Longer-term outcomes: what should we measure? part 2

I have made my concerns about developmental screening tests including the Bayley clear over the years, including in the previous post, which might make what I am going to say now seem odd: I do not think we should stop screening for developmental delay in neonatal follow up!

The problem is not doing the Bayley evaluation, the problem is thinking of Bayley scores as a hard endpoint which diagnoses clinically important impairment.

The tests that we perform in follow up should be adjusted to our goals of follow up. If we wish to screen for developmental delay in order to offer intervention, then that is a worthwhile goal, and performing a test early will identify more babies with low scores, so an 18-month test might be reasonable. Brett Manley and a group of CAP investigators analysed the factors which were associated with an improvement in test scores from 18 month Bayley version 2 scores to an IQ test at 5 years; we found that the major factor associated with having an improvement was the socio-economic environment. Identifying infants at 18 months of age who have delayed development and who are also socio-economically deprived identifies a group of children at high risk of lower IQ scores, and probably therefore of difficulties at school, who could well benefit from early intervention programs, while those who are socially and economically advantaged will usually get higher scores anyway in the future.

On the other hand, if we want to predict later impairment, the predictive value of Bayley scores for later intellectual difficulties is poor, especially at 18 months. The screening tests become more useful with age, but even at 30 months they (at least the Bayley version 3) only correctly identify around about 50% of infants. The table below (from the EXPRESS cohort) shows that, if defined as moderately “disabled” at 30 months of age, which in 2/3 of the cases was as a result of a moderately low Bayley 3 score, 44% of the infants were moderately or severely disabled at 6.5 years, again, mostly because of low cognitive scores, (using the WISC-IV).

You can also see from the table, that infants with no disability at 30 months still sometimes had moderate or even severe disability at 6.5 years (Serenius F, et al. Neurodevelopmental Outcomes Among Extremely Preterm Infants 6.5 Years After Active Perinatal Care in Sweden. JAMA Pediatr. 2016)

Ideally, a follow-up program should be able to identify infants that will benefit from therapy as well as to determine the outcomes of our neonatal interventions. If 2 arms of study have the same survival, then examining other aspects of the outcomes becomes of interest. Outcomes that affect the function of the child and their family are the ones we should focus on; and the rare infant with a significantly reduced quality of life, if different between arms of a study would also be valuable information. The newer versions of the Bayley scores include an evaluation of function, which in the Bayley version 4 is derived from the Vineland Adaptive Behaviour Scales, a well-supported scale for analysing function.

Outcomes of neonatal trials should be considered in a hierarchical fashion. As almost all survivors have an acceptable, good or excellent quality of life, survival should always be the primary outcome. The second level of the hierarchy should be impairments and clinical difficulties which affect function: disabling CP, blindness, gastrostomy feeding, recurrent hospital admissions, medical instrumentation at home, disruptive behaviour problems. The third level of the hierarchy should be things that affect function little but would be preferable to avoid: chronic medication use, developmental delay, need for physiotherapy. You may notice that I haven’t put in this schema intellectual limitations and learning difficulties, because I do not know where they should go, I think different families, would probably score them differently and different severities of those problems might put them in the 2nd or third priority group.

Ways of analysing trials that prioritize adverse outcomes in that way have been developed, and could be much more useful in deciding between therapeutic approaches than “death or NDI”. I have blogged about this previously, the “win ratio” where results are compared between groups with prioritized outcomes, so death is the worst outcome, survival with serious long term problems is next, and survival with moderately severe problems is next. By comparing the number of winners in the comparisons, Pocock SJ, et al. The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. European Heart Journal. 2012;33(2):176-82 you can analyse statistically which of two groups have the better outcome.

This is not just a theoretical methodology, there are now several trials, mostly in Cardiology, that have used the win ratio as a way to take into account death as well as non-fatal complications as part of a composite outcome, where death is the most important outcome, but others such as hospitalisation for cardiac events, are given secondary importance. (Redfors B, et al. The win ratio approach for composite endpoints: practical guidance based on previous experience. Eur Heart J. 2020;41(46):4391-9).

There are also logistical reasons for continuing to perform developmental screening tests at around 2 years, keeping infants in a follow-up program needs frequent contact, and waiting until a child has reached 5 years of age, risks losing many more children and decreasing the confidence in the results, funding for trials which can’t report their outcomes for 7 or 8 years is tricky. The CAP trial was for example funded initially for 18-month outcomes, and then repeated grant applications to extend follow up were required, and successfully obtained by Barbara Schmidt and her collaborators.

Finally, I have a question for my readers; is there any trial that has shown no difference in developmental outcomes at 2 years between two groups that has then found an important difference in neurological/intellectual/learning outcomes later on?

If the answer is no, and I can’t think of such a trial currently, them perhaps continuing to evaluate and report on developmental delay at around 2 years of age is reasonable, not as a hard endpoint of any clinical significance, but as a sort of a screen to decide which trials should then get funding for 5 or 6-year outcomes. Studies showing no difference in neurological impairment or developmental delay at around 2 years may be extremely unlikely to show a difference later; while those that show a difference could then be funded to examine clinically important outcomes and outcomes important to families at around 5 or 6 years of age. I think that the analysis of the 2 years outcomes should prioritize survival as the most important of the outcomes, and then as second priority neurological impairments (which are more likely to be long-term problems for the child) and then as third priority developmental delay, that analysis could be done using the win ratio method.

At later follow up we could measure outcomes which have an importance to families at 5 or 6 years, such as indicators of good health, behaviour problems, feeding difficulties, and those which could lead to adjustments in the way they are taught, such as measures of IQ and executive function.

Indeed we should be doing more research to find out which outcomes matter most to parents, such as the studies that Annie Janvier and her collaborators are doing.

Below is a youtube video of a webinar that Annie gave about the outcomes that parents care about, and about her on-going research on the topic.

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Longer term outcomes; what should we measure? part 1.

