We found more bad things, that must be a good thing

Frequent readers of this blog will know that I have been critical of the promotion of pre-discharge MRI as a universal screening standard for very preterm babies. The positive predictive value of most findings on MRI at term-equivalent age is low, especially when you take into account that most significant findings will already be seen on prior head ultrasound. The PPV in particular of white matter abnormalities is well below 50% in almost all studies. Nevertheless, people like to look, and try to convince themselves that seeing more bad things in the brain of a very preterm baby must be a good thing to do. Hence we get articles like this one : Melbourne L, et al. Clinical impact of term-equivalent magnetic resonance imaging in extremely low-birth-weight infants at a regional NICU. J Perinatol. 2016.

The authors report results from 103 term equivalent cerebral MRIs in infants with birth weight less than 1000g. They report that they found new abnormalities in about half of the MRIs, not seen or suspected on serial head ultrasounds. Where the paper gets weird is that they asked a pediatric neurologist to look at the scans (US and MRI) and predict what the prognosis would be, and they then use this prediction as an outcome variable, even performing a statistical test to show that “simulated prognosis” was worse when you looked at the MRI.

Only 26 of the babies actually had a follow-up assessment, so it’s not really even worth talking about that part, except to say that they note there were a lot of “false positives”. The authors note that based on the MRI 14% of those 26 babies (that is, 3.6 of them(?)) were predicted to have cortical blindness, and none of them did. The one baby with cortical blindness was not predicted by the MRI.

How on earth a pediatric neurologist can give a  prognosis of the degree of developmental delay based on an MRI is beyond me. There is so little correlation between MRI findings for an individual baby and Bayley scores, (or between head ultrasound findings and Bayley scores for that matter) that to predict that an individual will have moderate delay, or mild delay or severe delay is impossible. To use that prediction as the outcome variable for this study is bizarre. Of the very few babies with follow-up there were 9 who had a Bayley (version 2) MDI more than 2 SD below the mean, of whom 4 were predicted from the MRI, and 12% of the babies (3, I presume) were predicted to have that low an MDI and were false positives. Which is pretty useless.

The authors end the abstract with this statement:

TE-MRI detects new abnormalities and impacts developmental prognosis in the extremely low birth weight, which supports its use despite the added financial cost.

and end the entire article with a similar conclusion.

There is no data about how the parents felt about the new abnormal findings of doubtful prognostic interest.

The MRI cost $1600, which is a large additional cost at the end of already costly hospitalizations. They note that this cost “is not negligible and should not be incorporated into practice without measurable advantages to providers, patients and/or families.” I agree with the patients and/or families part of that sentence; I don’t think we should be doing things to babies that cost money and disturb them and their families because of benefit to providers, though. They certainly have not demonstrated any benefit to anyone of routine MRI.

Basically the authors are saying we found more bad things, so that must be a good thing. I would say that they discovered imaging findings of uncertain significance, and low prognostic value, and that might equally be a bad thing.

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Long term survival in trisomy 13 and 18

After my previous post on this topic, John Lantos wrote a comment pointing out this recent publication, Nelson KE, et al. Survival and Surgical Interventions for Children With Trisomy 13 and 18. JAMA. 2016;316(4):420-8. It is a large regional cohort, identified from hospital records and linked death data. Included patients were those with a hospital discharge diagnosis during the first year of life including trisomy 13 and 18, which could possibly be incomplete, and/or include patients with other disorders, but I think it’s probably as good, or better than many other methods. It also includes some children with mosaicism or translocations. 428 children were included in the study who were born between 1991 and 2012 in the province of Ontario, with these results for 1 year and 15 year survival:survival t13 and 18

As you can see survival to 1 year and to 15 years was not that unusual, as the results show

One-year survival was 19.8% (95% CI, 14.2%-26.1%) for children with trisomy 13, and 12.6% (95% CI, 8.9%-17.1%) for children with trisomy 18. At 10 years, 12.9% (95% CI, 8.4%-18.5% [n = 13]) of the trisomy 13 cohort was alive, and 9.8% (95% CI, 6.4%-14.0% [n = 16]) of the trisomy 18 cohort was alive.

They also investigated survival after surgery, 76 of the children had a surgical procedure, with a big variety of procedures, and most of them were in older infants, over 6 months of age, with the exception of the first cardiac or GI procedure among trisomy 18 infants. Most of the babies (about 70%) survived for at least a year after surgery.

