Improving Outlook in Neonatal Nutrition (Part 2)

Besides arguing for more aggressive and earlier use of intravenous protein, Dr. Adamkin noted that newer lipid emulsions (eg. SMOFlipid) are likely to be helpful due to the concentrations of docosahexaenoic acid (DHA) and arachidonic acid (ARA).  DHA and AA are the two main long chain polyunsaturated fatty acids (LCPUFAs) and are integral to the structural membranes of cells in the central nervous system and retina.

Slow Evolution of Lipid Emulsions

Slow Evolution of Lipid Emulsions

Decreasing Incidence of Growth Failure with More Aggressive Nutrtion

Decreasing Incidence of Growth Failure with More Aggressive Nutrition –average daily protein intake in most recent cohort during 1st 5 days is 3 g/kg/day (much higher than in previous years

At U of L, they have developed a quick card to calculate glucose infusion rate based on dextrose and fluid volume (mL/kg/day)

At U of L, they have developed a quick card to calculate glucose infusion rate based on dextrose and fluid volume (mL/kg/day)

Other points:

  • SGA infants have low lioprotein lipase –>higher triglycerides
  • Slow lipid infusion associated with better tolerance
  • Insulin may be needed if not able to provide a glucose infusion rate of at least 4 mg/kg/min; otherwise, he recommends avoiding insulin.
  • Dr. Adamkin recommended adding carnitine after 4 weeks of TPN
  • During transition to enteral feeding, in order to continue with 3.5-4 g/kg/day of amino acids, many infants will need a stock solution of IVFs with supplemental amino acids to supplement enteral feeds

Related blog posts:

Omega-3 Fatty Acids and Nonalcoholic Fatty Liver Disease

A recent study (Janczyk W. J Pediatr 2015; 166: 1358-63; editorial 1335-6) examines whether omega-3 fatty acid supplement would be helpful for overweight/obese children with nonalcoholic fatty liver disease (NAFLD).  This randomized controlled trial had 64 patients complete the study; the median age of enrolled patients was 13 years.

Free Full Text Article: Omega-3 Fatty Acids Therapy in Children with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial

The treatment cohort received doscosahexaenoic acid (DHA) and eicosapenatenoic acid (EPA) at a dose of 450-1300 mg/day.

Key finding:

  • After 6 months, omega-3 fatty acid supplementation did not increase the number of patients with decreased ALT levels and it did not affect liver steatosis on ultrasound.

The editorial reviews a previous positive study for DHA supplementation from Italy (n=60) but notes that other larger trials in adults have not shown efficacy of omega-3 fatty acids (Gastroenterol 2014; 147: 377-84.e1, Hepatology 2014; 60: 1211-21). It could be that much longer studies will be needed to determine whether omega-3 fatty acids will be helpful.

Take-home message: Overall, the sum of these studies indicates that supplementation with omega-3 fatty acids has not been shown to be effective for NAFLD and it is not likely to be a significant breakthrough.  Even if it were shown to help modestly, would pediatric patients be placed on therapy indefinitely?

Briefly noted:

Kusters DM et al. “Efficacy and Safety of Ezetimibe Monotherapy in Children with Heterozygous Familial and Nonfamilial Hypercholesterolemia” J Pediatr 2015; 166: 1377-84.  Ezetimbe (10 mg), a cholesterol absorption inhibitor, lowered LDL by 27% after 12 weeks from baseline. It was well-tolerated

Telaprevir-Based HCV Therapy is Expensive Too

With the arrival of newer expensive hepatitis C virus (HCV) therapies, there has been an effort to prove that the costs are within reason.  One study (Hepatology 2014; 60: 1187-95) looking at this issue examines the cost of a sustained virological response (SVR) with the previous best therapy: Telaprevir-Based Triple Therapy.

Design: Records from 147 patients who received telaprevir-based triple therapy in 2011 were reviewed.

According to the authors (supported by Gilead Sciences), median cost of care was $83,721 per patient and the median cost per SVR was $189,338.  The costs of two of the drugs, telaprevir and pegylated interferon, accounted for 85% of the total costs.  Other costs included adverse management (8%), ribavirin (4%), professional fees (2%), and laboratory fees (1%).

The main reason besides pharmaceutical prices for the high costs were the SVR rate of 44%.

Bottomline: If a patient requires HCV therapy, the newer, more effective, expensive agents are likely to compare favorably with the less new, less effective, expensive medications.