Many important trials include follow-up to about 2 years in order to ascertain longer-term effects. Such as this one:

Adams-Chapman I, et al. Neurodevelopmental outcome of preterm infants enrolled in myo-inositol randomized controlled trial. J Perinatol. 2021. Ira Adams-Chapman was one of our fellows when I was in San Diego; a wonderful gentle person, who would nevertheless stand up for herself, and for what she thought was right for her patients. I was never able to publish the study in piglets that we did together during her fellowship, as there were several technical issues that we couldn’t correct, but that didn’t stop her (or maybe even helped her!) becoming an important part of the neonatal world. After graduating from our program, she developed her research career in the follow-up arm of the NICHD network. I kept intermittent contact with her over the years, and remember a very pleasant breakfast in Atlanta when I visited a few years ago.

I was stunned to hear that she died towards the end of last year, far too young, having been predeceased by her husband, also far too young.

I mention this because I was pleased to see that, despite being unable to sign off on the manuscript which was submitted shortly after her untimely demise, she is still listed as the first author. I am sure that represents her contribution to this article, and to the high-quality work it represents.

The study is a report of the longer-term outcomes of infants enrolled in a trial of prophylaxis with myo-inositol for retinopathy prevention. Phelps DL, et al. Effects of myo-inositol on type 1 retinopathy of prematurity among preterm infants <28 weeks’ gestational age: A randomized clinical trial. JAMA. 2018;320(16):1649-58. At 2 years of age survivors were examined with the usual panoply of neonatal tests.

The new article notes that there was no difference in the composite outcome of “death or NDI” at 2 years corrected age mong survivors (95% of whom were evaluated; great work!) Which might suggest that either giving inositol or not were equally valid choices. But hang on, mortality was quite a bit higher in the inositol group, 20%, than the controls, 13%. The relative risk of dying was 1.53 (95% confidence intervals 1.08–2.18).

49% in each group of those followed up had neurological impairment or developmental delay (NIDD I will call it) and the summed outcome of NIDD or death was 60% (inositol) vs 56% among controls. As usual, infants with Bayley motor or cognitive scores <85 were the majority of those that had what they call “NDI”.

These results are a perfect example of why we should NOT be using “death or NDI” as the outcome for clinical trials.

More of the control babies survived, but the proportion of survivors with “NDI” was identical in the 2 groups, there were, therefore, numerically, more survivors with “NDI” in the control group, because there were more survivors!

When you then calculate the proportion of survivors without NIDD in the 2 groups, there is no “statistically significant” difference. Here is what that means for this study; in the Inositol group there were 62 deaths, and 14 babies not followed up, among the 289 babies with 2-year outcomes there were 112 with NIDD. In the control group, there were 39 deaths, and 14 babies not followed up, so among the 289 babies with 2-year follow up there were 122 infants with NIDD. This is my graphic of those results, the vertical axis being the absolute numbers of subjects.

If you were to choose betwen treatment 1 and treatment 2, with substantially more deaths in group 2, and exactly the same proportion of infants with low Bayley scores among survivors, I bet there are not many who would choose treatment 2!

But the abstract of the article just notes: “Treatment group did not affect the risk for the composite outcome of death or survival with moderate/severe NDI (60% vs 56%, p = 0.40)” which suggests that the results are equivalent and that it doesn’t matter which treatment you choose, but which is entirely the wrong interpretation of these data.

For this particuar trial we do have the intial study report which noted that “death or RoP” was more frequent in the inositol group; but other trials may have “death or NDI” as the primary outcome, and many people would read no further than the abstract noting no difference in the outcomes.

From a strictly scientific point of view, one should not change the primary outcome after the data are in; so from that point of view, if the initial plan for the analysis was to compare “death or NDI” between groups, then that is what should be published, and the results as published are accurate. But, from the perspective of someone wanting to determine the best treatment choice for a baby, this is totally wrong; dying and having a low Bayley score are in no way equivalent. The analysis plan should take that into account, giving much more weight to survival than the results of screening tests for developmental delay.

Are there any outcomes that can be balanced against survival? The few studies that have asked this of parents note that they generally think that survival with impairments so profound that the child is unable to communicate would be a category equivalent to mortality. Such outcomes are so rare in the NICU that they will likely never balance differences in survival.

The same considerations apply to any screening test for developmental delay, not just the Bayley; but also to neurological impairment, even if likely to be permanen. Is cerebral palsy with a GMFCS of 3 equivalent to being dead? Is blindness equivalent to being dead? Surely, if they are not equivalent we should design our studies and our analyses to acknowledge that.

Children with impairments have lives that are worth living, and enrich the lives of those around them, despite the major challenges they also bring. I was reminded of this, and also of how bad we are in predicting whether a child will not be able to communicate, when I recently watched this video from ‘Britain’s got talent”

I love that song and that performance. Valuing children (and adults) for who they are regardless of their impairments is the moral of that wonderful anthem. If you only have time to watch the song, it starts at 2:20.

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More thoughts about what to de-adopt

My post about de-adopting certain investigations or procedures in the NICU got a lot of suggestions and responses. Here are a few, either from the comments section or from Twitter. We should de-adopt the following:

