who received only human milk.

The potential advantages of adding insulin to the feeds of very preterm babies suggested by this study are such that further trials are definitely worthwhile. Those trials should only study babies receiving milk from optimal milk sources, they should include the higher risk babies (less than 26 weeks, small for gestational age, abnormal antenatal dopplers) and should have much stricter rules for terminating the trial for futility. They should be powered to investigate clinically important outcomes such as late-onset sepsis and NEC.

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Does Gastro-Oesophageal Reflux matter in BronchoPulmonary Dysplasia?

Posted on 6 March 2022 by Keith Barrington

The title is deliberately a bit vague as I wanted to discuss whether GOR contributes to the pathogenesis of BPD, and also whether it is important in infants with established BPD.

Does GOR contribute to the development of BPD? There is so little reliable data to answer this question that I can only offer the old Scottish verdict of “not proven”. It is a possibility that GOR and aspiration of refluxed intestinal contents could contribute to lung inflammation and damage. I don’t think it would be too difficult to prove, actually, intubated infants could have recurrent endotracheal aspirates examined for pepsin (which should ordinarily not be in the lungs) and a correlation between evidence of aspiration and the development of lung injury. As far as I know, this has only been done once, (Farhath S, et al. Pepsin, a Marker of Gastric Contents, Is Increased in Tracheal Aspirates From Preterm Infants Who Develop Bronchopulmonary Dysplasia. Pediatrics. 2008;121(2):e253-9) with a rather unconvincing increase in pepsin concentrations among infants who developed BPD compared to those without BPD. You can see the figure below, and although the difference is “statistically significant” it doesn’t look very useful with a major overlap between cases and controls. Of note, 92% of their samples (and all of the babies at least once) were positive for pepsin, suggesting that micro-aspiration is universal, the results suggest that perhaps that having a bit more pepsin in the lungs increases lung injury (at least using oxygen at 36 weeks as the indicator of lung injury).

Apart from that study I can find no real evidence that suggests that recurrent micro-aspiration is important in the pathogenesis of BPD. Even if we strongly suspected it to be true, the next question would be what to do about it? If the culprit were gastric acid, then gastric acid blockade should decrease BPD, but that has never been shown. If it was due to other enzymes and inflammatory responses then actually decreasing episodes of reflux should decrease BPD, but we don’t know how to do that. One observational study from a center which sometimes uses transpyloric feeds showed that those where the neonatologist decided to start transpyloric feeds in the first week of life had shorter duration of assisted ventilation and a little bit less “death or bpd” but there are major problems with this study design. Although the authors attribute this difference to reduced GOR and reduced aspiration, there is no evidence that transpyloric feeding in preterm infants actually decreases reflux. In a study in older children with transpyloric feeds, they all had at least one episode of reflux on impedance pH monitoring, and some had very frequent episodes despite receiving transpyloric feeds. Critically ill adults with transpyloric feeds almost all have reflux of duodenal contents into the stomach, and almost all have gastro-oesophageal reflux and pulmonary aspiration, with only minor differences to controls randomized to gastric feeding. The latest version of the Cochrane review of transpyloric feeding in the newborn notes an increase in mortality, more GI disturbances, no change in aspiration pneumonia/pneumonitis, no data on BPD, and an overall poor quality of available data.

Even if BPD were clearly more common among babies with recurrent micro-aspiration there is no evidence-based way to prevent, or even reduce, that phenomenon in the newborn.

But what about after lung injury has developed? Do babies with BPD have more reflux than those without? Does GOR adversely impact respiratory function or clinical progress in infants with BPD? Does treating reflux improve clinical outcomes in babies with established BPD?