Survival curves are presented in the supplementary appendix in a different way, they show for example that for trisomy 13, if the baby is alive at 1 week of age then survival to 1 month was 75% (95% CI 65-83%) survival to 1 year was 36% (CI 26-45%), to 5 years was 27% (CI 19-36%) and to 10 years was 23% (CI 15-32%). The corresponding figures for trisomy 18 are 67% (58-74%), 25% (17-32%), 22% (15-30%), and 19% (13-26%).

Because of the nature of these data there is, of course, no information about decision-making, which clearly has a large effect in this condition, as I noted in the previous post, death in the first day of life is almost completely confined to infants with a decision for comfort care only.

Dr Lantos writes the accompanying editorial, in which he discusses the decision-making ethics. He has the following to say:

The concept of quality of life is too vague and subjective to be helpful as a criterion for deciding about the appropriateness of treatment. No one can know with certainty what any infant is thinking, feeling, or experiencing, but what is observed can be interpreted. Children with trisomy 13 and 18 smile and laugh. They are not in pain. They give and receive love. These factors suggest that their subjective quality of life is not so poor that life-prolonging treatment should not be offered. Generally, the phrase quality of life is misused as a synonym for physical or neurological impairment. But if impairment is to be discussed, accurate terminology should be used. Some infants and children can have severe impairments and still have an excellent quality of life.

I’m not sure that I agree that Quality of Life is not helpful as a criterion, it seems that Dr Lantos isn’t sure either, as he states that subjective quality of life is “not so poor that life-prolonging treatment should not be offered” which seems to me to contradict the first sentence. I do agree though, that we shouldn’t just say that quality of life is OK, and then not take anything else into account, I don’t think it should be the only criterion. I think the insight about the misuse of the terminology is spot-on though, there are many health-care workers who don’t think that an impaired, or severely impaired child can have a good quality of life. John kindly references a publication I co-authored for that last statement (Payot A, Barrington KJ. The Quality of Life of Young Children and Infants with Chronic Medical Problems: Review of the Literature. Current Problems in Pediatric and Adolescent Health Care. 2011;41(4):91-101), I would have phrased that a little differently, and noted rather that there is little or no correlation between severity of impairments and quality of life. If we recall from one of Dr Saroj Saigal’s studies, the only participant who scored their quality of life lower than zero (worse than being dead) was one of the controls. Presumably a depressed adolescent who I hope got a psych referral.

John Lantos’s editorial is perceptive and clear, and I certainly agree with his conclusions; which are basically that the diagnosis is not by itself enough to deny active medical intervention for children with these conditions, that a complete evaluation of the baby (or fetus) should lead to decision-making driven by parental values.

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Sustained inflation during neonatal resuscitation? Not so fast…

A sustained inflation at birth of an asphyxiated lamb which lasts 30 seconds leads to much more rapid restoration of heart rate and blood pressure than either conventional ventilation or a series of shorter sustained inflations of 5 seconds each. This new study from the same group (Sobotka KS, et al. Single Sustained Inflation followed by Ventilation Leads to Rapid Cardiorespiratory Recovery but Causes Cerebral Vascular Leakage in Asphyxiated Near-Term Lambs. PLoS One. 2016;11(1):e0146574) shows that cardiac contractility, carotid artery flow and cerebral oxygen delivery also increase much more rapidly.

But, wait a minute, is that necessarily a good thing? What is important is the eventual re-establishment of a stable circulation, and a reduction in cerebral injury, and injury to other organs. One of the reasons we have switched to room air resuscitation (at least for full term infants) is that re-oxygenation injury is reduced compared to 100% oxygen resuscitation, maybe increasing cerebral perfusion and oxygen delivery very quickly might also have some harmful effects.

In this new study the authors also performed brain histopathology  of the lambs after resuscitation, mostly looking at how many blood vessels in each of 3 sections of the brain were surrounded by extravasated serum. There were significantly more disrupted blood vessels and extravasations in the  sub-cortical white matter of the single prolonged inflation lambs than the other 2 groups, and slightly more in the gray matter and the periventricular white matter also. Exactly why this occurs, what the potential impacts are and whether it might also occur in babies exposed to different kinds of sustained inflations is unknown, but will need to be investigated.