  1. Dopamine. This is a suggestion that I have a lot of sympathy with, the 2 major actions of dopamine in the newborn are to cause vasoconstriction and to suppress the pituitary. I don’t think that vasoconstriction is often what we want when we initiate cardiovascular support. All the studies of dopamine with analysis of haemodynamics have shown that if you give enough dopamine to increase blood pressure then you decrease cardiac output. In the occasional baby with vasodilated shock, a vasoconstrictor might be useful, but other agents may be more effective. Dopamine suppresses release of TSH and thus thyroxine, also suppresses prolactin and growth hormone, these actions are probably not beneficial and are not shared by other catecholamines. (Dopamine also suppresses respiratory drive and is associated with an increase in nosocomial sepsis.)
  2. Supra-systemic hypertension to reverse the shunt in PPHN. This is related to the first issue, an older idea about how to improve oxygenation in PPHN was to push the systemic pressures higher than the pulmonary artery pressures. Dopamine, which was for a while almost the only vasopressor that neonatologists used, was shown to cause vasoconstriction in the systemic and pulmonary circulations. A study by Willa Drummond in lambs noted that when extremely high doses of dopamine were given, systemic vasoconstriction exceeded pulmonary (at 270 microg/kg/min), she reported using dopamine in human newborns at 20 to 125 microg/kg/min. The extreme vasoconstriction with such doses impairs myocardial function. A balanced approach, supporting the systemic circulation where necessary without excessive vasoconstriction, and dilating the pulmonary arteriolar bed if needed, makes much more sense.
  3. Hi-FLo. I think that High Flow Nasal Cannulae are overused, and there are some suggestions that centres that have adopted widespread use of Hi-flo have more BPD. Because they are comfortable and well-tolerated by babies and parents I think they tend to get weaned less aggressively, which might lead to more BPD diagnoses. However, I do think that nasal injury is important, and patient comfort and parental wishes are important, so I would say a partial de-adoption, rather than complete, is more reasonable, and don’t forget to wean them whenever you can.
  4. Gentamicin levels after the 2nd or 3rd dose. We have already done this, gentamicin levels in our NICU are only ordered if the gentamicin is continued after 36 or 48 hours, so usually only when the cultures are positive. Which doesn’t happen very often. I also agree that trough concentrations are not very predictive of anything. Vancomycin levels are a similar issue, poorly predictive of either efficacy or toxicity. I think we do many of these levels for medico-legal concerns rather than to help our babies.
  5. Sodium Bicarbonate. I absolutely agree, I have prescribed Bicarbonate once in the last 25 years, when I was being pushed to do so by a cardiologist, I re-reviewed all the data I could find after that, and I won’t be doing it again.
  6. Treating all PDA, or even doing the echo to diagnose them. The example in the tweet regarding echos was an infant on 21%, tolerating feeds and urinating well. This is such a complex issue that I will post something about it soon, in particular in response to a new publication from Montreal. But I certainly agree that many PDAs don’t need to be treated, the question is: which ones?
  7. Checking residuals and stool guiac. Checking residuals can be done away with without any adverse consequences. Routine stool blood testing should also be thrown out, occasionally if you are not sure that there is blood present or not, then maybe confirmation with an occult blood test might be helpful, but if you need the test there can’t be much blood there!
  8. Spironolactone (my own addition). I don’t think there is any indication for the use of this drug in the neonatal period. See my recent post on medication use in BPD.
  9. Long term diuretics to prevent or treat BPD (also my addition). No evidence of benefit, substantial evidence of harm.

And one suggestion from Gil Wernovsky on LinkedIn

Using the term “Pulmonary Hypertension” in isolation. Should always be qualified with 1. Elevated PVR 2. Low PVR with elevated PA pressure due to intrasvascular communcation. As Gil notes, sometimes we end up treating babies with high flow/low PVR pulmonary hypertension with pulmonary vasodilators, which is usually a big mistake! I agree with this: treatment of pulmonary hypertension should always take into account the pathogenesis and the haemodynamics. Discuss it with the cardiologist (just don’t give them bicarbonate; at least not the baby, a bit of oral bicarbonate for the cardiologist might help his dyspepsia).

Also this was a question rather than a suggested addition

Milk thickeners for reflux. There is very little good neonatal data about this, we know that some thickeners (or perhaps just one) have been associated with NEC, specifically Xantham Gum. So avoid that completely. Other thickeners may be safe, that is not clear, but they probably do have some effect in reducing the number of regurgitation episodes, and perhaps the overall duration of acid reflux on pH study. I would say milk thickeners in any baby at risk of NEC should be de-adopted. For infants past term who have major regurgitation and no other risk factor for NEC (not a gastroschisis or congenital heart disease baby) they might be safe and reduce the number of regurgitations. (see Cochrane review)

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Medication use in babies with bronchopulmonary dysplasia

A few recent studies have noted the marked variability between sites in the use of medications in preterm infants with BPD.

Nelin TD, et al. The association between diuretic class exposures and enteral electrolyte use in infants developing grade 2 or 3 bronchopulmonary dysplasia in United States children’s hospitals. J Perinatol. 2021.
Bamat NA, et al. Loop Diuretics in Severe Bronchopulmonary Dysplasia: Cumulative Use and Associations with Mortality and Age at Discharge. J Pediatr. 2020.
Greenberg JM, et al. Respiratory medication use in extremely premature (<29 weeks) infants during initial NICU hospitalization: Results from the prematurity and respiratory outcomes program. Pediatr Pulmonol. 2020;55(2):360-8.
Tan C, et al. Diuretic use in infants with developing or established chronic lung disease: A practice looking for evidence. J Paediatr Child Health. 2020;56(8):1189-93.

The first 3 of these studies are multi-institutional observations, the 4th being from a single centre. Variations in medication use and in particular the use of diuretics are enormous, some centres seem to treat almost all of their babies with loop diuretics, while in others such use is limited. In my centre chronic diuretic use is quite unusual, while intermittent brief courses may be tried in a small percentage of babies.

Why such variation? One of the usual explanations for such variation is an absence of a strong evidence base; so what is the evidence for diuretic use for the prevention or treatment of BPD?

Diuretics were first tried I think because the early phases of BPD show interstitial oedema; so why not use a diuretic? The few mechanistic studies that were performed showed an improvement in some measures of lung mechanics, but little or no effect on gas exchange. One controlled trial of prolonged use in infants with BPD on non-invasive O2 therapy showed some decrease in FiO2, but no decrease in the duration of O2 therapy, and no residual effect after the furosemide was stopped.

Interestingly lung mechanics changes have also been shown in anephric dogs, the ion pump which is inhibited by the loop diuretics (NaK2CL co-transport) is present on the luminal surface of the thick ascending limb of the Loop of Henle. furosemide also inhibits chloride transport in the lungs, which may be relevant to its effects, especially in dogs without kidneys, the mechanism is probably related to Cl Na co-transport. There is a disconnect between diuresis and effects on pulmonary mechanics, for example, inhaled furosemide can improve compliance and resistance in infants with BPD, but without causing a diuresis. Another placebo-controlled study showed effective improvement in lung mechanics with alternate day furosemide, without an overall increase in urine output.

Improving mechanics of course is not really what I want when I prescribe a medication, I want to improve clinical status and clinical outcomes. There is little or no evidence that diuretics of any kind do this. The Cochrane review of loop diuretics in BPD found 6 trials (all furosemide) and no evidence of impact on clinically important outcomes (which weren’t reported in most trials). The Cochrane review of thiazides in BPD (both reviews are authored by Luc Brion, and were last updated in 2011, but I am not aware of any new trials) also showed in six trials no clinically significant effect. The only exception being the RCT of thiazides in intubated babies with BPD which showed less mortality with thiazides, but that trial only included 34 babies, the 15 controls were all boys except one, and with a higher pip and mean airway pressure than the 19 diuretic babies (8 females), therefore a significant chance of a type 1 error.

