Fluid restriction as treatment for BPD? This time with the summary of findings table.

I realize that many of my gentle readers may not have access to the Cochrane reviews in full text as soon as they are published. The NICHD do provide free access to the neonatal reviews, (together with a useful introduction to the value, limitations and methodology of the Cochrane reviews) but it seems to take a couple of months for them to catch up with a new review arriving. Even OVID, one of the ways of accessing some of the Wiley content, which is how I access the reviews from my university, hasn’t updated the Cochrane Library to include the fluid restriction review yet. Which means I can’t even access the full text on-line myself yet!

I will re-post about the 3 latest reviews that we have published as soon as full text is available from the NICHD web-site.

I thought therefore I would re-post this, about the fluid restriction SR, and add a slightly edited version of the Summary of Findings table, with the secondary outcomes of the systematic review that we included. You will note that I could not calculate the confidence intervals for the duration of oxygen therapy, the standard deviations weren’t included in the original article (rather they included the ranges). Nevertheless the means are so similar that the confidence intervals are likely to be wide, and certainly to be ‘not significant’.

fluid-restriction

I have never been convinced that fluid restriction is a good thing for kids with BPD. I think the common practice came about because of the short-term improvements in lung function that sometimes follow if you start diuretics. The idea being that if diuretics improve lung function, then giving less fluid will also.

But this is a false equivalency, diuretics cause sodium depletion, and therefore decrease total body water, and probably lung water content also. Fluid restriction in contrast leads to a reduction in urine output, and, within clinically reasonable limits, will not have an impact on total body water, and there is no reason to believe that they will reduce lung water content either.

Diuretics may have other direct effects on pulmonary function, that will not occur with fluid restriction. Inhaled furosemide, for example, improves pulmonary mechanics in BPD, presumably by acting on the same sort of ion pump that loop diuretics block in the kidney.

Even in adults with fluid overload (those with oedematous congestive heart failure) RCTs of fluid restriction show no effect, unless sodium intake is also severely restricted. Sodium restriction alone works as well, so the fluid restriction adds nothing.

Despite this, there are recommendations from usually reliable people that babies with BPD should have their fluid intake restricted, such recommendations are often accompanied by a reference, usually a reference to another recommendation or to a narrative-type review article.

I have been planning for years to do a systematic review for the Cochrane library, of fluid restriction as treatment for early or established BPD. We have finally finished the review and it has just appeared. (Barrington KJ, Fortin-Pellerin E, Pennaforte T. Fluid restriction for treatment of preterm infants with chronic lung disease. Cochrane Database of Systematic Reviews. 2017(2).)

Using the usual search procedures we could only find one relevant trial. In fact the initial search didn’t find the article (Fewtrell MS, et al. Randomized trial of high nutrient density formula versus standard formula in chronic lung disease. Acta Paediatrica. 1997;86(6):577-82.) even though I knew it existed; the Pubmed key words did not mention fluid volumes or restriction, so we tweaked the search to ensure that we found the article, and to make sure that we would find any others that exist.

So the only RCT evidence addressing fluid restriction is a study of 60 preterm babies with early chronic lung disease (needing oxygen at 28 days of age) who were randomized to either get 180 mL/kg/day of a regular formula, or 145 mL/kg/d of a concentrated formula. Unfortunately they didn’t report on one of our outcomes, oxygen requirement at 36 weeks, as it wasn’t, at that time, the standard outcome that it has since become.

That study showed no benefit of fluid restriction on any outcome. The fluid restricted group had more apneas, a finding unlikely to be due to chance, and also had more babies who needed more than 30% oxygen during the trial, a difference which may have been due to chance.

Fluid restriction risks nutritional restriction also; even though the idea may be to reduce the free water intake, babies often get fewer calories and less protein when fluid restricted, while babies with BPD actually need more calories. They will also produce more concentrated urine, which might increase the risk of nephrocalcinosis as well.