Two fairly recent randomized trials have concentrated on pulmonary outcomes:

In the first, nearly 300 infants from 25 to 29 weeks gestation were randomized, Lista G, et al. Sustained Lung Inflation at Birth for Preterm Infants: A Randomized Clinical Trial. Pediatrics. 2015;135(2):e457-e64. They either were placed on CPAP, or had a sustained lung inflation (25 cmH2O for 5 seconds) followed by CPAP. The SLI group were more likely to avoid mechanical ventilation during the first 72 hours of life, but the number ever intubated, the proportion who developed BPD and survival were not different. As the babies were not necessarily asphyxiated, this was really a trial of SLI as a lung protective strategy, which did not really show any benefit; other complications of prematurity, including IVH and PVL, were not different between groups.

The second study enrolled nearly 200 infants of 34 to 36 weeks gestation, Mercadante D, et al. Sustained lung inflation in late preterm infants: a randomized controlled trial. J Perinatol. 2016;36(6):443-7. They described the intervention as follows :

after oropharyngeal and nasal suctioning, a prophylactic pressure-controlled (25 cmH2O) inflation was sustained for 15 s using a neonatal mask and a T-piece ventilator, followed by the delivery of 5 cmH2O CPAP. In the following 6 to 10 s, CPAP was discontinued in the absence of signs of inadequate respiratory effort (that is, apnea or gasping) or heart rate 4100 beats per min (b.p.m.). In the presence of signs of inadequate respiratory effort and/or whenever the heart rate was between 60 and 100 b.p.m. despite CPAP, a SLI maneuver with the same parameters was repeated. If the heart rate was <100 b.p.m. after the second SLI maneuver, the infant was resuscitated according to the recommendations of the American Academy of Pediatrics (AAP).

This study showed no benefit of the procedure, and 3 babies in the SLI group, but none of the controls, developed a pneumothorax.

It seems to me we should be being very careful with this intervention, and I say this as someone who has done it intermittently for many years. I think I’ve mentioned before on this blog that Anthony Milner showed years ago in depressed full-term babies who were intubated before their first breath, that a prolonged (5 seconds) slow-rise inflation pressure, up to 30 cmH20 eliminated the apparent opening pressure of the lungs and led to rapid establishment of an FRC. My anecdotal experience is that sometimes when I take over ventilating a baby who the junior staff is having difficulty with, and I apply that kind of a long inflation, often the lungs will be easy to inflate, and then assisted ventilation is much easier, often with a recovery of other clinical signs.

I’m somewhat less convinced of the value of SLI as a lung-protective strategy for preterm infants, and certainly the clinical data so far do not support it. As a part of a resuscitative strategy for depressed babies, I think there is more promise; but it now looks like we will have to carefully examine potential neurologic compromise.

 

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Brave New World

As a teen (yes I can still remember that far back) one of my favourite books was “Brave New World” by Aldous Huxley, I haven’t reread it for many years now, but I would still recommend it (and I’m not alone). One of the features of the future dystopian world that Huxley imagined was the creation of different types of human beings, Humans no longer reproduce normally but are created in hatcheries and designed to have certain limitations so that they fit into one caste or another, the betas, deltas and so on. Only the alphas were allowed to develop without any added limitations.

Some ‘advances’ in modern medicine make me think of that book, and the ironic phrase of Shakespeare that the title of Huxley’s book was taken from

O wonder!
How many goodly creatures are there here!
How beauteous mankind is! O brave new world,
That has such people in’t.

Spoken by Miranda in The Tempest.

This study (Haque IS, et al. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316(7):734-42.) was funded by, and 5 of the 6 authors are employees of, “Counsyl’ a company that sells expanded prenatal carrier screening, using a test which screens for anomalies in 110 genes. Over 3 1/2 years, over 340,000 people were tested with one of their two technologies, people who had no specific clinical indication for testing, but decided to be screened to see if they were carriers for an abnormality in one of those 110 genes. 78% of them were women; I guess if the initial screen is negative, then the cost of testing the other parent can be avoided. They are also testing for some X-linked recessive conditions, not just autosomal. Many of the anomalies they are testing for are incredibly rare (with as few as total of 200 cases known in the world). The authors model how many affected fetuses would be detected, using many assumptions, including that the parents are both from the same ethnic group. Overall the predicted rates of affected fetuses vary according to ethnic group, with about 1 affected fetus per 1000 Hispanic patients to about 4 times as many for Ashkenazi Jewish subjects.