As a reminder to everyone, the Neonatal Cochrane reviews are all available at the Vermont Oxford Webisite, free of charge for anyone. https://public.vtoxford.org/cochrane-at-von/

What do these new publications say? The first, Nelin et al shows that babies on any diuretic also often receive mineral supplements and that babies on thiazides were more likely to receive them than babies on loop diuretics. That to me is entirely expected, thiazides often lead to hyponatraemia, whereas it is less frequent with furosemide. Chronic thiazide use often is accompanied by chronic sodium supplementation, which is a questionable combination, as you are using the diuretics because they cause natriuresis! Pushing sodium out by the kidneys and simultaneously supplementing it enterally makes little sense. Loop diuretics, however, cause more of a reduction in total body fluid, so less dilution of serum sodium. The study also calls into question the concurrent use of potassium-sparing diuretics, as babies receiving them in addition to thiazides (the most common use in this trial) were just as likely to receive potassium supplements. Again that should be of no surprise, spironolactone does not affect thiazide-induced potassium loss in the newborn infant. An RCT from 2000 showed that adding spironolactone to a thiazide had no additional benefit on lung mechanics, and did NOT spare potassium. Just as many babies received K supplements, and serum potassium was identical with and without spironolactone. As far as I can see, that study is the only scientific data that exists about the value of adding spironolactone to a thiazide, i.e. there is no value.

The second publication, Bamat et al showed, not for the first time, that loop diuretic use is extremely variable, and that the variability is explained by which hospital you are in, rather than the severity of your lung disease. The study examined data from infants with grade 2 or 3 BPD and showed that infants from hospitals that used a lot of loop diuretics did not get home any sooner, (PMA at discharge was around 47 weeks, showing these were quite sick babies) but were more likely to go home on diuretics. The hospitals ranged from use of loop diuretics on 8% of the days between birth and discharge among infants with moderate and severe BPD to 50%.

The third in my list , Greenberg et al is a prospective multicentre cohort of infants born between 23 and <29 weeks gestation, which produced this pretty figure :

Of note, this study was not solely babies with BPD, but nevertheless by 5 weeks of age half of the babies are on furosemide. Also, from the supplemental data, 45% of the babies who did not develop BPD had received furosemide before they reached 40 weeks.

The last of these studies (Tan et al) is a single centre publication from Monash and deals mostly with the thiazide/spironolactone combination. As a single centre study they were able to give some more data pre and post diuretics, which showed that 84% became hyponatraemic and 12% hypokalaemic after diuretics, which did not significantly improve gas exchange but did lead to a slow down in weight gain.

None of this is new. Slaughter JL, et al. Variation in the use of diuretic therapy for infants with bronchopulmonary dysplasia. Pediatrics. 2013;131(4):716-23.Laughon MM, et al. Diuretic exposure in premature infants from 1997 to 2011. Am J Perinatol. 2015;32(1):49-56. Our use of these medications, in particular, the diuretics, is non-evidence-based, extremely variable, off-label, and somewhat irrational.

We should do the following:

  1. Stop all use of spironolactone in the newborn. It does not improve electrolyte status, does not spare potassium, does not add to diuretic effects of thiazides, and has adverse effects, in particular blocking androgen receptors, but also with reports of thrombocytopaenia and agranulocytosis.
  2. Stop routine use of diuretics to prevent or treat BPD. There is no evidence that diuretics reduce the incidence of BPD, and no evidence of clinically important benefits in treatment.
  3. Stop prolonged use of diuretics to prevent or treat BPD. Prolonged use leads to serious electrolyte disturbance, not to mention nephrocalcinosis and bone demineralization, metabolic alkalosis and chloride depletion.
  4. Perform prospective controlled studies to determine potential indications for diuretic use and the balance of risks and benefits. The lack of clinical impact when comparing widespread to restricted diuretic use in these observational studies is clear evidence that equipoise should exist, and clinical trials are essential for these widely used agents.
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The ACOG patient information page; what should it say about 22, 23, 24 weekers?

I mentioned not so long ago that the web page of the US Obstetricians professional association has information for prospective parents of babies of less than 25 weeks gestation that is… questionable.

They state, for example, the following :

Medical advances have helped some preterm babies survive and overcome health challenges. However, the chances that a baby born extremely early will survive without disability are still small. With very rare exceptions, babies born before 23 weeks of pregnancy do not survive. Although survival rates increase for babies born between 23 weeks and 25 weeks of pregnancy, most survivors face serious, often lifelong disabilities. As gestational age increases, the outlook for preterm babies improves.

That statement is wrong factually: in Japan, with the majority of babies at 22 weeks receiving active intensive care, 50% of them survived in 2010, similar results from Uppsala can be seen with 53% surviving over a 10 year period, 2006-2016. In Iowa over a 10 year period survival at 22 weeks was 64% among babies receiving active intervention (almost all the live births), similar to the data from Cologne. A systematic review of the available data for babies of 22 weeks GA showed that infants receiving “proactive” treatment had an overall survival among published cohorts of 29%; survival was better in the later epoch (2010-2020) at 31% compared to studies from before 2010, 22%. I don’t know what ACOG thinks of as “very rare exceptions” but 1 in 3 babies surviving is hardly very rare. Similarly the statement: “most survivors face serious, often lifelong, disabilities” is factually incorrect. Most survivors have no disability or mild disabilities (for example 70% of survivors in Uppsala, 55% in Iowa), and, as most “disability” is because of low scores on Bayley testing, the proportion with disabilities decreases with time.

Why our Obstetrical Colleagues are so biased against the most immature babies confuses me. You would think that they would be our greatest allies in trying to improve outcomes for the patients we have in common, that they would want to help mothers and their partners to make the best decisions based on accurate information.

What would unbiased information actually look like? I think it should include the following information which is critically important to parents facing the challenge of a potential delivery at <25 weeks.