The final message is that there is no evidence to support the practice of fluid restriction of babies with early or established BPD. There is no physiologic rationale either. There are potential risks to the practice.

We should stop doing it.

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New Publication: Does fluid restriction improve the clinical status of babies with BPD?

I have never been convinced that fluid restriction is a good thing for kids with BPD. I think the common practice came about because of the short-term improvements in lung function that sometimes follow if you start diuretics. The idea being that if diuretics improve lung function, then giving less fluid will also.

But this is a false equivalency, diuretics cause sodium depletion, and therefore decrease total body water, and probably lung water content also. Fluid restriction in contrast leads to a reduction in urine output, and, within clinically reasonable limits, will not have an impact on total body water, and there is no reason to believe that they will reduce lung water content either.

Diuretics may have other direct effects on pulmonary function, that will not occur with fluid restriction. Inhaled furosemide, for example, improves pulmonary mechanics in BPD, presumably by acting on the same sort of ion pump that loop diuretics block in the kidney.

Even in adults with fluid overload (those with oedematous congestive heart failure) RCTs of fluid restricion show no effect, unless sodium intake is also severely restricted. Sodium restriction alone works as well, so the fluid restriction adds nothing.

Despite this, there are recommendations from usually reliable people that babies with BPD should have their fluid intake restricted, such recommendations are often accompanied by a reference, usually a reference to another recommendation or to a narrative-type review article.

I have been planning for years to do a systematic review for the Cochrane library, of fluid restriction as treatment for early or established BPD. We have finally finished the review and it has just appeared. (Barrington KJ, Fortin-Pellerin E, Pennaforte T. Fluid restriction for treatment of preterm infants with chronic lung disease. Cochrane Database of Systematic Reviews. 2017(2).)

Using the usual search procedures we could only find one relevant trial. In fact the initial search didn’t find the article (Fewtrell MS, et al. Randomized trial of high nutrient density formula versus standard formula in chronic lung disease. Acta Paediatrica. 1997;86(6):577-82.) even though I knew it existed; the Pubmed key words did not mention fluid volumes or restriction, so we tweaked the search to ensure that we found the article, and to make sure that we would find any others that exist.

So the only RCT evidence addressing fluid restriction is a study of 60 preterm babies with early chronic lung disease (needing oxygen at 28 days of age) who were randomized to either get 180 mL/kg/day of a regular formula, or 145 mL/kg/d of a concentrated formula. Unfortunately they didn’t report on one of our outcomes, oxygen requirement at 36 weeks, as it wasn’t the standard outcome that it has since become.

That study showed no benefit of fluid restriction on any outcome. The fluid restricted group had more apneas, a finding unlikely to be due to chance, and also had more babies who needed more than 30% oxygen during the trial, a difference which may have been due to chance.

Fluid restriction risks nutritional restriction also; even though the idea may be to reduce the free water intake, babies often get fewer calories and less protein when fluid restricted, while babies with BPD actually need more calories. They will also produce more concentrated urine, which might increase the risk of nephroclacinosis as well.

The final message is that there is no evidence to support the practice of fluid restriction of babies with early or established BPD. There is no physiologic rationale either. There are potential risks to the practice.

We should stop doing it.

Posted in Neonatal Research | Tagged , , , | 2 Comments

The FDA warns against anaesthesia in the very young

There has been accumulating evidence of the potential risks of anaesthetic agents, such as risks of enhanced apoptosis in animal models and long-term functional effects in  those various animal models also. All anaesthetic agents appear to be affected, which I guess should not be too much of a surprise. A molecule which is capable of making you comatose for a short time presumably has an effect on the brain!