In 1989 a publication compared acid reflux to the proximal oesophagus between preterm infants (on full feeds, at about term) with and without BPD. They actually found less reflux in the BPD infants. A more recent study from 2004 also using pH-metry found the same thing, less reflux among babies with BPD compared to controls of similar gestational and post-menstrual age without BPD. A 2015 study, using impedance as well as pH monitoring showed no difference in reflux events between BPD and control babies who all had “symptoms consistent with GOR”. That study was only able to find a difference after multiple quantile regression analysis, and only in pH-only events, that is, events which dd not show evidence of bulk fluid movement into the oesophagus.

I haven’t been able to find any reliable evidence to address the second and third questions, which are obviously linked. Even though GOR does not appear to be more common in babies with BPD compared to control preterm infants, it could still be associated with worse lung injury and babies could possibly benefit from treatment, and evidence of an adverse impact would be strongest if reducing GOR actually improved lung function. The big problem of course is the lack of effective treatments of GOR. Although commonly referred to as anti-reflux treatments, acid blockade with histamine receptor antagonists or proton pump inhibitors do not, of course, reduce reflux. Unless symptoms are only due to acidic GOR they will have no effect. There is no good evidence to support the use of any prokinetic agent, those that have been investigated are as likely to show an increase in reflux as a decrease.

The recent article about medication use in the NICU that I already discussed was somewhat reassuring that there had been a decrease in the use of lansoprazole between 2010 and 2018, (and of ranitidine, but that had been taken off the market). I couldn’t see much else on the list that is being used to replace them, there is rare use of famotidine and omeprazole. I was surprised to see both sucralfate and simethicone on the list of NICU drugs, which maybe are being given for perceived GOR symptoms, but simethicone doesn’t even work for colic, the usual indication, at least as according to the only placebo controlled RCT that was performed; Sucralfate is 21% aluminium by weight, so probably not a good idea to give to developing brains.

In summary then, there is no good evidence that GOR and microaspiration are important in the pathogenesis of BPD, there is no good evidence that infants with BPD have increased GOR compared to other preterm infants, and there is no good evidence that GOR has an impact on respiratory function in established BPD.

Even if, in an individual patient, you thought that GOR might be contributing to their pulmonary symptoms, I reiterate that there isn’t much you can do about it. There is no evidence-based effective medication that safely decreases GOR or GORD. Thickening feeds has a minor effect on reflux, but has never been shown to improve any clinical aspect of GORD. Transpyloric feeding does not eliminate GOR, and, in the only trial in infants with established BPD, transpyloric feeding seemed to increase hypoxic spells. All you can do is try and keep the babies upright especially after feeds (this might have no direct evidence base, but kangaroo care has many benefits, and gravity can be our friend), and wait for improvement.

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What is Gastro-Oesophageal Reflux Disease (GORD, or GERD if you prefer) in the neonate?

Posted on 4 March 2022 by Keith Barrington

All babies have reflux, repeated transient lower oesophageal sphincter relaxations are universal. Almost all babies have overt regurgitation, I often say that if a baby never regurgitates it may be a sign that they aren’t getting enough milk!

So when does GOR become GORD? There are 3 groups of symptoms that are often ascribed to reflux in the NICU: apnoeas and recurrent bradycardias; respiratory deterioration/bronchopulmonary dysplasia; oesophagitis and resulting feeding problems.

There are many studies of the relation between GOR and either apnoeic or bradycardic spells. In order to have any idea of the reality of that relationship we need prolonged multichannel recordings which measure reflux objectively in addition to cardiorespiratory recordings which include airflow. In a study I did a few years ago now in San Diego we used pH recordings and found no relationship evident between apnoeic events and acid reflux. But, of course, most GOR in newborn infants is either neutral or alkaline, so its possible that we could have missed something.

Most of the available studies which have used impedance, and therefore detected non-acid reflux also, show no temporal relationship between episodes of reflux and acute respiratory events, some show that apnoea (particularly obstructive apnoea) may precede reflux events. There are one or two that have reported that acid reflux may trigger apnoeas in some infants, and a couple of studies, usually in small highly selected groups of babies, showing a temporal relationship between GOR events and obstructive apnoeas. One study, for example, in 7 former preterm infants around term found that among the 4 who had extremely frequent obstructive apnoeas (>6 per hour) there were 3 who seemed to have apnoeas preceded by GOR.

