More is Not Better: Protein for Preterm Infants

FH Bloomfield et al. NEJM 2022; 387: 1661-1672. Early Amino Acids in Extremely Preterm Babies

My take: For preterm infants <1000 gram, this study showed that the usual dosing of amino acids 2.5 gram to 3.5 gram per day (the placebo group) appeared to have better secondary outcomes (though within confidence intervals) than those who received an additional 1 gram per day.

Slides from video summary:

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Neurologic Impairment with Biliary Atresia at Time of Diagnosis

Previous studies have indicated that prolonged cholestasis before liver transplantation is associated with adverse neurodevelopmental outcomes. LH Rodijk et al (JPGN 2021; 72: 592-596. Full text: Early Motor Repertoire in Infants With Biliary Atresia: A Nationwide Prospective Cohort Study) prospectively investigate early neurologic impairment in infants with biliary atresia (n=35).

The author’s utilized Prechtl’s General Movement (GM) Assessment which is a noninvasive, cost-effective, and worldwide used method to identify infants who are at risk of neurodevelopmental impairments. This requires video recordings of 10 minutes; this was avoided in the 24 hours following liver biopsy or general anesthesia.

Key finding:

  • The proportion of infants with atypical GMs was significantly higher in BA (46%) than in 2 reference groups of healthy infants (vs 10%, P < 0.001; vs 18%, P < 0.001).

My take (from authors): “At the time of diagnosis, almost half of the infants with BA showed an atypical early motor repertoire, suggesting that neurological impairment is present already in early infancy. Compared to healthy infants, approximately 2 to 3 times more infants showed an atypical motor repertoire.”

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Arlington, VA -February 2021. Thanks to Seth for this image

Does SMOFlipid Improve Neurocognitive Outcomes?

M Thanhaeuser et al. J Pediatr 2020; 226: 142-148. A Randomized Trial of Parenteral Nutrition Using a Mixed Lipid Emulsion Containing Fish Oil in Infants of Extremely Low Birth Weight: Neurodevelopmental Outcome at 12 and 24 Months Corrected Age, A Secondary Outcome Analysis

This study evaluated neurodevelopmental outcomes using Bayley Scales. the authors provided a secondary outcome analysis of a double-blind randomized trial of 206 extremely low birth weight infants.  Participants received either SMOFlipid or soybean oil-based lipid. Lipids were dosed at </+ 3 g/kg/day.

Key findings:

  • Parenteral nutrition using a mixed lipid emulsion (SMOF) containing fish oil did not improve neurodevelopment of extremely low birth weight infants at 12 and 24 months corrected age
  • At 24 months of age, specifically, there was again no significant differences in any of the following areas (median values):
    • cognitive: SMOF: 95 & soybean oil: 95
    • language: SMOF: 89 & soybean oil 89
    • motor scores: SMO 94 & soybean oil: 94

Limitations: One of the reasons why this study did not find any difference is that it was not powered for assessment of neurodevelopmental outcomes. The authors provide other potential reasons:

  • DHA in SMOFlipid provided 43 mg/kg/d, while more than the soybean-lipid, is at the lower end of published fetal accretion rates (40-67 mg/kg/day)
  • DHA deficits may not have been pronounced enough in this study to see an effect of SMOFlipid on neurodevelopement
  • Full feeds were reached after 23 days (IQR, 17-37 days); thus, it is possible that infants with longer term dependency on parenteral nutrition would benefit more

My take: SMOFlipid has not been proven to have more favorable long-term neurocognitive effects than intralipid. However, for children with prolonged need for parenteral nutrition, SMOFlipid is more likely to allow full dosing which in itself may be an important contributor to better outcomes. That is, soybean-lipid emulsions are more likely to be reduced due to cholestasis and this could lead to nutritional deprivation.

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Neurocognitive Function with Pediatric Intestinal Failure

Lately, there have been a lot of articles on neurocognitive function.  The latest (A Gold et al. JPGN 2020; 70: 225-31) describes the myriad of problems facing children with intestinal failure (IF). The authors literally used 12 different measures of neurocognitive and academic measures –though not all 28 subjects had each of these measures (Table 2).


  • The authors specifically excluded 5 children with severe neurodevelopmental problems that precluded participation in standardized assessment and 10 children who were transplant recipients.
  • Also, when judging the results, it is important to keep in mind that their cohort had a good maternal education level; 68% were college graduates.

Key findings:

  • 13 of 28 (46%) received a diagnosis of cognitive/learning DSM diagnosis
  • 29% met diagnostic criteria for a learning disability, 7% for ADHD, and 11% for intellectual disability; comparison Canadian prevalence rates are 4%, 5%, and 1% respectively
  • The number of first-year septic episodes was associated with poorer outcomes; ≥2 or more episodes increased the likelihood.
  • Sustained cholestasis was associated with poor outcomes
  • The average level of intellectual functioning in their sample of 28 children was within 1 standard deviation of the population mean

There are a lot of risk factors for neurodevelopment impairment in these children with IF: prematurity, nutritional status/specific nutrient deficiencies, cholestasis, need for anesthesia/surgeries

My take: More than half of children with IF had neurodevelopemental impairment.  In this cohort, recurrent sepsis in the first year of life and sustained cholestasis were associated risk factors.