Whether these impacts cause lasting damage in humans has been very difficult to ascertain. How would you do a prospective RCT with and without anaesthesia? Long term evaluations of the subjects in such a study would be very difficult and expensive. And yet such a study has been done, the GAS trial randomized young infants to sevoflurane inhalation in one arm, and awake regional anaesthesia (which was either a spinal or a caudal) with bupivacaine in the other. They included over 700 infants of less than 60 weeks post-menstrual age who were having hernia repairs. Many of the children (about 55%) were of course premature babies, which is why the entry criterion of 60 weeks PMA was chosen, which works out to a corrected age of up to 4 months. They included babies down to 26 weeks gestation at birth. 70 of the babies in the awake regional anesthesia group had to instead have a general anesthetic; the paper does not state why this was the case, but either technical failure or need for sedation are not uncommon in kids of this age. The authors analyzed by treatment actually received (per protocol analysis) and also secondarily by intention to treat, which I think when looking for toxicity is the appropriate type of analysis.

This report (Davidson AJ, et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. The Lancet. 2016;387(10015):239-50.) is actually a report fo the secondary outcomes of the trial, the primary outcome will be 5 year IQ testing.

This follow-up published so far, to 2 years of age, shows no difference between the groups in the GAS trial. Interestingly the composite scores on the Bayley 3 scales of infant development all average a bit below 100, whereas in general in the population they are above 100 because of the way the scales were normalized. The actual scores reported, in both groups, are quite similar to the scores from very preterm children reported by the Victoria group in Australia, who were all less than 30 weeks gestation. The lack of difference between groups in the GAS trial might mean that sevoflurane given for an average of about 50 minutes is safe, or that regional anesthesia, with bupivacaine, is equally as toxic! There is actually some evidence of bupivacaine neurotoxicity, but there should be very little reaching the central nervous system, so I don’t think that is likely to be the explanation of the lowish scores in both groups. Perhaps all of the risks that increase the rate of having an inguinal hernia also are associated with slightly lower Bayley 3 scores at 2 years, or just the stress of having a surgery. About 14% of the babies in the study had to have at least one other anaesthetic, and over 30% had to be hospitalised for something else. These extra risks for developmental effects were in both groups, which might reduce any impact of the anaesthetic approach, and might also account for the slightly low scores.

The only way to be absolutely sure would be to do an RCT of surgery with different anaesthetic approaches, and include a 3rd no surgery group. However, in general, surgery in early infancy is not optional. Apart from circumcision, aesthetic surgery is uncommon! Which brings me back to the new FDA warning. The results of observational studies of anaesthesia exposure and developmental outcomes are inconsistent, some showing adverse effects, and others. especially with short or single exposures, showing little or no impact. It isn’t clear to me what triggered the FDA to release its new warning, their last advisory committee meeting was in 2014, and I don’t know if there is anything much new since then, apart from the GAS trial which doesn’t show adverse effects.

The new warning starts like this:

The U.S. Food and Drug Administration (FDA) is warning that repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains.

I really don’t understand what the motivation of the FDA is to issue this warning, are they hoping that children will not have unnecessary prolonged or repeated surgery because of this warning, which they otherwise would have done? Why 3 years precisely? The observational studies have had varying entry criteria, and if the agents are toxic at 2 and a half years, they probably are at 3 and a half also. There also doesn’t actually appear to be any data about effects on the fetal brain, at least not in humans, and anaesthesia in pregnant women is never performed without a really good indication.

It is quite rare that a major surgery requiring prolonged anaesthesia can be delayed in a young infant, and when it can be delayed safely, that is already done. Maybe the FDA are trying to get more funding for their SmartTots initiative, which is an important initiative, but the burden this new warning places on anesthetists (American spelling for a mostly American impact) may be substantial. An editorial in the FPNEJM makes some of these same points, and also notes