One interesting study from Jadcherla’s group in Columbus Ohio used the sort of intensive monitoring I have described, but with oesophageal manometry rather than impedance measures, and then introduced artificial pharyngeal stimulation with up to 0.5 mL of sterile water as a bolus. They found that overall former preterm babies who were evaluated at 36 to 40 weeks PMA with or without recurrent bradycardia had very similar responses to pharyngeal stimulation. A subgroup of the babies had more severe bradycardia after stimulation, the definitions the authors used are rather weird as they are based on the resuscitation guidelines NRP and PALS, which are of course completely irrelevant for episodic bradycardias in otherwise stable infants. Nevertheless, this study does suggest that some babies are more sensitive to pharyngeal stimulation than others and may have more severe bradycardias, but these studies were performed after discharge home, at around term post-menstrual age, and therefore not necessarily relevant to apnoea in the NICU.

Fig. 1

This remarkable image shows a reflux event, using overlaid data from oesophageal manometry in addition to multiple impedance (the white lines). The reflux event starts with a transient relaxation of the LES, lower oesophageal sphincter, and the progressive drop in impedance in a cephalad direction is the bolus of liquid climbing the oesophagus, followed by major increases in pressure which are swallowing movements in the pharynx and then the purple wave of increased pressure moving down the oesophagus to clear the reflux. In the interesting review article from which that image was taken (Badran EF, Jadcherla S. The enigma of gastroesophageal reflux disease among convalescing infants in the NICU: It is time to rethink. Int J Pediatr Adolesc Med. 2020;7(1):26-30). There are other images also which show an association between episodic symptoms preceding a reflux event.

This looks to me as if the arching and irritability, or the grunt, caused the reflux, rather than the other way around! Indeed when symptom scores have been compared with objective recording of reflux in NICU patients, there has usually been no correlation. There are several studies that have almost all failed to show that symptoms ascribed to reflux are actually caused by reflux, four that I quickly found in my files are listed below.

I teach residents and fellows that the only clinical sign which is reliable for the presence of reflux is overt regurgitation. Even though reflux might sometimes cause clinical consequences (GORD) there is no way to determine its presence without prolonged impedance monitoring, which should be combined with pH and multi-channel recordings to have any confidence that clinical events are caused by reflux.

Also vitally important, most reflux in the newborn in the NICU is not acidic, and there is no evidence that the acidity of reflux episodes is associated with the likelihood of a reflux episode causing a clinical event. Using acid blocking medications therefore has no rational basis in the treatment of GORD if the justification for treatment is the presence of episodic cardiorespiratory events. And probably not for other possible respiratory indications either, a subject to which I shall return.

Funderburk A, et al. Temporal Association Between Reflux-like Behaviors and Gastroesophageal Reflux in Preterm and Term Infants. J Pediatr Gastroenterol Nutr. 2016;62(4):556-61. Snel A, et al. Behavior and gastroesophageal reflux in the premature neonate. J Pediatr Gastroenterol Nutr. 2000;30(1):18-21. Kohelet D, et al. Esophageal pH study and symptomatology of gastroesophageal reflux in newborn infants. Am J Perinatol. 2004;21(2):85-91. Mousa H, et al. Testing the association between gastroesophageal reflux and apnea in infants. J Pediatr Gastroenterol Nutr. 2005;41(2):169-77.

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What do we tell families at 22 weeks?

Posted on 28 January 2022 by Keith Barrington

When we counsel families about the potential outcomes for infants born profoundly preterm, I think we would all agree that we should be honest, transparent and truthful. Which includes, I would suggest, truthfulness about our own local results, as well as what is possibly available elsewhere.