Related blog posts:

Also noted: Hepatology 2014; 60: 1211-21.  “WELCOME” Study tested whether 15-18 months of docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) decreased liver fat and histology in nonalcoholic fatty liver disease (NAFLD). n=101, with 51 in treatment group. Findings the DHA+EPA had a “trend toward improvement in liver fat” percentage but no improvement in fibrosis.

What to Feed Your Baby

“What to Feed Your Baby” — is the title of a recent, easy-to-read, practical book written by one of my colleagues, Stan Cohen.  I had the opportunity to read it and recommend it as an excellent resource for parents.  This book is not just for selecting formula and introducing foods, but it also reviews gastroesophageal reflux, colic, stooling problems, poor weight gain, overweight issues, prematurity, and allergies.  In addition, the subtitle, “Cost-Conscious Nutrition for Your Infant,” is an important element throughout the book.

The first few chapters highlight the advantages of breastfeeding but acknowledge that formula-feeding is an acceptable alternative.  Specific advantages that are outlined in Table 2.2 include decreased infections, decreased risk for several illnesses like sudden infant death syndrome (along with many others like diabetes and obesity), protection from allergies, and improved intelligence.  Advantages for the mother, like weight loss and better emotional health, are discussed as well.

Almost any question that a new mother would ask about the logistics of breastfeeding are answered in the 3rd chapter: “How long should each feeding be?” “Should I wake the baby?” “Do I need to stop if I have a cold?” “How long can the breastmilk be stored?”  The latter question has its own table 3.1 and the answer depends on the storage temperature.  At room temperature, covered breastmilk should be durable for 6-8 hours.  In addition, Dr. Cohen explains the need for vitamin D supplementation.

Chapters 4 and 5 help parents understand the highly marketed formulas and to understand a rationale for choosing one formula over another, including cost as a factor.  Dr. Cohen provides data on mean docosahexaenoic acid (DHA) content in breastmilk throughout the world.  In the U.S., the level is relatively low at 0.29 (as a percentage of fatty acids).  The breastmilk DHA level is nearly three times higher in Japan and Artic Canada.  These discrepancies account in part why formula companies may choose different target concentrations for some of their components when trying to mimic breastmilk.

While Dr. Cohen explains that some of the differences between formulas are akin to differences between Coke and Pepsi, he expresses a preference for the current Mead Johnson formula Enfamil Premium due to its higher DHA content –“though the research is not thoroughly established.”  However, he states that the differences probably do not justify a much higher cost.  For a generic brand, the Costco brand, “Kirkland Signature…are reasonable and less expensive, FDA-approved options.”

In addition, these chapters question whether infant organic formulas are truly organic (page 55), explain the issue of burping, and discuss the pragmatic advise regarding cleaning nipples/bottles; “kitchen clean” with soap and a washing with hot water should suffice and sterilization is not needed.

The most inciteful comments, in my opinion, are in chapter 5:

  • Lactose-free formulas: “Mead Johnson pulled its product from the market because lactose sensitivity is rare, rare, rare in infants…Abbott, in a shrewd marketing move, renamed its formula, originally called Lactofree, to Similac Sensitive, and that labeling has convinced an enormous number of mothers that this formula makes a difference.”  Similac Sensitive accounts for >10% of formula market.  A similar product is Gerber (previously Nestle) Good Start Soothe.
  • Elemental formulas: “cost as much as a monthly Porsche payment.”  Monthly costs of each type of formula are detailed in Table 5.3.  Routine cow’s milk based formula $149.88, soy-based $153.56, cow’s milk with rice starch $159.39, hydrolyzed (broken down protein) formula (e.g.. Alimentum, Nutramagen) $223.56, and elemental amino acid based $511.83.
  • Among extensively hydrolyzed formulas, Dr. Cohen indicates a preference for Alimentum (from Abbott) over its competitors due to better acceptance by infants.
  • The rationale for not switching from contracted WIC products is explained.  When changing from a contracted product to a non-contract product, the costs are much greater and among the same type of formula there is not a scientific rationale.
  • Reasons why goat’s milk are not a good choice and “dangerous” for infants are detailed.  “The protein content is over three times higher than cow’s milk…additionally, goat’s milk is deficient in folate and vitamin B6.”

As noted above, the book covers a variety of pediatric gastroenterology problems in the newborn.  As part of the chapter on undernutrition, additives to increase calories are detailed (pg 136).  For example, a tablespoon of polycose adds 23 cal, a tablespoon of rice cereal 15 cal, and  a tablespoon of vegetable oil 124 cal.