At Texas Children’s Hospital, approximately 13,000 (anesthetics) involve patients under 3 years of age, and about 1300 of these patients undergo anesthesia for more than 3 hours; two thirds of these cases of prolonged anesthesia are for procedures related to congenital heart disease. Essentially all these prolonged procedures are for serious or life-threatening congenital conditions for which there are no alternative treatments and for which treatment cannot be delayed until the patient reaches 3 years of age. Approximately 1400 patients at Texas Children’s Hospital who are less than 3 years of age undergo two or more procedures requiring general anesthesia in any year, and 2000 undergo sedation or anesthesia for magnetic resonance imaging examinations. After deliberation among its leaders in anesthesiology, surgery, and hospital risk management, the hospital has changed its practice in response to the FDA warning. The FDA warning itself will now be discussed before surgery with parents of all children younger than 3 years of age who would be receiving an anesthetic. And the hospital has adopted the warning’s recommendation that a discussion occur among parents, surgeons and other physicians, and anesthesiologists about the duration of anesthesia, any plan for multiple general anesthetics for multiple procedures, and the possibility that the procedure could be delayed until after 3 years of age; parent-education materials will also cover these topics.

I have no problem with informing parents of possible risks, but when there is (as there usually is) no medically appropriate alternative to the surgery the many thousands of worrying discussions with the parents may not achieve much except increased anxiety.

Adding a discussion of possible, and unproven, long-term adverse effects of unknown severity and unknown importance for quality of life, to the discussions which are already taking place of risks of surgery, risks of intubation, other risks of anesthesia seems questionable.  There are many other potential, unproven, possible risks also.

Some procedures, especially in the preterm infant, are also often performed using high dose opiates, which in some animal models also cause apoptosis. These agents aren’t mentioned in the FDA warning, but we shouldn’t suppose that they are safe for the long term either.

Maybe the message should be, “don’t do surgery in young infants unless you need to” which I think we can all agree to.

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Premature labour changes a mother’s brain, and her baby’s

In this rather weird, but interesting study from Italy, 10 mothers of preterm babies (less than 32 weeks or less than 1500 grams) without ultrasound brain injury or severe retinopathy, and 11 mothers of full term babies were shown photos of their own baby or photos of an unknown baby (from one of the other mothers) while they had their head in an MRI magnet. (Montirosso R, et al. Greater brain response to emotional expressions of their own children in mothers of preterm infants: an fMRI study. J Perinatol. 2017). The photos were of their baby’s face while happy, neutral, or crying. Using functional MRI the researchers determined the activation of several different brain areas, at 3 months corrected age.

All the mothers had more activation in several areas when looking at their own baby’s face than when looking at the unknown baby.

When they compared the responses between the groups, the preterm mothers had greater activation in several areas both when looking at their own baby’s face, and also when looking at the unknown baby’s face, than the term mothers, and when viewing their own infant’s face they showed increased activation in an emotion processing area (i.e., inferior frontal gyrus) and areas for social cognition (i.e., supramarginal gyrus) and affiliative behavior (i.e., insula). The mothers were reasonably well matched, and not suffering from postnatal depression or anxiety.

The weeks of stress in an NICU watching their baby and being able to do little to protect them look like they change a mother’s brain function.

Now what about the dads?

Another article (Paules C, et al. Threatened preterm labor is a risk factor for impaired cognitive development in early childhood. Am J Obstet Gynecol. 2017;216(2):157 e1- e7). and a very interesting editorial, compared 3 groups of children at 2 years corrected age. Babies born late preterm  and infants who had been  born at term, after an episode of preterm labour. And a group born at term, without a history of preterm labour. The groups were fairly small, (22, 23 and 42 respectively). The episode of threatened preterm labour occurred between 25 and 36 weeks gestation, and isn’t described in this paper, in terms of actual gestational age or other complications associated, except that the membranes were not ruptured. Some of the mothers received steroids, and that was different between the late preterm born babies (55%) and the term delivering babies (100%).

The babies born after threatened preterm labour, whether they delivered at term or late preterm had scores on the developmental/cognitive/motor function screening test which were very similar to each other in almost all domains, and also lower in almost all domains than the controls. Overall, the Odds Ratio for what they call “mild delays in development” (more than 1 standard deviation below the mean, which is really in the lower part of the normal distribution), at 2 years was about 2.0, after an episode of preterm labour.

