Improved survival and improved Bayley scores among infants born in the periviable period.

If you were to report survival and other outcomes among infants with a very high risk of dying or having long-term impairments, why would you include babies for whom a decision was made to let them die?

Let me put it this way, if 1000 babies are born in each of 2 epochs, and 900 are left to die, and the survival rate was 40% in the first epoch, and 60% in the second, among the 100 babies who were treated, then this is either not significantly different p=0.051 or highly statistically significant p=0.0072, depending on whether you analyze the data using the denominator as all live births, or only the live births who received active care with an attempt to have them survive.

In a brand-new report in the FPNEJM, almost all of the data regarding survival and long-term outcomes are presented as proportions of live births. The denominator used for almost all of the analyses was the 4274 live births, of whom over 1000 did not receive active care, leaving 3158 for whom neonatal intensive care was instituted.

I can see reasons for doing some of the analyses like this: if the decision not to intervene was made based on an analysis of risks, and only the very highest risk babies were not actively treated, then leaving them out could skew the data, and make them look more positive. But in reality we know that the major determinant of whether you get intensive care in this gestational time period (in the NICHD NRN, and I am sure in many other places also) is the hospital that you are born in, not their risk profile necessarily.

However, in those hospitals that are selective in treating the most immature babies, if the babies who were not treated did indeed have a higher risk of mortality, then leaving them out would make the data look better than they would be if all infants received active treatment.

That is indeed what the previous NRN data seem to show. In the paper from 2015, examining data from 2006 to 2011, it was the centers that treated all the babies who had the best survival when expressed as a proportion of live births, ranging from 10 to 20% at 22 weeks, for example. But if you look at survival among all those who received active treatment (including the babies from the universal treatment hospitals) at 22 weeks 23% survived, which is a little better than the survival in the centers that treated all the babies. Those hospitals that treated none of the 23 week infants had no survivors.

So how should we calculate survival rates? If there are many babies not receiving active treatment, then a shift to treating more babies might decrease the proportion of survivors among those treated, but increase the total survival among the  live born.

I think that both numbers should be reported, as well as the numbers not actively treated, that is the only way you can really understand what is happening.

The new publication from the FPNEJM (Younge N, et al. Survival and Neurodevelopmental Outcomes among Periviable Infants. The Formerly Prestigious New England journal of medicine. 2017;376(7):617-28.) concentrates on survival among all live births of less than 25 weeks gestation, and barely reports survival and outcomes among those infants who received active care: only the Odds Ratios for those outcomes being reported in one section at the end of table 4.

It is possible to calculate some of the other outcomes, with the proviso that the exact numbers could be slightly different  to the numbers I present below, depending on rounding errors, and other sources of variation.

The article reports outcomes from 3 non-overlapping epochs, infants born in 2000-2003, 2004-2007, and 2008 to 2011. They include data from 11 centers that were part of the Neonatal Research Network (the NRN) in all of those years. The previous study I mentioned had data from 25 centers that were members of the NRN from 2006 to 2011, so these new data include a subset of the data from Rysavy MA, et al. (Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants. The New England journal of medicine. 2015;372:1801-11) and add to that data from earlier years, and give more information about outcomes at about 2 years, the Bayley scores from version 2 for the earlier epoch, changing to Bayley 3 during the second Epoch. They use different thresholds for developmental delay for the different versions of the BSID, and concentrate on the cognitive composite from version 3.

The data show an improvement in survival (a small improvement but not likely to be due to chance) and an improvement in survival without the famous NDI (which, from here on, I will call neurological impairment or developmental delay, NDDI. I continue to insist on the fact that a low Bayley score is NOT an impairment, but a screening test showing a potential delay in development). For example at 23 weeks the frequency of that outcome increased from 7% to 11% to 13%, when calculated based on all live births, but increased from 9% to 16% to 19% when calculated based on babies who received active treatment.

Overall survival at 23 weeks is reported as 20%, 20% and 24% in the 3 epochs as reported in the article, but, when based only on those who received active treatment, it is 27%, 28% and 35%.

I have seen comments that these data show absolutely no improvement at 22 weeks, but in fact, expressed as survival among those who received active treatment, survival increased from 10% to 21 % and 17%, which may not be statistically significant, but is about a doubling of survival from the first epoch to the 2 later epochs.