In order to communicate such results we need to have a good idea of what those results are. I think it is entirely acceptable to say, for example “we don’t have much experience with babies of 22 weeks gestation, they don’t come along very often, and until recently we didn’t think that active care of such infants was a good idea. We have changed our approach and will do the best we can for your baby, whatever we choose together for her”. The rest of the conversation should follow the parents leads, while trying to determine what is important for them.

All of that, of course, requires that you have some idea about the likelihood of survival and of long term functional outcomes. Unfortunately many professionals in the chain of decision making are not well informed themselves. In a recent blog post I discussed an article which asked health professionals in the UK involved in neonatology to estimate survival and severe disability among survivors, and found major variability in estimates, generally estimates of survival were lower than a published calculator, and estimates of “severe disability” were higher.

Another article addressing similar estimates among health care workers who might be asked to talk to mothers with threatened profoundly preterm has been published from the state of Victoria in Australia. Boland RA, et al. Disparities between perceived and true outcomes of infants born at 23-25 weeks’ gestation. Aust N Z J Obstet Gynaecol. 2021. Obstetricians, neonatologists, midwives and nurses in tertiary and non-tertiary hospitals were questioned.

Estimates of the respondents were compared to recent actual local data, including outborn babies. Overall, as in several previous studies, survival was underestimated, and “major disability” was dramatically over-estimated.

As this study again shows, the majority of survivors at every gestational age do not have major disability, whereas respondents think that the proportions are reversed. Obstetricians and nurses tended to be more pessimistic than neonatologists, another typical finding.

The authors compared their results to a survey from 2010, and found that respondents were more pessimistic than they were previously, when comparing estimates to contemporary results. Survival is improving, but it seems likely that mothers are receiving inaccurate, unnecessarily pessimistic information.

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Active intensive care at 22 weeks gestation

Posted on 27 January 2022 by Keith Barrington

Even the New England Journal are getting in on the act (Lee CD, et al. Neonatal Resuscitation in 22-Week Pregnancies. N Engl J Med. 2022;386(4):391-3), I guess that someone talked to the editors about the practice variation in resuscitation of profoundly immature babies, and in response they have published this short vignette with 2 somewhat opposing views, Leif Nelin who promotes the idea that we should recommend universal active intervention, and Elizabeth Foglia who is in favour of recommending selective resuscitation.

I find it very interesting that there is not a 3rd author promoting an approach which still happens in many centres, i.e. recommending universal comfort care.

It is also interesting that there is no real disagreement on the facts, that without active intensive care mortality is 100%; that with intensive care some babies survive, and the majority of the survivors have good lives. The actual proportion of survivors is, of course, very variable, and it requires a commitment of both obstetrics and neonatology to work together to achieve the best results.

Dr Foglia says 2 things that require some reflection, she notes that “almost all extremely preterm infants require resuscitative interventions after birth to survive” which is sort of true, but depends on what you mean by “resuscitative interventions”, in most centres all such babies have endotracheal intubation shortly after birth, but further “resuscitative interventions” are uncommon. The second thing is “The current limit of viability is 22 weeks’ gestation.” That is stated as a verity, but it ignores 3 things, 1. we never know exactly what the GA is, except after IVF, so if you actively intervene for all 22 week GA babies, you will have intervened for some at 21 weeks. 2. If survival at 23 weeks can be as high as 60%, surely at 21 weeks and 6 days it would not suddenly drop to zero! 3. There are reported survivors who were thought to be <22 weeks.

Current guidelines do not often recommend antenatal steroids at 22 and 23 weeks, which is partly because of a lack of such infants in randomized controlled trials, but we are unlikely to have substantial numbers of mother in trials at those gestations for a while, if ever, so observational data are all we are likely to have. Rossi RM, et al. Association of Antenatal Corticosteroid Exposure and Infant Survival at 22 and 23 Weeks. Am J Perinatol. 2021(EFirst). This article, as one example, calculated the probability of survival at 22 and 23 weeks of GA, according to whether steroids were given prior to delivery. The data source they used had no information of timing of steroids, it was just a checkbox, yes or no. It probably includes, therefore, many babies with brief steroid exposure. Survival is only presented for babies who received active neonatal intensive care. The overall survival at 22 weeks, to one year of age, is shown below, divided by birth weight categories.