1. Determination of the exact gestational age is inexact. Remember that if you have an assigned gestational age of 23 weeks and 1 day, for example, you might be at 22 weeks and 3 days or at 23 weeks and 6 days.

2. Threatened extremely preterm delivery often calms down, and many mothers deliver at less frightening gestations.

3. Many factors affect your babies chances if delivery actually happens, more than just the number of weeks: the weight of the baby, whether it is a boy or a girl, a single baby or one of twins, presence of infections, whether you had a chance to get a steroid injection, where you actually deliver the baby. All of these can make a difference between having a very small chance of survival and having a much better chance.

4. In some hospitals babies under 24 weeks, and in others under 23 weeks, are not offered intensive care. Other hospitals have a much more proactive approach. Ask your obstetrician if your hospital has any policies, and any experience, in giving intensive care support to babies at your estimated gestational age.

5. Before 22 weeks best estimate of gestational age there are only very few babies in the whole world who have survived. After 22 weeks estimated gestational age chances improve, and continue to improve with each day. Overall, in a hospital that gives babies at 22 weeks GA a chance, 1 out of 4, to as many as 1 out of 2, babies can survive.

6. Almost always, babies at 22 to 23 weeks gestational age have several complications during their hospital stay, they tend to have infections, feeding problems, lung development problems and many have serious complications.

7. If your baby survives the first 24 -72 hours their chances will improve. Most babies who don’t make it die within that period. However, some who have multiple or very serious complications can get into serious difficulties later and may die after many weeks of intensive care.

8. Babies who survive frequently have challenges during their first years, many have lung problems and hospital visits, or re-admissions, often for lung problems. Some will need surgery, such as for a hernia.  Some will need extra attention from physiotherapists, occupational therapy specialists, and other medical specialists. Almost all have an excellent quality of life, are able to communicate, and enrich the families they are born into.

As I was preparing this post, a highly relevant review article by John Lantos was published (Lantos JD. Ethical issues in treatment of babies born at 22 weeks of gestation. Arch Dis Child. 2021) John points out how strange the response has been to the incredible successes in looking after the most immature babies:

One might expect that such a startling medical breakthrough would stimulate excitement, admiration, emulation and research. Oddly, it seems to have generated none of those things. Instead, key professional societies have either ignored or misrepresented the outcome data.

He suggests that what is holding us back is inertia “Treatment of babies born at 22 weeks of gestation shows very promising results. Parents seem to want such treatment. It is cost-effective. The reticence of many centres to provide such treatment seems to be a result of institutional inertia.”

I am not so sure that is all it is, the bias of obstetrical groups against these babies is strong. I wonder if it is because they sometimes perform terminations at 22 weeks for babies without congenital anomalies, so they would rather believe that they are non-viable. There is also an extremely negative sentiment regarding cesarean delivery at extremely low gestational ages, but I think that the decision to be proactive with care does not mandate that a cesarean delivery be performed. Some centers with good results (like Uppsala) have zero CS at 22 weeks, others do some caesareans. Iowa also reports no C-Sections at 22 weeks, but over 1/3 at 23 weeks. I think like everything else it should be an individualized decision, taking into account, among other things, the mother’s future reproductive plans. A mother who is 40 years old with previous pregnancy losses, and a 20 year old in her first pregnancy will probably have a different balance of risks and benefits.

I do believe that my obstetrical colleagues are working for what they think are the best interests of their patients, and I also think that active intervention at 22 weeks should be a shared decision with the mothers. But, in order to make that shared decision, mothers, and their partners, need accurate information, with realistic predictions of what will be the result of insituting NICU care. The current ACOG website, last reviewed in August 2019, is full of inaccurate information, that was incorrect in 2019, and even more so today.

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What should we de-adopt in Neonatology?

When practices become ingrained in practice it can be very difficult to change them, even when new evidence becomes available, or a review of existing evidence points out that the practice is worthless.

An editorial towards the end of last year in JAMA (Powers BW et al De-adopting Low-Value Care: Evidence, Eminence, and Economics. JAMA. 2020) discusses “Evidence, Eminence, and Economics”, 3 factors that are important in whether or not useless therapies or investigations continue to be common or are de-adopted. Briefly, good quality evidence that a procedure or test is ineffective often has little effect on practice patterns. Statements by learned societies tend to have some effect but it is variable and often a small effect. When a system stops paying for a test or procedure the impacts tend to be major and rapid.

The choosing wisely campaign recommended 5 common neonatal procedures that could be abandoned (Ho T, Dukhovny D, Zupancic JA, Goldmann DA, Horbar JD, Pursley DM. Choosing Wisely in Newborn Medicine: Five Opportunities to Increase Value. Pediatrics. 2015;136(2):e482-9).

These are my top 4, there is some overlap with Ho et al.

  1. Routine day 3 head ultrasound, (followed by day 7-10, day 30, 36 weeks and pre-discharge, near term).
    • Routine investigations as a universal screen should be proven to improve outcomes in some way. Clearly, that has never been shown for routine repetitive head ultrasounds, but they have become standard practice and are often performed on multiple occasions.
    • Generally speaking, investigations should only be done if they will change the clinical approach. A good rule of thumb is to ask the question, what will I do if the test result is negative, and what will I do if it is positive? If the answers are the same: don’t do the test.
    • I think we should do head ultrasounds only if they are going to have an impact on clinical care.
    • We should therefore focus on finding treatable conditions, which in this situation means acute post-haemorrhagic ventricular dilatation.
    • A single head ultrasound at 5 to 7 days of age in infants who are at risk of that complication, such as babies under 27 weeks and those who have been critically ill, would suffice. Further head ultrasounds are only needed if the initial images show a lesion that could lead to post-haemorrhagic hydrocephalus.
  2. C-Reactive Protein
  3. Anti-acid medications
    • Many babies with symptoms attributed to reflux receive either H2 blockers or PPIs
    • There is no clinical sign that is adequately diagnostic of reflux except for overt regurgitation
    • Most reflux in the newborn is non-acid, either neutral or alkaline
    • There is no evidence that clinical signs attributed to reflux are due to acid
    • Gastric acid is good for you, blocking it changes the intestinal microbiome, increases translocation, and increases infections and necrotising enterocolitis
  4. Prokinetic/”anti-reflux” medications
    • Even if you have proved, by multiluminal impedance, that a baby has reflux which is temporally related to their symptoms, prokinetics don’t work. There is no evidence of beneficial effects of prokinetics on reflux in the newborn, and they are all toxic.