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Sunrise in Sandy Springs


Neurodevelopmental Outcomes: Biliary Atresia

A recent study from the Netherlands (LH Rodijk et al. J Pediatr 2020; 217: 118-24) which included 46 children provides data on the suboptimal neurodevelopmental outcomes of children with biliary atresia (BA).  This cohort did not exclude children born prematurely or those with a history of intracranial hemorrhage; the children had undergone Kasai portoenterostomy (KPE) between 2002-2012 and had a median age of 11 years.

Key findings:

  • 36 of 46 (78%) had undergone liver transplantation
  • Median age at time of KPE was 60 days
  • 12 (25%) received special education (vs. 2.4% in ‘normal’ population)
  • Motor outcomes were affected with up to half scoring low on motor skills
  • Total IQ was 91 (compared with 100 in norms)
  • There were no significant differences in the cognitive outcomes of the patients with their native livers compared to those who had undergone liver transplantation (*small sample size)

Potential explanations:

  • Detrimental affects of cholestasis
  • Major surgery/anesthesia may result in impaired neurodevelopment

My take: This study documents a fairly high rate of neurodevelopmental problems in children with BA.  The information we need now –how to mitigate this.

VL NG et al. J Pediatr 2018; 196: 139-47. This study with 148 children examined the neurodevelopmental outomes of young children with biliary atresia (ChiLDRen Study). Key finding: Children with their native livers were at increased risk for neurodevelopmental delays at 12 and 24 months.  This risk was more than 4-fold increased among those with unsuccessful Kasai procedure.

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Liver Shorts -January 2020

S Nagai et al. Clin Gastroenterol Hepatol 2019; 17: 2759-68. For patients who underwent liver transplantation during 2016–2017, a significantly lower proportion of patients with NASH survived for 1 year after transplantation than patients with HCV (P = .004) or ALD (P < .001). 1-year patient survival rates: NASH 90.4%, HCV 92.8%, ALD 93.5%. Full Text: Increased Risk of Death in First Year After Liver Transplantation Among Patients With Nonalcoholic Steatohepatitis vs Liver Disease of Other Etiologies

JE Squires et al. JPGN 2020; 70: 79-86.  Using a prospective, longitudinal database, this study from ChiLDReN network with 93 children with biliary atresia and native liver found that NO increased prevalence of neurodevelopmental delays. Markers of advanced liver disease (high bilirubin/GGT for those ≤5 yrs, and portal hypertension for those >5 years) did negatively affect neurodevelopmental measures.

C Jaramillo et al. JPGN 2020; 70: 87-92.  This pilot study with 21 patients found that degree of fibrosis, quantified by collagen hybridizing peptide, at time of Kasai, was associated with the risk of requiring a liver transplantation by age 4 years.  Total bilirubin >2 mg/dL and Albumin ❤ g/dL at 3 months post-Kasai were also associated significantly with need for liver transplantation.

H-S Chen et al. Hepatology 2019; 70: 1903-12. In this study from Taiwan with 182 children (median age of 10.6 at enrollment) with hepatitis B and a normal ALT, a baseline anti-HBc titer of >500 IU/mL was associated with spontaneous HBeAg seroconversion with hazard ratio of 2.81.  Over the median follow-up of 19.8 years, 85 subjects (46.7%) had HBeAg seroconversion. Thus, anit-HBc reflects anti-HBV immune response in the HBeAg-positive patients with normal ALT.

SMOF Neurodevelopmental Data Looks Good –In Five Years We’ll Know More

A recent study (C Binder et al. J Pediatr 2019; 211: 46-53) examined electrophysiological brain maturation in a randomized double-blinded controlled trial of SMOF lipid compared to soybean lipid emulsion for extremely low birth weight (ELBW) premature infants. This was a prespecified secondary outcome analysis of a randomized trial of 230 infants (2012-2015).

It is recognized that the ELBW infants have very little nutritional reserve.  In addition, DHA which is transferred to the fetus in high amounts in the last trimester is absent from parenteral soybean lipid emulsions.  Thus, the authors explored whether SMOF lipid which is a mixture of lipids (30% soybean oil, 30% medium-chain triglycerides, 25% olive oil, and  15% fish oil) and contains DHA would have a favorable effect on neurocognitive outcomes.

In this study, the authors examined amplitude-integrated electroencephalography measurements (aEEG)  to assess neurodevelopment. Both groups received similar lipid dosing, SMOF 2.2 g/day and Soybean 2.1 g/day.

Key findings:

  • Among the available 121 infants in the subgroup with aEEG (n=63 SMOF, n=58 soybean), maximum maturational scores on aEEG were achieved 2 weeks earlier in the SMOF group (36.4 weeks vs 38.4 weeks, P<.001).


  • aEEG is a marker of neurocognitive development; however, more adequate outcomes of  neurodevelopmental progress are needed. The authors plan to follow these infants up to 5 years of age.