ANCS= antenatal corticosteroids

They don’t have the same sort of birth weight breakdown for the 23 week babies, but overall 1 year survival was 58% after antenatal steroids, and 48% without steroids. Relative risk 1.5 (95% compatibility intervals, 1.3-1.6). 62% of the 22 week deaths of babies who had antenatal steroids were before 7 days of age, as were 53% of the 23 weeks infants.

Currently all the data about such deliveries is consistent, ANS administration is associated with a major improvement in survival, the NNT is actually smaller than at any later GA. All the studies, unfortunately, suffer also from the same biases, which are sort of self-evident.

What is also consistent, is that centres with the best results, have a co-ordinated approach with obstetrics, and routinely give steroids as soon as the mothers are admitted.

As for my response to the NEJM article? I would perhaps phrase it a little differently, I think that active neonatal intensive care should be offered as an option to all mothers presenting with an increased risk of delivering at 22 to 24 weeks gestation, and that option should be presented as a reasonable choice which will be supported by the whole team, who will then do whatever they can to have the best possible outcome. When additional risk factors are present, such as growth restriction, imminent delivery without benefit of significant ANS exposure, then the discussion of the options must recognize those facts. When increased risk is very great, such as estimated weight <400g or florid chorioamnionitis, then it is vitally important to be realistic. It is also important to recognize that the decision to give steroids, as soon as possible, does not mandate active neonatal care, but will give the best chance for the baby if the later decision is indeed to proceed with intensive care. And that a decision for such care does not mandate a cesarean delivery, which should be considered a separate (obviously related) decision, which takes into account additional factors, including maternal age, risk factors etc.

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Speak French to your babies (or Chinese) in the NICU

Posted on 25 January 2022 by Keith Barrington

This is a fascinating study from Columbus Ohio in mildly preterm babies when they reached term. (Richard C, et al. Randomized Trial to Increase Speech Sound Differentiation in Infants Born Preterm. J Pediatr. 2021) We know that prematurity and NICU care both have adverse impacts on language acquisition, and these authors wondered if there are ways we can mitigate those impacts. The babies were late preterms who were enrolled at term or slightly after (post-menstrual age of 36 to 52 weeks. They had a normal hearing screen using brainstem responses, and their families spoke only English. The investigators recorded female voices speaking American English, Mandarin Chinese, or French (they don’t say if it was Parisian French or Quebecois), with speech patterns such as those used for speaking to young infants, which they characterise as “a slower rate of speech, higher vocal pitch, simpler sentence structure, more variable prosody (rhythm, stress, and intonation of speech), and elongated vowels.” These are characteristics of infant-directed speech in many languages (and also of speech directed to our pets). The recordings also included lullabies in the relevant language, and the recordings were played to the babies for 15 minutes, twice a day for a couple of weeks.

They then tested the responses by playing synthesized syllables, consisting of a vowel and a consonant, from each of the languages, and measured auditory responses using temporal electrodes, obtaining the responses before and after the intervention.

Using this methodology, they were able to identify the brainstem responses to individual sounds, and also to see if pairs of sounds gave the same response, if responses differed it meant that there was differentiation between the syllable sounds.

https://ars.els-cdn.com/content/image/1-s2.0-S0022347621010283-gr1.jpg
Figure 3. Examples of Grand average tracings of ERP in response to different speech sounds for each language intervention group, pre- and post-exposure in T6. Only responses to representative speech sounds for the intervention language are shown, (eg, response to French sounds for the French-contingent intervention group). Examples of individual speech sounds are shown as dashed and dotted lines; absolute difference in mean amplitude between speech sounds is shown for each contrast (solid line). Differentiation of speech sounds is calculated as the absolute difference in mean amplitude between speech sound pairs in the 250 ms-400 ms poststimulus time window (grey bars). Increased speech sound differentiation occurs after interventions.