Anyone have other suggestions?

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Long term outcomes; the 2 year Bayley tells us very little

The Bayley Scales of Infants Development were created to screen babies for developmental delay, and can be used as one way of identifying children with potential problems, and then determining whether they might benefit from intervention. Unfortunately they have become a way of measuring outcomes of neonatal interventions, and are often used to determine whether such a neonatal intervention is of benefit or not.

The 5 year follow up of the CAP (Caffeine for Apnea of Prematurity) trial was fascinating for me, we compared the resuts of 18 month Bayley scores (version 2) to IQ testing done at 5 years. Only 18% of babies who had a Bayley score below 70 at 18 months had an IQ score below 70 at 5 years.

I have added 2 lines to the graph that we published. The babies whose scores are represented by the dots to the left of the blue line are those who had a Bayley MDI <70. The children under the red line are those with an IQ score <70 at 5 years. The black line is from the original and shows the regression between the Bayley score and how much it changed compared to the IQ at 5 years, which shows that the lower the Bayley scores the more, on average, that they increased by 5 years.

A new publication from the ELGAN study group has done a similar thing, but in a lot more detail, and has defined adverse outcomes at 10 years of age, comparing the results of the Bayley version 2 scores (BSID) and motor evaluation (Gross Motor Functional Classification Score) at 2 years of age to IQ tests and other evaluations at 10 years. (Taylor GL, et al. Changes in Neurodevelopmental Outcomes From Age 2 to 10 Years for Children Born Extremely Preterm. Pediatrics. 2021)

At 2 years, they defined profound NDI as BSID-II MDI ,50, PDI ,50, or GMFCS 5 and moderate to severe NDI as BSID-II MDI 50 to 70, PDI 50 to 70, GMFCS 3 to 4, bilateral legal blindness, or bilateral hearing loss requiring amplification, the others were considered “none to mild”.

At 10 years the expert panel they put together came up with these definitions : moderate impairment (IQ 55–70, GMFCS 3, bilateral hearing loss requiring amplification, bilateral legal blindness, Autism Spectrum Disorder level 2, or epilepsy), severe impairment (IQ 35–54, GMFCS 4, or ASD level 3), or profound impairment (IQ ,35, GMFCS 5, or ASD level 3 combined with IQ 35–54). They had data at both times for just over 800 babies <28 weeks gestation.

The first publication I remember that made this clear to me was by Maureen Hack (Hack M, et al. Poor Predictive Validity of the Bayley Scales of Infant Development for Cognitive Function of Extremely Low Birth Weight Children at School Age. Pediatrics. 2005;116(2):333-41). She showed that, of 78 babies with a 20 month MDI <70, only 29 had an 8 year IQ score <70. She also noted that the babies who were less likely to improve were those with neurosensory abnormalities.

The new study also seems to show that infants with profound “NDI” at 2 years who had severe motor problems GMFCS 4 or 5 were less likely to improve. Looking at their table 3, most of the babies with severe GMFCS scores either stayed profoundly impaired or worsened from 2 to 10 years, only a few improved from profound to moderate or severe.

Overall these data are rather encouraging, the proportion of babies with adverse outcomes, and, in particular, severe or profound impairments is much lower at 10 years than the 2 year evaluation would suggest, and importantly, for individual patients predictions are quite unreliable.

Looking at things from another point of view, a publication from the NICHD network examining the outcomes at 2 years of age (Rysavy MA, et al. The relationship of neurodevelopmental impairment to concurrent early childhood outcomes of extremely preterm infants. J Perinatol. 2021) compared the Bayley version 3 results of close to 3,500 babies of 22 to 26 weeks gestation to other outcomes such as hospital readmission, surgery in infancy, feeding problems leading to gastrostomy tube placement, medication use, and medical equipement needs at home.

Although many of those outcomes were more frequent among infants with so-called “Neuro-Developmental Impairment” or NDI they also occurred in infants without this label, and some outcomes such as re-hospitalisation for respiratory illness or surgery were very similar across groups of infants with no “NDI” to severe “NDI”.

As the authors of this study note, many of the outcomes that are reported in this paper are things which are important to parents, and impact their families, but are usually not collected or presented in detail.

They also note the following:

NDI does not have a consensus definition. Published definitions vary widely across studies. Small variations in the definition of NDI can have a substantial influence on its rate in a population and on its association with specific variables. Despite this, studies of NDI in children born extremely preterm are used as the basis for recommendations to make treatment decisions, including whether to direct care toward survival or palliation, and are frequently used as a component of the primary outcome of major clinical trials.

You will have noted that I usually put “NDI” in quotation marks as it is a term that I think should be abandoned. Most infants at 2 years of age are labeled as NDI because of a low score on the Bayley scales. But a low score on a developmental screening test is NOT an impairment. Although of some value for identifying infants who might benefit from further evaluation or intervention, they should not be used to determine whether a baby’s life is worth living.

The Bayley 4 is coming, I think it was released in 2019, I don’t know if the standardisation will prove to be more reflective of the general population, but I know it was re-standardized, or if it will be more predictive of longer-term impairment. But I doubt if any test designed to detect developmental delay in early childhood can predict school difficulties or persistent intellectual difficulties. Using such scores well beyond their initial intended purpose, such as for a definition of profound impairment, and then using the chance that a baby may have “profound impairment” in decision-making, is an enormous mistake.

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Coagulopathy and intraventricular haemorrhage

Intraventricular haemorrhages continue to be a source of concern to families of very preterm babies, and to all of us; severe hemorrhages are associated with poorer outcomes, especially bilateral extensive periventricular haemorrhagic infarction.

This is one of my occasional series of reviews of a particular neonatal issue, that are not particularly triggered by a new publication but by a question about current clinical practice. The question being: “When we find a serious intracranial haemorrhage in an at-risk very preterm baby, should we perform coagulation studies?” and of course the related questions “how should we interpret the results?” and “how should we respond to the results?”