An accompanying editorial is worth reading, its written by a specialist in molecular/genomic medicine:

He notes that many of us were taught in medical school that we all carry an average of 6 deleterious recessive gene variants, he specifies that that that number was not based on any apparent actual data, he continues

it is now known from clinical genomic sequencing that each individual carries several hundred potentially harmful gene variants, along with thousands of less characterized coding variants that differ from the so-called reference human genome sequence, and millions more in the noncoding regions of the genome that are largely uninterpretable. In most clinical settings it is unknown whether many of these gene variants result in net harm to patients.

He notes that these extended carrier screens may lead to a diagnosis of abnormalities that may not even cause disease, that they may lead to a diagnosis of diseases (with very good outcomes) that are already screened for in the neonatal period, such as PKU (but don’t necessarily pick up all the hundreds of genetic variants that might cause PKU) and that one of the conditions most commonly picked up is Fragile X syndrome, for which no-one recommends screening, largely because expansion of the triplet repeats into the disease-causing range is uncommon and unpredictable, with uncertain impacts on the family who screens positive, but has no clinical impact.

The criticisms make me wonder why this article was published, as it seems to be mostly a marketing exercise for Counsyl, and as far as I can see the enlarged carrier screening can create almost nothing but heartache. Most positive screens, with a rare gene abnormality will, of course, not be confirmed in a partner in the second stage of testing, and even when the partner is positive, only 1 in 4  of their children will be affected. Who has the expertise, and the time and resources, to explain the implications of every one of the 100 abnormalities being screened for? If the answer is almost no-one, then informed consent is really not being done. We already have many situations where a negative test is mis-interpreted by parents as meaning that the baby will be fine, or where a positive test of uncertain significance leads to incredible stress and soul-searching for no apparent benefit.

What I couldn’t find in this publication is the proportion of initial screens that showed a potential risk, which would then be followed by a partner screen that would almost always not show an anomaly in the same gene. Some of the gene frequencies of individual anomalies can be found in some supplemental material, and many are extremely rare. Only about 20 abnormalities for a gene for Andermann syndrome were detected (among the 340,000 screens), the likelihood of a non-consanguineous couple being both positive for such an anomaly is so vanishingly small, that to include such tests in a carrier screen is ridiculous. Do parents, when they shell out the cash, realize that they are much more likely to win the lottery than to find that they are both carriers for this disease?

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Neonatal Updates: Recent Nutritional Publications part 2.

Breast Milk and how to use it

Colacci M, et al. Growth and Development in Extremely Low Birth Weight Infants After the Introduction of Exclusive Human Milk Feedings. American journal of perinatology. 2016(EFirst). This is a before and after study from a center where they changed to “exclusive” human milk feedings. About 40 babies before and after the switch are included, all with a birth weight under 1 kg. In fact the group with “exclusive” human milk feeds were exclusive for at least 4 weeks and then had bovine products introduced when they reached 1500 g or 34 weeks, whichever occurred first. Why that was done is not described, maybe it was a cost issue, human milk based fortifier was used up until the switch over (or at least it was started when the babies were receiving 100 mL/kg/day of milk). The introduction of bovine fortifier (or cows milk based formula) may have been because as the babies get bigger it becomes more expensive to provide human milk-based products. More than 90% of the babies in each group received some maternal breast milk, but most (about 80%) got at least some formula.

The authors report growth outcomes, some clinical short-term outcomes, and long-term neurologic and developmental outcomes. Macronutrient intakes were not different between groups, and were not very good during the first week at least, 3 g/kg/d of protein, and 82 kcal/kg/d, feeds were started on average on the 4th day of life, on average. Of interest, the incidence of NEC was identical between the groups, at 10%.Growth outcomes were also not different, with the loss of about 1.5 weight z-scores between birth and discharge, finally all the scores on developmental assessment were just about identical between the groups.