Survival does seem therefore to be improving, the proportion receiving active treatment has not changed, however; in this study the improvement in survival is therefore probably a real improvement in our capacity to look after these babies, rather than a change in who we select for intensive care.

Among survivors, the proportion with NDDI has decreased somewhat, the discussion of the article puts it like this

the rate of survival without neurodevelopmental impairment and the rate of survival with neurodevelopmental impairment increased similarly (adjusted relative risk, 1.27; 95% CI, 0.99 to 1.65).

I guess ‘increased similarly’ is the way that is stated because the lower 95% CI is 0.99, I think you could put that differently and state that, among survivors, the Odds of not having NDDI increased from the 1st to the 3rd epoch, by a factor of 1.27. Although the CI include 1.0, I think that is very reassuring.

With this improvement in survival, I think there should be a reconsideration of hospital policies, and a lower threshold for intervening, an overall survival of about 1 in 5 at 22 weeks about 1 in 3 at 23 weeks (among babies who received active care) would both seem to make intervention more reasonable for more infants; not necessarily for everyone, as always, family values and wishes are extremely important in these decisions, but as survival improves, it makes sense that our willingness to try for survival should also improve.

The most encouraging thing about these data is that there is no evidence at all that increased survival increases the proportion of impairment among survivors, with the limitations of the data presented, the opposite is much more likely to be true.

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Fluid restriction to prevent BPD?

In response to my previous post, one of the comments was a question about fluid volumes in the first few days of life, and whether fluid and/or sodium intake was important for the development of BPD during the early neonatal transition.

In response I will share a slightly edited preprint version of a section of an article I published in Seminars in Perinatology a couple of years ago. Barrington KJ. Management during the first 72h of age of the periviable infant: An evidence-based review. Seminars in Perinatology. 2014;38(1):17-24.

Even though it is a couple of years old, I don’t think there are new RCTs addressing the issues that I reviewed in this section. That article also had sections on cardiovascular support, respiratory management, nutrition, neurologic interventions, protocolized care and research networks.

Also it is important to note that the “systematic reviews” were performed according to the usual standards, but they do NOT conform to the PRISMA guidelines. With the limited space available I couldn’t have done that.

Fluids, electrolytes and renal function

Renal vascular resistance is high immediately after birth, and falls rapidly in the first 24 hours. This fall is associated with a major increase in glomerular filtration rate, and urine output, which is usually clinically evident as an increasing diuresis by the end of the 1st 24 hours of life. After this transition, preterm renal function is marked by a low ability to excrete a sodium load, but little restriction in maximal water clearance.

There are few studies on which to base a decision regarding total fluid management in the extremely immature newborn (EIN).  The skin of the very immature infant is very permeable, and huge trans-epidermal water losses (TEWL) occur if they are placed in a dry environment, the evaporation of water from the skin of the infant leads to cooling due to the latent heat of vaporisation, and it may be impossible to keep the EIN warm in a dry environment under a radiant heater. Most centers have now moved to placing EINs in incubators, although there is no RCT evidence that this is preferable to being under a radiant heater, it seems likely to be the case. If a radiant heater is used it must be combined with an arrangement to keep the humidity around the infant at a high concentration, such as covering the infant with plastic.

One problem with keeping EINs in a high humidity environment is that whenever they are accessed to give care (for example by opening the incubator portholes) the humidity drops precipitously. This is even more evident when the ‘roof’ of an incubator with a retractable cover is lifted. Therefore further methods to reduce trans-epidermal water loss have been examined, including using ointments or semi-permeable membranes. Ointments such as Aquaphor can reduce trans-epidermal water loss, but whether they can improve overall water balance or improve clinical outcomes is uncertain. The only large study in ELBW infants enrolled infants (500 to 1000 g birth weight) starting at an average of about 24 hours of age, and showed an increase in late-onset coagulase negative staphylococcal sepsis during prolonged treatment . Maturation of the epithelial barrier after preterm birth occurs rapidly, a briefer period of barrier treatment could potentially have benefits without this risk. Semi-permeable membranes have also been tried, in a small pre-post study TEWL appears to have been reduced, fluid requirements and peak sodium was lower, and there may have been less BPD, (n=69 birth weight <1000g) but there is no data from adequately powered RCTs examining other clinical outcomes.

Total fluid intake

What should the total fluid intake be? Clearly this will depend on overall fluid losses. But the interaction between the physical environment, and subsequent TEWL, and fluid administration requirements has not been well studied. Several studies have randomly compared infants by total volume of fluid administered. The results are very inconsistent. Those studies have varied in design, in particular by how sodium intake was controlled.