Reviewing the literature for this is frustrating, there are not a large number of publications but they are contradictory.

Some studies have found an association between serious IVH and prolonged clotting times, whereas others have not. Some have shown associations between genetic abnormalities relating to clotting factors, whereas others have not.

Earlier studies from the ’70s and ’80s tended to use the same normal values for babies of all gestational ages. But babies with haemorrhages are generally less mature, and less mature babies have more prolonged clotting times, even in the absence of an IVH. For example, Christensen et al showed that babies under 28 weeks had longer PT and aPTT than babies of 29 to 34 weeks. Neary et al enrolled more extremely immature babies and showed that at 23 to 24 weeks the mean PT was 22.6 s with a Standard Deviation of 7 seconds (at 24 to 25 weeks the mean was 21s), the aPTT was a mean of 83s, with an SD of 37 s in the most immature babies, and 72 s (SD 21s) at 25 to 26 weeks, this study only included babies without serious IVH. Another study by the same group also showed very low concentrations of factors II and IX, and a low concentration of factor VII in the preterm

As more immature babies have more IVH and also have more prolonged clotting times in the lab, then, by chance, there will seem to be an association between coagulopathies and IVH, unless you use gestational age-adjusted normal values, or adjust statistically for GA. It is of course possible that the reason more immature babies have more IVH is because they have disrupted coagulation. The only way to be sure would be to have large numbers of babies with and without IVH of each gestational age and determine within GA strata whether babies with longer clotting times are more likely to have IVH.

We also should remember that as well as lower concentrations of procoagulant factors, newborns, adn preterm newborns in particular also have lower concentrations of anticoagulant factors (Protein C, Protein S, and Antithrombin). Full term newborn at least are at higher risk of thrombotic complications as a result.

In general, among very preterm babies, I find that those studies which prospectively obtained cord blood, or early blood samples prior to the occurrence of IVH show no difference between babies with and without haemorrhages (such as Neary et al 2015). Those which studied coagulation tests taken later on, such as at 48 hours, show more prolonged clotting times in babies with IVH, which suggests that perhaps prolonged coagulation tests are a result, rather than a cause, of IVH. This is illustrated by a study by Beverly et al. Babies who had “grade 4 IVH” had a mean of 28.7 weeks compared to those without IVH (32.3 weeks), cord blood aPTT was somewhat longer in those who eventually developed an IVH, but only by 10 seconds, at 48 hours, those without an IVH had an aPTT which had shortened by 10 seconds, whereas the IVH babies had not changed much, and the difference was then “statistically significant”.

The answer to the first question I asked therefore is “not clear”, it doesn’t appear that there is much difference between the baseline coagulation studies of very preterm babies who go on to develop IVH compared to GA matched controls without IVH, so routinely measuring coagulation studies is of no proven value. Results should probably be evaluated compared to GA appropriate standards if you do obtain them, recognizing that among the most extremely immature infants’ values are not well documented (Neary’s study for example only had 9 babies of 23-weeks).

If you find clotting times which are even longer than GA appropriate standards, what should you do about it? There are four RCTs of Fresh Frozen Plasma use analyzed in the Cochrane Review, which appears to have been last updated in 2004. That review includes all of the interventions which could be classified as “volume expansion” but has one of their comparisons as FFP versus no treatment. The analysis shows no overall difference in IVH between groups, but none of the studies had coagulopathy as an entry criterion. It is interesting that one small controlled trial (Beverley 1985) seemed to show a reduction in IVH with FFP administration, but did not show that FFP improved coagulation study results! The 2 groups had practically identical PT and aPTT after either FFP or no treatment, and only slightly higher fibrinogen concentration after FFP.

To answer my initial questions, then: “When we find a serious intracranial haemorrhage in an at-risk very preterm baby, should we perform coagulation studies?” I would say this is of no proven value, disturbed coagulation studies may be a result rather than a cause of IVH; of course, the occasional patient with congenital coagulation disorders that may warrant intervention may be missed if we never do such tests. Haemophilia A in Canada has an incidence of about 20/100,000 male births, and Haemophilia B is about 4/100,000, Von Willebrand’s is about 12/100,000 births, and other factor deficiencies together are somewhere between Haemophilia A and VWD; so overall about 0.05% of boys and 0.025% of girls.

Given the low risk of missing a congenital disorder, I think it is reasonable to limit coagulation screens to babies with something unusual in their presentation, such as an unexpected IVH, or bleeding in other sites in addition to the IVH; unless, of course, new data in the future demonstrates a clear link between disturbed coagulation studies and the development of IVH.

“How should we interpret the results?” I think we should use GA appropriate standards, with the proviso that different laboratories give different results; but differences between good quality labs are nowhere near the same order of magnitude as the differences between mildly, moderately, and extremely preterm infants. So if your lab does not have good normals for a 25-week infant (for example) you won’t go far wrong using published normal values.

“How should we respond to the results?” I think that unless a baby is actively bleeding we have no evidence that responding to abnormal coagulation studies will improve any outcomes. If we do find a result which is outside of GA appropriate normals, then replacement of the missing factors could possibly be the right thing to do, but volume expansion may be hazardous, so I think giving the replacement as slowly as feasible, or giving factor concentrates if a specific factor deficiency is discovered, should be the approach.

It is also possible that haemorrhages cause disturbances of coagulation which then lead to progression of the grade of IVH, but that also is unproven, and seems to me to be unlikely, as the pathophysiology of the worst haemorrhages appears to be venous infarction rather than continued bleeding.

A large prospective study of very early coagulation studies among babies under 27 weeks gestation, with enough numbers to determine with more certainty the link between coagulopathies and IVH would be great. It is getting harder to obtain cord blood now that delayed clamping is the norm, so such a study would be difficult to complete, but it would really help in the clinical care of our tiniest, at-risk, babies.

Posted in Neonatal Research | 7 Comments

Back to blogging

I have been unable for various reasons to blog for a while, but getting back in the saddle is a good feeling, and I plan to try and blog at least once a week. There have been a few blog posts that have been partially completed over the last 3 months, some of which I will work on and post in the next few days. In the meantime, as an added treat, here are a few pictures of birds! The first 3 are from western Europe, the other 3 are Québecois.