Belfort MB, et al. Breast Milk Feeding, Brain Development, and Neurocognitive Outcomes: A 7-Year Longitudinal Study in Infants Born at Less Than 30 Weeks’ Gestation. The Journal of pediatrics. 2016. This is a cohort study from Melbourne of babies under 30 weeks gestation, for whom donor breast milk was not available. They analyzed breast milk intake during the first 28 days of life, and correlated the number of days that more than 50% of the intake was breast milk, and the daily breast milk intake, to outcomes at 2 years and 7 years and MRI brain volumes at term and at 7 years of age. 180 babies were in the study, and the more days you get more breast milk the more deep nuclear gray matter you have when you reach term.

At 7 years of age the babies who had more days with more than 50% breast milk had better performance on “IQ (0.5 points/d; 95% CI, 0.2-0.8), mathematics (0.5; 95% CI, 0.1-0.9), working memory (0.5; 95% CI, 0.1-0.9), and motor function (0.1; 95% CI, 0.0-0.2) tests.”

At 7 years of age the total brain size was somewhat bigger (about 2 cc for every day of breast milk >50%) which sounds like a lot to me, but it wasn’t significant when adjusted for covariates, in fact at 7 years none of the MRI volumes were significant after adjustment.

 Bharwani SK, et al. Systematic review and meta-analysis of human milk intake and retinopathy of prematurity: a significant update. J Perinatol. 2016. A systematic review and meta-analysis of observational studies of the effects of maternal milk (in this review studies were excluded if they were only examining the effects of donor milk, but 2 were included that used some maternal and some donor milk) on the development of RoP and of severe RoP. Despite the major limitations of these kinds of studies, and the difficulties in trying to meta-analyze them, there does seem to be a real association between receiving any amount of human milk and a reduced risk of retinopathy.

Rosas R, et al. Experimental study showed that adding fortifier and extra-hydrolysed proteins to preterm infant mothers’ milk increased osmolality. Acta Paediatrica. 2016. The authors here took breast milk from mothers who had delivered preterm and added a commercial fortifier (from Nestlé) at the usual concentration, recommended by the manufacturer, and then at a slightly higher concentration, and then with added oligopeptides at 2 different concentrations. They refrigerated the mixture and then measured the osmolality at intervals for 23 hours. Osmolality increased progressively, being around 296 for the unfortified breast milk, with standard fortification this increased immediately to 380 and then continued to increase more slowly up to about 450. With higher concentrations of fortifier, the immediate increase was to over 450, with not much difference when protein was added, and then continued to increase to about 530.

The composition of the Nestlé fortifier is somewhat different to the Enfamil and Similac that we use in Canada. There is an error in the publication, but I think that the fortifier is supposed to have 400 kcal/100 g (and not 4 as it says in the table!), the additional calories are mostly as carbohydrate (66g/100g) with very little fat (0.4g/100g). When you add the fortifier at the recommended concentration you supposedly add 20 kcal per 100 mL of milk, 1 g of protein, and 3.5 g of carbohydrate, and 0.02 g of fat; I can’t make that add up to 20 kcal, I think it is more like 18 kcal. Enfamil powdered fortifier in contrast has very little carbohydrate, so when you use at the recommended concentration you add 1 g of fat, 1.1 g of protein and almost no carbohydrate, per 100 ml. The Similac fortifier in contrast has a bit less protein (1g additional per 100 mL of breast milk) and 1.8 g of carbohydrate and about 1/3 g of fat. The Similac carbohydrates are “corn-syrup  solids” which is mostly glucose, whereas in the Nestlé FM 85 they are malodextrins, which are less osmotically active.

You clearly can’t extrapolate these new data to the other fortifiers, or to using higher concentrations of the other fortifiers with or without added protein, how important these numbers are is difficult to know, but osmolality closest to human milk is probably best. Currently it looks like the Enfamil fortifier increases osmolality the least, by about 24 just after it is added, but what happens to that over the next 24 hours I don’t know.

McLeod G, et al. Comparing different methods of human breast milk fortification using measured v. assumed macronutrient composition to target reference growth: a randomised controlled trial. The British journal of nutrition. 2016;115(3):431-9.

In this randomized trial 40 infants under 30 weeks were assigned to either get standardized nutritional management, or an individualized approach which required a weekly analysis of  a pooled milk sample from that week, and then adjustment of the fortification to achieve, I think, between 3.8 and 4.4 g/kg/d of protein and between 545 and 629 kJ/kg/d (that’s 130 to 150 kcal/kg/d), I say “I think” because that is only mentioned in the introduction and not in the methods, where they say they planned to target the upper range of those recommendations.