The last few chapters provide ample advice on transitioning to solid foods, reviews nutrients and mineral oils.  In addition, he provides growth charts (for full term, premature infants, and infants with Down syndrome) as well as tables on infant formula contents.

Take-home message: this is a terrific resource for parents to help understand the what, why and when of feeding their infant.  At the same time, the book provides advice on the most common pediatric gastroenterology problems of infancy like reflux, colic, stooling difficulties, allergies, and poor weight gain.

Book’s website and how to purchase:

To purchase the book:

Here is the link:


Other favorable reviews ( have come from influential pediatricians like Jay Berkelhammer and pediatric gastroenterologists like Jeff Hyams and Allan Walker.

In this book, Dr. Stanley Cohen, a pediatric gastroenterologist and nutritionist with longstanding interest in infant nutrition, provides a practical and pragmatic approach to a major concern for new mothers, namely What to Feed Your Baby.

— Allan Walker, M.D., director, Division of Nutrition, Conrad Taff professor of pediatrics and nutrition, Harvard Medical School

Related blog entries:

New lipid emulsions — lacking data to support usage

According to a systematic review of the literature regarding ω-3 (n-3FA) fatty acid lipid emulsions, there is a “lack of sufficient high-quality data to support the use of parenteral n-3FA lipid emulsions in children” (JPEN 2013; 37: 44-55). Thanks to Kipp Ellsworth for this reference.

The authors of this study researched 4 databases up to March 2011 and extracted relevant studies.  Five randomized controlled trials and 3 high-quality prospective cohort studies were included.  The strength of evidence was “consistently low or very low across all lipid emulsion comparisons and outcomes.”

Specific criticisms:

  • Few studies examined important outcomes like length of hospital stay or intensive care stay.
  • There was lack of data on growth, cognitive development or potential long-term effects/harms.
  • All of the studies in children varied considerably with regard to the dosing regimens, duration of administration, and duration of followup.
  • The studies were small with sample sizes ranging from 28-91 patients.
  • The 5 RCTs had unclear risk of bias due to inadequate blinding of participants and study personnel.
  • All of the RCTs were funded by the manufacturer.
  • While some biochemical outcomes improved, no difference in mortality has been identified.  A biochemical response is a poor measure of effectiveness.  In fact, several studies have shown deterioration in liver histology and fibrosis despite improved biochemical measures in infants on Omegaven.
  • For Omegaven (fish oil) treatment, all studies used a historical control group.  In these studies, typically the Omegaven dose was half the dose of Intralipid used in the control group.

This article (in its Table 1) identifies the constituents in the commercial available lipid products which include Intralipid, Clinoleic, Liposyn II, Omegaven, SMOFLipid, and Lipoplus.  Intralipid which is widely used is devoid of substantial arachidonic acid (ARA) and docosahexaenoic adic (DHA).  This is particularly important in premature infants as noted in recent blogs:

Omegaven, in particular, and SMOFLipid, to a lesser degree, have much more AA and DHA.  As such, both of these emulsions have the potential improve vision and cognitive outcome in premature infants.

Related blog posts:

Visual Acuity and LCPUFA

Long-chain polyunsaturated fatty acids (LCPUFA) have been examined due to their potential to affect infant cognition (Longchain polyunsaturated fatty acids, breastmilk  – gutsandgro).  A recent meta-analysis has reviewed 19 studies with regard to LCPUFA supplementation and infant visual acuity (Pediatrics 2013; 131: e262-72 -thanks to Mike Hart for sharing this reference).

Since 75% of U.S. infants are formula fed by 1 year of age and there is widespread dependence on formula for nutritional completeness, these formulas have been designed to mimic breast milk composition.  Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are the two main LCPUFAs and are integral to  the structural membranes of cells in the central nervous system and retina.  DHA comprises >50% of the phospholipid content of the retinal membrane bilayer.

These 16 studies (in the abstract it erroneously states 19 studies), identified by a literature search, involved 1949 infants.  Overall, a significant benefit of LCPUFA supplementation on infants’ visual acuity was noted at 2, 4, and 12 months of age when assessed by visual evoked potential.  A benefit was also seen at 2 months of age by using behavioral methods.  Studies were included if they were randomized control trials comparing LCPUFA supplementation to unsupplemented formula.  Initially, 286 citations were identified but most did not meet inclusion criteria.