What they found was that exposure to the foreign language increased differentiation between pairs of sounds in that language, but not in the other language, and it had no negative effect on differentiation between pairs of English sounds.

As a background, you should realize that preterm infants have been shown to be able to differentiate syllables at 30 weeks gestation, and young infants can differentiate hundreds of speech sounds (phonemes), an ability which we gradually lose as we acquire a language.

This probably explains some of my difficulty in pronouncing French correctly, as I learned to speak French relatively late in life, I had already lost much of my ability to differentiate certain phonemes, an ability which is hard to relearn. To a native French speaker there is a world of difference between “tu” and “tout”, but it is much more difficult for others. Similarly, many native French speakers have great difficulties with my name as “…th” doesn’t exist in French, and their brains have difficulty in figuring out how to make that sound. Which leads to me frequently being called “Keet” or “Kees” by fellows in our program who are from France! Interestingly Quebec natives, who are generally brought up with a massive exposure to English during their infancy, have much less difficulty and can usually manage “Keith”. “th” both as a hard and a soft sound (‘they’ compared to ‘think”) are common phonemes in English, and Quebec infants probably have major exposure to them.

The research seems to give clues to ways that we might, in the future, enhance language development and perhaps overall executive functioning. In general terms, children from bilingual families have language development which mirrors that of unilingual families, if both languages are taken into account, and in the long term have superior language skills. There is evidence that a bilingual upbringing improves executive function, and there is evidence that that applies to preterm babies. At least one study has shown that preterm babies born to bilingual families have enhanced executive function skills copmared to the monolingual (Baralt M, Darcy Mahoney A. Bilingualism and the executive function advantage in preterm-born children. Cogn Dev. 2020;55).

Exposure to human speech during the NICU stay seems to improve some indicators of early language development of the premature, (Kostilainen K, et al. Repeated Parental Singing During Kangaroo Care Improved Neural Processing of Speech Sound Changes in Preterm Infants at Term Age. Front Neurosci. 2021;15:686027) and a wide exposure to different types of language, one important example being reading stories to NICU babies (Lariviere J, Rennick JE. Parent picture-book reading to infants in the neonatal intensive care unit as an intervention supporting parent-infant interaction and later book reading. J Dev Behav Pediatr. 2011;32(2):146-52), seems to be beneficial. This new study suggests that we should perhaps extend that to language exposure in more than 1 language; even if the parents aren’t bilingual, it could be that exposing our NICU babies to recorded speech in other languages will be beneficial.

I think it is now clear, even as research is ongoing, that reducing exposure to noxious sounds, and increasing exposure to human voice is important for enhancing future development of preterm NICU babies. It is important that we structure our NICU care to allow major exposure to human voices, reading to babies, talking to them using appropriate speech patterns, singing lullabies, and possibly talking to them in a second language. It is one thing we can encourage parents to do in order to be involved in their baby’s care and have a positive impact on their long term outcomes.

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More musings on the microbiome

Posted on 21 January 2022 by Keith Barrington

We are fortunate in neonatology to not have to worry about C difficile, partly because the name has been changed for this germ as well (now Clostridioides, rather than Clostridium), and it is one less name change to keep up with, but more seriously because it can be devastating, difficult to eliminate and frequently recurring. There are some parallels with NEC, however, including an association with prior antibiotic use, an association with gastric acid production inhibitors, a deranged intestinal microbiome preceding the condition, and a predilection for the most fragile patients. Probiotic prophylactic studies have generally shown efficacy, but one very large trial found no effect (I think because the control group rate was so low), and probiotic prophylaxis is not universal despite a favourable risk-benefit and cost-benefit profile.