A very interesting editorial confirms that this is probably the first study to have published such outcomes, although previous studies have shown an increase in SGA after threatened preterm labour. In this new study, also, the threatened preterm labour babies born at term weighed 200 grams on average less than the controls despite being born only 1 day earlier. If this finding is true (and in such a small study we should be careful about relying on it too much) then the big question is: why? Why should an episode of threatened preterm labour, which resolves with eventual delivery at term have an effect on cerebral development? Is it an antenatal influence of perhaps increased intra-amniotic inflammation? Does such an episode affect the home environment? Is it related to the somewhat higher educational level of the control mothers? (Although this was included in the logistic regression model, the differences are quite large, 30% of term delivering babies after preterm labour only had primary education, compared to 14% of controls).

If this finding is confirmed it might lead the way to further research studying the mechanisms, and help us get a handle on the impacts of preterm birth after preterm labour also.

 

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Should we freeze maternal breast milk in the NICU? Pasteurize it?

Maternal breast milk is what we should be giving to every preterm infant as much as possible. But we know that there are cases of transmission of cytomegalovirus (CMV) and reports of transmission of other pathogens to babies from breast milk. Transmission of CMV is probably very common, with some reports stating that as many as 37% of extremely low birth weight infants of seropositive mothers may acquire the virus from mothers milk.

I introduced universal freezing of breast milk (in 2001 I think) to our NICU when I was at the Royal Victoria Hospital following 2 serious cases of breast milk acquired CMV disease, we did that to try and reduce CMV transmission, but with the full knowledge that the evidence base was limited.

An overview of the literature I think shows that not much has changed since then. CMV acquisition by extremely preterm infants from maternal breast milk is common, most cases are asymptomatic, but there is an increase in BPD among babies who acquire CMV postnatally and there are occasional serious infections with hepatic dysfunction, persistent thrombocytopenia and pneumonitis. The most serious complications appear to be in the most immature infants, and in those who already have some liver or pulmonary injury. I reviewed some of the recent studies last year. Long term follow-up doesn’t show much neurodevelopmental impact, and also does not reveal an increase in deafness.

Freezing breast milk reduces CMV activity in breast milk, even 3 hours of freezing has an effect, but 72 is probably preferable, and, after freezing many samples will no longer contain viable, culturable CMV, and others have reduced activity.

However, there is no good prospective evidence that this reduces CMV acquisition, or prevents serious disease. It seems likely that if you reduce the viral load there will be fewer cases, and fewer cases of symptomatic disease, but that is not proven, and it may be that the overall reduction in viral viability is not enough to prevent transmission.

Also, a policy that all breast milk will be frozen prior to giving it to the babies will have an impact especially during the first few days of life, when a victorious mother arrives in the NICU with 3 mL of colostrum. If we then freeze and later re-thaw the precious liquid that will delay the infant receiving all the goodies, and it might also potentially harm transmission of infection protecting components even while reducing CMV load.

Our NICU at Sainte Justine until recently froze most breast milk brought to the NICU by parents, but did not routinely freeze during the first days when the volumes were low, so most babies received some non-frozen milk in any case. Later on, as stores increased, it was usual for the milk technicians to unfreeze a stored sample for the day’s feeds, newly arriving milk was frozen for later use.

Changes in our NICU milk kitchen have made us re-evaluate the practice.