My take: This study is very favorable for the use of SMOF lipids in premature infants.  — SMOF lipid emulsion by itself may improve neurocognitive outcomes. In addition, clinicians are more likely to provide adequate amounts of lipid calories with SMOF as compared to soybean emulsion which is often restricted to minimize liver injury.  Giving adequate lipid calories is also likely to enhance neurological outcomes.

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Incredibly blue waters of Crater Lake, Oregon -from Wizard Island


What’s Happening on the Edge of Viability

A study (N Younge et al. NEJM 2017; 376: 617-28) provides some data on the slowly changing survival and neurodevelopmental outcomes among periviable infants (22-24 weeks gestation).

From epoch 1 (2000-2003), to epoch 3 (2008-2011), there has been some improvements. Overall survival increased from 30% to 36% and the percentage without neurodevelopmental impairment increased from 16% to 20%.

Mortality and Neurodevelopmental Outcomes at ~18 months of age (combined data and 11 centers)

Mortality and Neurodevelopmental Outcomes at ~18 months of age (combined data and 11 centers)

The insightful commentary (pgs 694-6) notes that there has not been improvement in survival in infants born at 22 weeks.  Furthermore, in reviewing multiple studies on outcomes, neurodevelopmental impairment was >94% in patients born at 22 weeks and between 80-90% for infants born at 23 weeks.  At 24 weeks, neurodevelopmental impairment was present between 51-72%


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Weight Gain in Preemies, Neurodevelopmental Outcomes, and Reverse Causation

Since a trial which randomizes premature infants into groups that are well-nourished and poorly-nourished and then following them prospectively is never going to happen, it is difficult to know with certainty the effects of optimal nutrition are with respect to long-term neurodevelopmental outcomes.

An article I enjoyed reading on this subject (MB Belfort et al. J Pediatr 2016; 168: 30-5) pushes back on the correlation between good weight gain, as a surrogate marker for nutritional status, and neurodevelopmental outcomes.

In this study, 1070 infants between 23-27 weeks gestational age were followed with weights on days 7-28 along with weights at 12 and 24 months.  This data was compared with several indices on neurodevelopmental outcome.  Here is the key finding:  “Weight gain in the lowest quartile from 7-28 days was not associated with higher risk of adverse outcomes.”

In commentary on their findings, the authors point out that “we found no evidence to suggest that faster weight gain from 7 to 28 days of life reduced the risk of adverse outcomes…almost all of the associations between low weight gain..were attenuated or eliminated when we restricted our analysis to those children able to walk independently.”

“Overall, it appears that low weight in children with severe neurodevelopmental impairments may be caused by factors closely related to the impairments themselves…reverse causation may be at play.” Thus, underlying brain damage may limit body weight gain, rather than poor nutrition limiting brain development.”

My take: I may be apt to ‘confirmational bias’ as this study reinforces my view that improved nutrition may not change outcomes appreciably.  To be clear, I still believe that efforts to optimize the nutrition of premature infants are a good idea but we need to be skeptical about the magnitude of benefit that we will derive.

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A Few Years Ago in Yosemite

A Few Years Ago in Yosemite

Improving Outlook in Neonatal Nutrition (Part 1)

I recently had the opportunity to hear a terrific lecture by David Adamkin (University of Louisville) on neonatal nutrition.  Unlike previous lectures that I’ve highlighted on this blog (Neonatal Nutrition Lecture -What We Know Right Now …) which focused on enteral nutrition and breastmilk.  This lecture focused on providing early parenteral nutrition to prevent postnatal growth failure.

"Father" of TPN was Stanley Dudrick (1968)

“Father” of TPN was Stanley Dudrick (1968)

Introduction of TPN dramatically improved survival for many infants.  In disorders like gastroschisis, TPN increased survival from ~10% to 90%.

Extreme premature infants have minimal energy reserves

Extreme premature infants have minimal energy reserves

At 24-28 weeks gestational age, fetuses are ‘bathed in amino acids’ and extreme premature infants need early amino acids.  At University of Louisville, the neonatologists try to deliver ~3 gm/kg/day of amino acids in 1st 1-2 days in order to match intrauterine growth and prevent growth failure. Half of postnatal weight loss is water; other half is related to proteolysis.  To facilitate TPN at all hours, they use a stock solution (4% amino acids at 60 mL/kg/day delivers 2.4 mg/kg/day of protein; 80 mL/kg/day delivers 3.2 mg/kg/day of protein.

Return to Birth Weight Time is Correlated with Growth Failure

Return to Birth Weight Time is Correlated with Growth Failure.  Extreme prematurity has been correlated with slower return to birth weight

Screen Shot 2015-11-11 at 10.59.04 PM

Lack of correlation between BUN and Protein Intake

Lack of correlation between BUN and Protein Intake

BUN increases with any protein intake but not affected by protein intake -issue has to do renal fxn, comorbidity.  Smaller & sicker have higher BUN.

Key points:

  • The more premature, then the longer it takes to return birth weight and more growth failure
  • Poor growth related to neurodevelopment outcomes
  • With higher protein intake, there is better glucose tolerance; protein intake helps with glucose tolerance & lowers chance of hyperkalemia

More tomorrow…