The study required the analysis of over 1,800 samples of breast milk. An enormous work load for just 40 babies. However they didn’t achieve any increase in nutritional intakes in the intervention group, and intakes in the intervention group were well below the targets. The reason for which seems to be that they arbitrarily limited fortifiers to maximum allowable concentrations (Standard fortifier powder (Wyeth): maximum 4 g/100 ml;
protein supplement: maximum 0·5 g/100 ml; and an extra calorie supplement: maximum 3·0 g/100 ml) As a result, and with the low power of this small study, they showed no improvement in any growth outcome with the intervention. With almost identical nutritional intakes in the 2 groups, this is hardly surprising. There are a couple of other surprising things, fortification was not started at all until the babies were on full feeds, so not until 20 days of age on average. The babies were discharged a 38 weeks, and only weighed 2.3 to 2.5 kg on average at discharge.

I think this idea still has a lot of merit, whether it is viable with the workload involved is questionable, but targeting substantially higher protein intakes than these achieved here, will likely improve growth, and fat-free growth at discharge, individualizing the supplementation of breast milk should be further investigated, in similar RCTs, but aiming for over 4 g/kg/d of protein. Perhaps the best model would be to enroll and study only infants with sub-optimal growth; those who have good growth (not just weight gain) on standard fortification, and here are many, will probably have little benefit from individual adjustments of fortification.

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Neonatal Updates: Recent Nutritional Publications part 1.

As there is no way I can catch up after the break, I will post a few ‘neonatal Updates’ to point my readers to things I found interesting over the last couple of months, this first group is all about nutrition.

Impacts of undernutrition

First off two animal studies:

Wedgwood S, et al. Postnatal Growth Restriction Augments Oxygen-Induced Pulmonary Hypertension in a Neonatal Rat Model of Bronchopulmonary Dysplasia. Pediatr Res. 2016. Neonatal rats exposed to room air or 75% oxygen were randomized to either get usual nutrition or to get reduced nutrition. This was done by either putting 10 rats in a litter, or 17. The rats who were 17 to a litter will automatically get less nutrition, as apparently the dam (the mummy rat) produces milk which is larger volume, similar in lactose and protein, but has a lower fat concentration. After 14 days of this they weighed only 24 grams compared to the controls that weighed about 33 g. The growth restricted rats were even smaller if they were also hyperoxic (21 g).

Individually, hyperoxia and growth restriction increased pulmonary arterial pressure, right ventricular wall thickness, and pulmonary arterial medial wall thickness, and led to fewer pulmonary vessels. The rat pups who were both growth restricted and hyperoxic were worse off than either of the comparison groups. They also did some metabolomics and other fancy analyses that I will let you read about yourselves. Basically though undernutrition (in this case specifically too little fat) makes the lungs more susceptible to oxygen toxicity.

Joss-Moore LA, et al. Alveolar formation is dysregulated by restricted nutrition but not excess sedation in preterm lambs managed by noninvasive support. Pediatr Res. 2016. This looks like a great study, unfortunately I found some of it hard to understand. Preterm lambs (we don’t know how preterm as the gestational age at delivery doesn’t seem to be in the manuscript) were intubated at birth and extubated within 3 hours to get non-invasive ventilation. They were then randomized to either have good nutrition and standard sedation, or have reduced nutrition, or excessive sedation (using pentobarbitol in all cases, around about 0.8 mg/kg/d for the usual sedation groups an 6 times as much for the high sedation group). I can’t tell you how much nutrition the restricted group received, the normal nutrition groups got a goal of 150 kcal/kg/d and the restricted group was “based on the volume of milk tolerated by historical preterm lambs managed by invasive ventilation”. In the results, the table 2 notes that the controls received 283 kcal/kg on day 20, but the restricted nutrition group got 211 kcal/kg less than that (I think), and basically didn’t gain any weight at all between birth and day 20.

There were major impacts on lung alveolarization, which is of course an important part of BPD, and which suggests that lungs need nutrition to grow and to repair.

And a human epidemiologic study:

Guellec I, et al. Effect of Intra- and Extrauterine Growth on Long-Term Neurologic Outcomes of Very Preterm Infants. The Journal of pediatrics. 2016;175:93-9 e1. This is an analysis of data from the EPIpage study, which was a regional cohort of babies born between 22 and 32 weeks gestation in 9 regions of France. They report the association between growth, from birth to 6 months of age, and neurologic and developmental outcomes.