Avocet with worm
Greenshank and Snipe
Dipper
Pileated Woodpecker
Purple Finch
Bobolink
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The HIP trial, treating hypotension in the extremely preterm infant.

I guess the HIP trial should be about screening for congenital dislocation, but in reality, it stands for Hypotension In Preterm infants. The long road to the unsatisfactory conclusion of the trial started more than 10 years ago, in discussions with Gene Dempsey, after he left his fellowship with me in Montreal, we continued to discuss how best to answer the questions about the treatment of hypotension, which then was, and still is, a major controversy. We wanted a large pragmatic trial comparing usual therapy, which was to give a bolus of saline and then start dopamine if the mean BP remained below the gestational age in weeks, to an approach where treatment was only given if there were signs of poor perfusion. We realized that it would be ethically difficult to randomize, to placebo, babies with clinical signs of poor perfusion (even though we have no good idea how to treat hypotensive babies with poor perfusion either!) so the only eligible babies should be those without such signs.

The protocol that we thought best would be to allow rescue treatment for enrolled babies if they became profoundly hypotensive or developed other signs, but preferably with something other than dopamine.

Fortunately for me and the other investigators, Gene Dempsey didn’t leave this as a pipe dream, but put together an application to the EU under the FP7 scheme, and was successful in securing funding. Gene’s brilliance and his ability to get things done have recently been rewarded by Ireland’s first and only chair in Neonatology! Congratulations Professor Dempsey.

Part of the justification for granting these funds was that we should develop a specific neonatal formulation of dopamine. As you might imagine the clinician/investigators didn’t care a bit about that, we would have been happy to study off-the-shelf dopamine made by anybody, but as dopamine is not approved for use in the newborn in Europe, (or Canada or the USA in fact) we were mandated to perform the study as a basis for a neonatal approval for the drug.

Unfortunately, that led to enormous delays in getting the study started, as the company we were working with wanted a formulation without preservatives (as did we, if possible), and a manufacturer told them it was possible, but then it turned out not to be stable, so we waited for a formulation with a preservative but designed for newborns, and finally, as we were starting to get worried about running out of time, we received approval to use off-the-shelf dopamine, and had a one-year extension to the grant. Once we actually started recruitment it was slow going, which was somewhat expected, but the PIP (pediatric investigation plan) that had been approved by the EMA forced us to restrict the study to only babies with arterial catheters in place. I understood the restriction, non-invasive blood pressures are very unreliable in very tiny babies, especially when they are hypotensive! I will usually try to put in an arterial catheter in a baby if I start some inotrope/vasopressor treatment, but in my centre, generally for babies at 25 weeks and above we don’t otherwise routinely put in arterial catheters, we restrict them to those who have clinical compromise, who wouldn’t actually be eligible for the trial!

The PIP also mandated that babies have a head ultrasound prior to enrolment to document a lack of severe abnormalities. Again I can see the point, serious head ultrasound abnormalities were part of the primary outcome, but the reality of clinical practice is that babies are often hypotensive in the first few hours of life, and head ultrasounds are often not available when the decision to treat is made.

So in our centre, despite screening babies for many months we weren’t able to randomize anyone. Other centres were more successful, either because they used more arterial catheters or had more hypotensive babies, and often the attending neonatologist performed the head ultrasounds. Over the 2 years that the trial was recruiting there were over 800 babies less than 28 weeks gestation born in participating hospitals, 307 of whom had an arterial catheter in place, 91 of those were eligible for the trial, and finally 58 were randomized. We had planned for 830 babies, which would have been feasible if we had 3 times as many centres and twice as much time.

Finally, the grant expired and we had to terminate the trial, which was a huge disappointment. However, it is nevertheless the largest prospective RCT of hypotension in the preterm and the largest placebo-controlled RCT of dopamine use in newborn infants. (Dempsey EM, Barrington KJ, Marlow N, O’Donnell CPF, Miletin J, Naulaers G, et al. Hypotension in Preterm Infants (HIP) randomised trial. Archives of Disease in Childhood: Fetal and Neonatal Edition. 2021). I recount all these difficulties for anyone planning to study similar issues in the future. In older studies, about 50% of extremely preterm babies were hypotensive, whereas in HIP a bit less than 33% of extremely preterm babies with arterial catheters in place satisfied our criteria for enrolment, which were: 1. Less than 28 weeks 2. mean arterial pressure below the gestational age in completed weeks for at least 15 minutes 3. a head ultrasound without serious IVH.

In the 2 groups, the study drug (dopamine or placebo) was given in increasing doses (up to a maximum of 20 mcg/kg/min) until an acceptable BP was achieved, (above the GA) or they developed profound hypotension or signs of shock. That was quantified as a mean BP more than 5 below the treatment threshold, or at least 2 of the following: BP more than 3 below threshold; capillary filling time more than 4 seconds; serum lactate over 4 mmol/L.

The primary outcome was survival without severe brain injury on ultrasound, which was slightly more frequent among placebo infants, 69%, than among dopamine babies, 62%. Mortality was almost identical (7 babies vs 6), and other outcomes were also similar, obviously the final trial size was severely underpowered.

The only difference of note between groups was that the placebo babies were more likely to get back-up treatment 66% vs 38%.

The study illustrates some of the difficulties in doing such a study. We really wanted to do a pragmatic study that reflects current clinical practice, which was not consistent with the requirement to have a head ultrasound prior to starting treatment, at least in most North American sites where radiology organizes the imaging. Similarly the restriction to only babies with arterial lines while justifiable, I think does not reflect universal practice.

How could we do another study to get sufficient power to answer the questions? I think that a grant from an agency that commonly funds clinical trials in newborns, with a focus on just getting a clinical answer without concerns about specific neonatal formulations would help. Using the clinical research networks that are in place or currently developing would really help, although we have made some great relationships in planning and performing this trial.

The long term outcome of these babies is being collated and analysed at present, this was a co-primary outcome, and will also, of course, be greatly underpowered, but might be able to give us a hint as to whether avoiding dopamine in the first few days of life has a major impact on development. There will also be other publications addressing side studies, the first of them, which will be appearing soon, first author Liesbeth Thewissen, evaluates the impacts of hypotension and its treatment on cerebral NIRS signals. Watch this space!

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