Some recent articles about breast milk storage and handling have shown the following (many reviewed in  Peters MDJ, et al. Safe management of expressed breast milk: A systematic review. Women and Birth. 2016;29(6):473-81):

Lactoferrin concentrations are much higher  in human milk than in bovine milk (and almost absent in bovine milk based preparations), they are high in milk from preterm delivering mothers, and stay high for a couple of months.  (Turin CG, et al. Lactoferrin concentration in breast milk of mothers of low-birth-weight newborns. J Perinatol. 2017. Albenzio M, et al. Lactoferrin Levels in Human Milk after Preterm and Term Delivery. American journal of perinatology. 2016;33(11):1085-9.) Storage of EBM at usual freezer temperatures, -20 degrees, substantially lowers activity of lactoperoxidase, and immunoglobulin A, with a smaller impact on lactoferrin, and lysozyme. (Akinbi H, et al. Alterations in the host defense properties of human milk following prolonged storage or pasteurization. Journal of pediatric gastroenterology and nutrition. 2010;51(3):347-52.) But the impact on lactoferrin concentrations is still important (Raoof NA, et al. Comparison of lactoferrin activity in fresh and stored human milk. J Perinatol. 2015;36(3):207-9) prolonged storage leading to about a 50% drop in lactoferrin.

An observational study from Spain including 22 neonatal intensive care units suggested that freezing breast milk might be effective in reducing postnatally acquired CMV (Balcells C, et al. Vertically transmitted cytomegalovirus infection in newborn preterm infants. Journal of perinatal medicine. 2016. p. 485.)

We now know that breast milk contains probiotic organisms, as well as potential pathogens. In one study freezing at -20 for 2 weeks did not clearly affect bacterial CFUs, (Marin ML, et al. Cold Storage of Human Milk: Effect on Its Bacterial Composition. Journal of Pediatric Gastroenterology & Nutrition 2009;49.) and the probiotic organisms were still present after thawing, but the data I can find are limited, you can certainly imagine that the precise way the milk is frozen and thawed might have an impact on bacterial contamination. One study showed that freezing the thawing and rewarming breast milk led to lower bacterial counts, and the same group showed that bacterial colony counts continued to fall during 9 months of freezing.

One study showed that antioxidant activity of breast milk decreases during storage at -20, but not at -80, (Aksu T, et al. The effects of breast milk storage and freezing procedure on interleukine-10 levels and total antioxidant activity. The journal of maternal-fetal & neonatal medicine : 2015;28(15):1799-802) but another study contradicted that and found a reduction at -80 also.

Milk has bactericidal capacity, which decreases during storage and is better maintained after freezing than after refrigeration, especially after 48 hours.

What we need, of course is a randomized controlled trial, and lo and behold, there is one! Omarsdottir S, et al. Cytomegalovirus Infection and Neonatal Outcome in Extremely Preterm Infants After Freezing of Maternal Milk. Pediatric Infectious Disease Journal. 2015;34(5):482-9. In this study 140 babies less than 28 weeks gestation whose mothers were intending to breast feed were randomized to receive only frozen maternal milk, (at -20 for at least 72 hours) with pasteurized donor milk used during the first days until thawed breast milk was available. The control group received fresh breast milk as soon as possible, and did get some donor milk, they also received some frozen milk, as milk was kept refrigerated for a maximum of 72 hours, and then frozen for later use if necessary. There were 66 of the mothers who had detectable CMV in their breast milk. Of those there was a transmission rate of 8% (minor different between groups could have been due to chance, 9% frozen, 6% fresh). Of note, the intervention period lasted 6 weeks, and 2 of the CMV transmissions in the frozen breast milk group were detected after that period, when the babies had been receiving fresh milk, leaving only 1 (3%) who is known to have developed CMV during the frozen breast milk phase. None of the CMV cases appeared to be symptomatic. What this means, unfortunately is that the study is underpowered to detect a major potential impact on CMV transmission, but there was no evidence of protection found from freezing breast milk for the 1st 6 weeks of life on transmission of  CMV during the entire neonatal ICU stay. The study did find that the only cases of fungal sepsis were in the fresh breast milk group, from a secondary analysis of their data. Candida may be inactivated by freezing, according to the authors, but I can’t find the original data.