Although the Cochrane review “Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants” suggests that restricted fluid intake improves several clinical outcomes, this result is marked by significant heterogeneity, also one of the better studies did not enrol babies until the 3rd day of life, and therefore is of little relevance to the current review. After the initial period of adaptation as mentioned above, the preterm kidney has a relatively good ability to clear a fluid load. Thus there is little reason to hypothesize that variation in total free water administration, within reasonable limits, will affect total body water.

One of the 5 trials of water restriction gave fluids with identical sodium concentrations in each 100mL of the intravenous fluid, another was designed to examine a relatively complex protocol allowing either 10% or 15% body weight loss and therefore varied both water and sodium intakes. These 2 studies were therefore studies of combined sodium and water restriction.

I have performed a systematic review of RCTs of different fluid administration rates starting on the first day of life, which I have meta-analyzed using the RevMan software, fixed effects model. I found 5 controlled trials (a table showing the articles is at the bottom of this post, followed by a list of references), 3 of which had similar sodium intakes in each group, 2 varied both the fluid and the sodium intake.

Figure 1.Effects of varying fluid intakes on mortality.

figure-1-fluid-restriction

As can be seen, the studies with varying water intake, but no difference in sodium intake showed no effect on mortality, whereas those which varied both showed a reduction in mortality with restricted water and sodium intake. Of note this second result is largely the result of a single trial with a very high mortality in the high water/high sodium group, and this subgroup shows substantial heterogeneity, an I2 of 72%.

Figure 2. Effects of varying fluid intakes on BPD

forest-plot

Clearly there is no effect on BPD, RR 0.93 (95% CI 0.68, 1.27). Survival without BPD was also not different overall.

Sodium intake

In contrast the preterm kidney has a limited ability to excrete a sodium load, and excessive sodium administration may lead to increases in total body water and increases in water content of vital tissues. This is true even though there is a natriuresis in the first few days of life, at least after the first 24 hours, which accompanies the postnatal diuresis. Administration of sodium during this period may well upset the postnatal progressive decrease in extra-cellular fluid which is a normal phenomenon in more mature infants.

I performed a systematic review and meta-analysis of RCTs in preterm infants which compared 2 regimes of sodium administration starting on the first day of life (see the table below). The search found 5 studies, two of which are as mentioned also studies of varying water intake and are mentioned above, and one with very limited description of clinical outcomes (other than death). The total numbers of infants in these trials is a disappointing 271. Nevertheless there appears to be a reduction in mortality RR 0.44 [95% CI 0.22, 0.90] with reduced sodium intake, a possible reduction in BPD, RR 0.76 [95% CI 0.56, 1.04] and a reduction in the combined outcome of death or BPD, RR 0.39 [95% CI 0.23, 0.67].

Figure 3. Effects of different sodium intakes on A. mortality, B. Bronchopulmonary Dysplasia, and C. combined outcome of death or BPD.

figure-2-sodium

The data are therefore probably best interpreted as showing that delaying all sodium intake until after either 3 days of life or after a 5% weight loss improves outcomes whereas restricting free water intake by itself has little or no effect. The major limitation of these data being that very few extremely immature babies have been included in any of these studies.

Table Randomized trials comparing 2 levels of fluid intake or 2 levels of sodium administration in the preterm.

Study ID
n
Characteristics of included infants
Comparison, fluid intakes
Sodium intakes
Primary Outcome
Tammela9
100
<1751 g BW, >23 wk
50,60,70,80,90,100,120 then 150 ml/kg/d vs
80,100,120,150 then 200 ml/kg/d
3 mM/100 mL Na in all the fluids
BPD
Lorenz12
88
750-1500 g BW, day 1 of life
Designed for 10% birth weight loss vs 15%, initially
1,000-1,500g 70 ml/kg/d 750-1,000g 80 ml/kg/d. Thereafter varied according to weight loss.
Higher in high fluid group, 1 mM/kg/d on day 1 increasing to 3 in high fluid group or decreasing to 0.5 in low fluid group, by day 4
No clear primary outcome
Von Stockhausen13
56
Premature, day 1 of life
60 mL/kg/d vs 150 mL/kg/d for 3 days
unclear
No clear primary outcome
Kavvadia14
168
<1501 g BW, day 1 of life
70 increasing to 150 by day 6, 40 increasing to 150 by day 7
Adjusted to achieve serum concentration of 135 to 145 mM/100mL, no difference between groups
Survival without BPD
Costarino15
17
<1000g, <29wk, day 1 of life
Individualized, not different overall  between groups
0 vs 3 to 4 mM/kg/d
Risk of hypernatremia and large fluid volumes
Hartnoll16
46
25 to 30 wk with RDS
Individualized, not different between groups
4 mM/kg/d starting on day 2 vs 0 until weight decreased by 6%
Risk of continuing oxygen dependency
Ekblad11
20
<35 wk
50 increasing to 110 in each group
0 increasing to 2, vs 4 mM/kg/d
No clear primary outcome