This study findings differ from two recent Cochrane reviews on the effect of LCPUFA on visual acuity.  The Cochrane reviews failed to combine trials that  measured “visual acuity in logMAR and cycles/degree and assessed preterm and term infants separately.”  The authors state that this reduced the Cochrane reviews power to detect potential benefits of LCPUFA supplementation.

While this study demonstrates improvement during the first year of life, there is a scarcity of data beyond this time point.  Limitations of this review included heterogeneity in the study results, varying doses of LCPUFA supplementation, variable DHA/AA ratio supplied, and variability in maternal diets.

Related blog post:

Low levels of LCPUFA in Premature Infants  – gutsandgrowth

Low levels of LCPUFA in Premature Infants Associated with Intravenous Lipids

Low levels of the long-chain polyunsaturated fatty acids (LCPUFA) docosahexanenoic acid (DHA) and arachidonic acid (ARA) in premature infants are correlated with an increased risk of developmental, respiratory, and infectious morbidities in premature infants.  A new report suggests that prolonged exposure to intravenous lipids exacerbates these low levels and could contribute to poor neurodevelopmental outcomes (J Pediatr 2013; 162: 56-61).

This study followed 26 extremely low birth weight premature infants with serial blood draws during the first two months of life using a prospective cohort design.  Infants who received more than 28 days of intravenous lipid emulsion had significantly decreased DHA levels compared to infants with shorter duration of parenteral lipid exposure; at 8 weeks, the DHA levels were 2.7 ± 0.6 compared with 4.2 ± 1.9 (all levels reported as g/100 g).  DHA levels at birth were 5.5 ± 1.4.

ARA levels decreased in a similar fashion in both groups, though values were mildly lower in the prolonged lipid group.  At 8 weeks, the ARA values were 9.4 ± 1.6 and 11.5 ± 2.5 respectively.  Thus, with a larger study group, this could be a significant finding as well.

These lower LCPUFA (especially DHA) levels may reflect a suboptimal intravenous lipid emulsion.  Alternatively, the underlying reason for the prolonged lipids, like sepsis and NEC , could result in these lower levels.  Perhaps attention to LCPUFA in parenteral formulations can improve neurodevelopmental outcomes in this vulnerable population.

Related blog entry:

Long-chain polyunsaturated fatty acids, breastmilk, and infant cognition

A lot has been written about improving infant cognition and breastfeeding, even on this blog (More evidence that breastfeeding improves cognitive development).  Formula companies in their efforts to duplicate the nutritional value of breast milk have supplemented with a number of agents, including long-chain polyunsaturated fatty acids (LCPUFA).  But, does this work?

A meta-analysis of LCPUFA supplementation failed to show any significant effect on early infant cognition (Pediatrics 2012; 129: 1141-49).  Twelve trials with 1802 infants met inclusion criteria.  Included trials were randomized clinical studies that measured cognition with Bayley Scales of Infant Development.

LCPUFAs have been hypothesized to be a potential reason for improved cognition.  LCPUFAs are vital for cell membranes and play a critical role in development and growth.  The two main LCPUFAs are docosahexaenoic acid (DHA) and arachidonic acid (AHA). “An estimated 30-fold increase in the amount of DHA and AA in the infant forebrain occurs between the last trimester of pregnancy and the first 2 years of life.”

The authors note that while breastfed babies tend to have higher intelligence, confounding factors have made it difficult to determine whether actual nutritional differences in breast milk are the reason for this difference.  On average, breastfeeding mothers have higher intelligence, larger incomes, and spend more time with their infants.  Thus, bonding/social interactions as well as other breast milk properties (eg antimicrobial, antiinflammatory, and immunomodulatory) may be important factors.

On the same subject, a second article in the same issue (Pediatrics 2012; 129: 1134-40) also showed that breastfed infants had slightly improved cognitive development compared with formula-fed babies (both cow’s milk and soy formula).  This conclusion was based on Bayley Scales of Infant Development and the Preschool Language Scale-3.  In total, this study examined 391 infants at ages 3, 6, 9, and 12 months.  The authors state that “models were used while adjusting for socioeconomic status, mother’s age and IQ, gestational age, gender, birth weight, head circumference, race, age, and diet history”  –that’s a lot of variables to adjust!

More on breast milk from previous blog entries:

Breastfed babies less likely to develop fatty liver

Breastfeeding: protection from asthma