It may be that freezing to inactivate CMV is not as effective as previously thought, using very sensitive techniques one group found that samples were often still infective even after freezing. (Hamprecht K, et al. Cytomegalovirus (CMV) Inactivation in Breast Milk: Reassessment of Pasteurization and Freeze-Thawing. Pediatr Res. 2004;56(4):529-35.) Which may account for several case reports of babies who only ever received frozen-thawed milk, and still acquired CMV, apparently from the milk. To be certain what we should do we really need a much larger randomized trial, probably including only seropositive mothers.

At present I think that the evidence of protection from acquisition of symptomatic CMV infection by freezing and thawing of breast milk is lacking. There are potential adverse effects on immunologic components of breast milk, so we probably shouldn’t routinely freeze all maternal breast milk prior to giving it to extremely preterm infants.

Some countries recommend pasteurization of stored maternal breast milk (in France, for example). Holder pasteurization, heating the milk to 62.5 degrees for 30 minutes is the usual method (also used for milk banks in general). Holder pasteurization has major impacts on protein content of the milk severely degrading lactoferrin, lysozyme, immunoglobulins, reducing erythropoietin levels and cytokines, as well as epidermal growth factor and transforming growth factor. (for a complete review see ; Peila C, et al. The Effect of Holder Pasteurization on Nutrients and Biologically-Active Components in Donor Human Milk: A Review. Nutrients. 2016;8(8).)

Holder pasteurization does do what it is supposed to though, it does inactivate viruses, fungi, and bacteria. CMV is comprehensively inactivated by Holder pasteurization. Other pasteurization techniques (high temperature short duration) also inactivate the virus, and seem to have less impact on the immune characteristics of human milk, but aren’t widely used.

I have previously posted about the randomized controlled trial of pasteurization of mother’s breast milk, which actually showed a slight increase (potentially due to chance) in late onset sepsis compared to feeding fresh breast milk.

A new observational study from France, as part of Epipage2 (Dicky O, et al. Policy of feeding very preterm infants with their mother’s own fresh expressed milk was associated with a reduced risk of bronchopulmonary dysplasia. Acta Paediatrica. 2017.) showed that those NICUs that followed the national recommendation and pasteurized the milk of mothers of very preterm babies had more bronchopulmonary dysplasia. This was only shown on the adjusted analysis, whereas a possibly higher rate of NEC with raw milk from the univariate data disappeared on the adjusted analysis. They also did not show an effect on late onset sepsis.

With all of the major impact on human milk immune functions, I think that routinely pasteurizing maternal breast milk is not warranted, particularly in view of the lack of evidence of a benefit.

Final message, breast is best, and fresh is probably the best breast.

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Neonatal Updates

McLanders ML, et al. The cognitive aids in medicine assessment tool (CMAT) applied to five neonatal resuscitation algorithms. J Perinatol. 2016.In many delivery rooms around the world, algorithms for neonatal resuscitation steps are posted on the walls. Do they help? Are they constructed to the best current standards? This paper reports an analysis of common algorithms, and the result is clear, there are serious limitations of all the available algorithms. Apart from a lack of clarity, and difficulty in using them during a real resuscitation, they are not even consistent with the standards on which they are supposedly based. Most end up on an infinite loop of administration of intravenous adrenaline, evaluation and re-administration of intravenous adrenaline. I hope the next step in the research of this group is to construct a better, clearer algorithm which does meet these standards. And then test whether it really helps resuscitation teams in the real world.

Logan JW, et al. Early postnatal illness severity scores predict neurodevelopmental impairments at 10 years of age in children born extremely preterm. J Perinatol. 2017. This study compares SNAP-II scores from babies in the ELGAN cohort and their neurodevelopmental outcomes at 10 years of age. Being very sick in your first 12 hours of life (SNAP-II more than 30, 23% of the subjects) increases the chances of lower scores on a range of neurocognitive tests. The differences are not enormous when expressed as the difference in the median z-scores (compared to population norms) but many are unlikely to be due to chance alone; many of the adjusted Odds Ratios show an increased Odds of the adverse outcome by a factor of around 1.6. There were also statistical associations with poorer social outcomes, and behavioural outcomes.