References

  1. Lorenz JM, Kleinman LI, Ahmed G, Markarian K. Phases of fluid and electrolyte homeostasis in the extremely low birth weight infant. Pediatrics. 1995;96(3 Pt 1):484-9.
  2. Pabst RC, Starr KP, Qaiyumi S, Schwalbe RS, Gewolb IH. The effect of application of aquaphor on skin condition, fluid requirements, and bacterial colonization in very low birth weight infants. J Perinatol. 1999;19(4):278-83.
  3. Knauth A, Gordin M, McNelis W, Baumgart S. Semipermeable polyurethane membrane as an artificial skin for the premature neonate. Pediatrics. 1989;83(6):945-50.
  4. Nopper AJ, Horii KA, Sookdeo-Drost S, Wang TH, Mancini AJ, Lane AT. Topical ointment therapy benefits premature infants. The Journal of pediatrics. 1996;128(5 Pt 1):660-9.
  5. Edwards WH, Conner JM, Soll RF, for the Vermont Oxford Network Neonatal Skin Care Study Group. The Effect of Prophylactic Ointment Therapy on Nosocomial Sepsis Rates and Skin Integrity in Infants With Birth Weights of 501 to 1000 g. Pediatrics. 2004;113(5):1195-203.
  6. Bhandari V, Brodsky N, Porat R. Improved Outcome of Extremely Low Birth Weight Infants with Tegaderm[reg] Application to Skin. 2005;25(4):276-81.
  7. Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Cochrane database of systematic reviews (Online). 2008(1):CD000503.
  8. Bell EF, Warburton D, Stonestreet BS, Oh W. Effect of fluid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. The New England journal of medicine. 1980;302(11):598-604.
  9. Tammela OKT, Koivisto ME. Fluid restriction for preventing bronchopulmonary dysplasia? Reduced fluid intake during the first weeks of life improves the outcome of low-birth-weight infants. Acta Paediatr. 1992;81:207-12.
  10. Drukker AMDP, Guignard J-PMD. Renal aspects of the term and preterm infant: a selective update. Current Opinion in Pediatrics. 2002;14(2):175-82.
  11. Ekblad H, Kero P, Takala J, Korvenranta H, VÄLimÄKi I. Water, Sodium and Acid-Base Balance in Premature Infants: Therapeutical Aspects. Acta Pædiatrica. 1987;76(1):47-53.
  12. Lorenz JM, Kleinman LI, Kotagal UR, Reller MD. Water balance in very low-birth-weight infants: relationship to water and sodium intake and effect on outcome. The Journal of pediatrics. 1982;101(3):423-32.
  13. Stockhausen H, Struve M. Die Auswirkungen einer stark unterschiedlichen parenteralen Flüssigkeitszufuhr bei Früh- und Neugeborenen in den ersten drei Lebenstagen. Klinische Pädiatrie. 2008;192(06):539-46.
  14. Kavvadia V, Greenough A, Dimitriou G, Hooper R. Randomised trial of fluid restriction in ventilated very low birthweight infants. Archives of disease in childhood Fetal and neonatal edition. 2000;83:F91-F6.
  15. Costarino ATJ, Gruskay JA, Corcoran L, Polin RA, Baumgart S. Sodium restriction versus daily maintenance replacement in very low birth weight premature neonates: a randomized, blind therapeutic trial The Journal of pediatrics. 1992;120(1):99-106.
  16. Hartnoll G, Betremieux P, Modi N. Randomised controlled trial of postnatal sodium supplementation on oxygen dependency and body weight in 25-30 week gestational age infants. Arch Dis Child Fetal Neonatal Ed. 2000;82(1):F19.
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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.

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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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