They classify babies into appropriate and small for gestational age, and then into whether they gained or lost more than 1 Standard Deviation in weight, between birth and when they reached 6 months.

Babies who were AGA and lost 1 SD had worse outcomes, with much more cerebral palsy, and much more cognitive delay; both evaluated at 5 years of age. Those who stayed in their percentiles or gained weight (relatively) were similar.

Among the SGA babies there were only 5 who lost percentiles, the remainder either stayed on their percentiles or had some “catch-up”; those who had catch-up had in general slightly better outcomes than the SGA babies who remained in their percentiles, although the differences  may have been due to chance.

Good postnatal nutrition aiming at staying on the same percentile or improving percentiles if you are SGA should protect against BPD, and is associated with improved long-term neurologic and developmental outcomes. Improving growth outcomes is possible without increasing complications.

 

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Early neonatal outcomes in trisomy 13 and 18

One of the things that has changed greatly over the years, in my practice and in medical practice in general, is the approach to some congenital anomalies, particularly to serious chromosomal anomalies. Trisomy 13 and 18 specifically have seen an enormous change in the attitudes of many physicians; from an near-universal denial of active interventions to a more individualized approach, which takes into account the wishes and values of the parents, and recognizes that the lives of children with impairments are also of value. (I nearly started a new hashtag “trisomic lives matter”, then I thought better of it.)

Many infants who are live-born with these diagnoses can benefit from relatively modest medical interventions, and sometimes from more invasive treatments as well. Two recent articles from the American Journal of Perinatology demonstrate how things have changed. Both have sample sizes on the small side, compared to regional database studies, the first from a single centre (university of N Carolina) they include 32 fetuses approaching term with trisomy 13 or 18, and compared outcomes among those whose parents had elected to have some active interventions, and those who had chosen comfort care only.

Dotters-Katz SK, et al. Management of Pregnancy and Survival of Infants with Trisomy 13 or Trisomy 18. American journal of perinatology. 2016(EFirst). Intrapartum stillbirth only occurred among the babies with a decision for comfort care, and death on the first day of life only occurred (with one exception) among those in the comfort care group. It is interesting to note that more than 50% of the babies in each group survived to hospital discharge, so even if the decision is for comfort care, if you get through the first 24 hours, discharge to home is likely.

The second article only includes infants with trisomy 18 and starts at birth, admitted to one of 2 hospitals in Memphis.
Dereddy NR, et al. Neonatal Hospital Course and Outcomes of Live-born Infants with Trisomy 18 at Two Tertiary Care Centers in the United States. American journal of perinatology. 2016(EFirst).  There are 29 infants in this series, and their survival to discharge was somewhat lower, but still significant. They also happened to have more babies with very serious heart defects (most of the cardiac defects in trisomy 13 and 18 and VSDs), perhaps because of the way the cohort was put together, which may have affected survival. Among those babies who did not have ‘critical heart disease’ about half went home, whereas all but one of those with critical cardiac malformations died before discharge.

And by way of contrast, an enormous regional database study with nearly 2,000 babies (693 with T13 and 1,113 with T18), in such studies the amount of individual data available is usually much less, so there is no analysis of decision-making in this study, Meyer RE, et al. Survival of children with trisomy 13 and trisomy 18: A multi-state population-based study. Am J Med Genet A. 2016;170(4):825-37.

Among children with T13, 5-year survival was 9.7%;
among children with T18, it was 12.3%. For both trisomies,
gestational age was the strongest predictor of mortality.
Females and children of non-Hispanic black mothers had
the lowest mortality. Omphalocele and congenital heart
defects were associated with an increased risk of death for
children with T18 but not T13. This study found survival
among children with T13 and T18 to be somewhat higher
than those previously reported in the literature, consistent
with recent studies reporting improved survival following
more aggressive medical intervention for these children.

1 month and 1 year survival in that study were 24% and 11.5% for T13 and 36.1% and 13.4% for T18.

Barb Farlow, Annie Janvier, and I have a new article which will be appearing soon, which covers some of the same questions; of course, as soon as it appears there will be more discussion on this blog.

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