I don’t think that this necessarily means that the first 12 hours are critical for brain development, infants with higher early SNAP scores are more likely to have a range of other later complications also (such as necrotising enterocolitis), so the mechanisms behind this association are uncertain. Being very sick certainly is associated with an increased risk of a range of different outcomes, though.

Horne RS, et al. The Longitudinal Effects of Persistent Apnea on Cerebral Oxygenation in Infants Born Preterm. The Journal of pediatrics. 2017. This group from Monash University studied former preterm infants with polysomnography after they reached term. They included 24 babies between 27 and 36 weeks gestation at 2 to 3 weeks, 2 to 3 months and 5 to 6 months corrected age. They defined apneas as greater than 3 seconds (as long as not associated with periodic breathing). The studies lasted 2 to 3 hours on average, getting shorter as the kids got older, and therefore slept less. All of the babies had some apneas in all of the studies, about 250 total apneas on the 1st study falling to 150 on the 3rd. Average duration of the apneas was between 4 and 5 seconds, heart rates fell during the apneas by on average around 14 beats per minute, saturations fell by 2 to 4% and Brain oxygenation, measured by NIRS and expressed as the Tissue Oxygenation Index, fell by between 5 and 10% around the apneas, with the decrease being greatest at the oldest age.

I am not sure what this all means, the frequency of the apneas is actually quite similar to the frequency recorded in babies who had been full term, I don’t know if NIRS has been recorded in full term babies at these postnatal ages with apnea. It may be that the continuing pulmonary dysfunction in the ex-preterm baby makes them desaturate faster during an apnea, but I don’t know. Intermittent hypoxia  is associated with adverse outcomes in preterm infants, and this study shows it may persist for a long time. Is it associated with worse long-term outcomes? Is it affected by other treatments? Maybe we should be giving them caffeine until they stop having apneas at all, or until they go to school.

Thome UH, et al. Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2017. This is a neurological and developmental follow-up of 233 babies from the 311 survivors of the randomized trial of CO2 targeting from Germany. Bayley Scores of Infant Development were not different between groups, nor were neurological findings, nor anything else. Permissive hypercapnia seems safe from this analysis, even though the original publication of the trial did not show a clear advantage.

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Reducing antibiotic use in full term babies.

Early onset neonatal sepsis currently has an incidence in North America among term infants of about 0.5 to 1 per thousand live births. But 15% of newborn infants have risk factors and they end up receiving antibiotics if current guidelines are followed. The group from Kaiser Permanente have developed an algorithm that could markedly reduce sepsis workups and antibiotic utilisation, they have tested this in their own population and showed that if their calculator was used many fewer babies required sepsis evaluations, and all babies who actually developed sepsis were evaluated and treated quickly.

The calculator they created is now available on-line.To use the calculator you need some data from the mothers course during labour and a physical examination  of the baby.

This new publication (Warren S, et al. Impact of neonatal early-onset sepsis calculator on antibiotic use within two tertiary healthcare centers. J Perinatol. 2016) is from an independent group who looked at all the babies who had a septic workup and antibiotic treatment in two hospitals, of the 205 babies most (92%) required evaluations and antibiotics following the CDC/AAP guidelines, but if the calculator had been used only 23% of them would have got antibiotics. They had no cases of actual culture-positive sepsis, seven patients were defined as having culture negative sepsis, and all were treated according to both CDC guidelines and the sepsis calculator. Although it seems a very reasonable approach, I think that fear of liability will prevent many people from using this calculator until the official guidelines change. They certainly need to change, when only 1 infant benefits from antibiotics for every 150 treated, the other 149 are only having adverse impacts of our current standards, including long-term effects on the intestinal microbiome. The consequences of missing a case, on the other hand, are important, and we need more data about the safety of using the calculator, preferably from a big enough sample to include some positive culture babies.

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