There are also differences, including the clear efficacy of an intervention that has not been tried in preterm neonates (to my knowledge): fecal transplantation. And now a trial, just published in the NEJM (Feuerstadt P, et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. N Engl J Med. 2022;386(3):220-9), of a probiotic preparation specifically designed to prevent recurrence using a mixture of spore bearing Firmicutes, was dramatically successful in reducing recurrence, from 40 to 12%, relative risk 0.32, compatibility intervals 0.18, 0.58. There were zero adverse effects. The role of bile acid metabolism was something I did not know about, but the Firmicutes metabolize primary to secondary bile acids, preventing the C difficile from having access to primary acids, a further analogy with the role of Bifidobacteria in metabolizing HMOs.

With the risk of giving too much press to one specific commercial strain of probiotic for the newborn, another recent publication regarding B longum susbsp infantis (Bajorek S, et al. B. infantis EVC001 Is Well-Tolerated and Improves Human Milk Oligosaccharide Utilization in Preterm Infants in the Neonatal Intensive Care Unit. Frontiers in Pediatrics. 2022;9) looked at stools of 15 VLBW infants before and 15 infants after introduction of probiotic administration in their NICU. None of the control group became colonized with the organism, compared to all of the intervention group, the more heavily colonized the baby was, the less Enterobacteria were present in their stools. The B infantis was very efficient at metabolizing oligosaccharides, leaving practically zero of the measured HMOs in the babies’ stools.

The abbreviations refer to commonly studied HMOs, 2′-fucosyllactose (2′-FL), 3-fucosyllactose (3′-FL), lacto-N-tetraose (LNT), Lacto-N-fucopentaose I (LNFP I) and 6′-Sialyllactose (6′-SL). I don’t know if the LNT is the same thing as the DSLNT (disialyllacto-N-tetraose) that I have previously discussed, but if so it is an extremely important HMO, and the ability to metabolize it may be important for probiotic efficacy.

Antibiotics are well known to effectively kill the probiotic organisms as well as the pathogens against which they are directed. A broad range of molecules (penicillins, macrolides, clindamycin) seems to destroy Bifidobacteria and Lactobacilli, they do this when administered antenatally, with prolonged impacts on the intestinal microbiome (Diamond L, et al. Impact of intrapartum antibiotics on the infant gastrointestinal microbiome: a narrative review. Arch Dis Child. 2021), and of course when administered directly to the infant (Tapiainen T, et al. Impact of intrapartum and postnatal antibiotics on the gut microbiome and emergence of antimicrobial resistance in infants. Sci Rep. 2019;9(1):10635). A recent study from Shanghai randomized 55 full term infants with suspected early onset sepsis receiving 7 days of piperacillin-tazobactam, to either control, 1 week of concurrent probiotics, or 1 week of probiotics after the antibiotics finished. (Zhong H, et al. Impact of probiotics supplement on the gut microbiota in neonates with antibiotic exposure: an open-label single-center randomized parallel controlled study. World J Pediatr. 2021;17(4):385-93). They showed a simplification of the microbiome and near elimination of Bifidobacteria with pipi-tazo when stools were sampled 1, 2, and 6 weeks later. When a probiotic mixture of Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis was given after the antibiotics it wasn’t very effective at restoring the microbiome. When probiotics were given concurrently they modified the “devastation” of the microbiome by the antibiotics, allowing a faster recovery, particularly of the Bifidobacteria.

We start probiotics along with the feeds (maternal or donor breast milk) in our extremely and very preterm babies, and I have often wondered whether it was effective to give probiotics with the feeds to those babies who were receiving antibiotics, or whether we should wait until the antibiotics have stopped. Although obviously not directly relevant to our preterm babies with our probiotics and our usual ampicillin/gentamicin treatment, this study suggests that maybe it is worth doing after all.

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