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Sustaining DHA Accretion during Recovery from Acute Malnutrition with Improvements in Ready-to-Use-Therapeutic Foods

This article at a glance

  • Two recent studes have explored the possibility of adjusting the fatty acid composition of Ready-to-Use Therapeutic Foods (RUTF) that are used to rehabilitate malnourished children, with the aim of better supporting omega-3 LCPUFA status.
  • DHA levels drop during the recovery of malnourished children treated with a standard RUTF – this is likely to be caused by suppression by excess omega-6 linoleic acid of increased accretion of DHA for the growth of the central nervous system.
  • Two ways to sustain DHA accretion are shown: direct supplementation with fish oil alongside a standard RUTF, and adjustment of RUTF composition with the inclusion of a low-linoleic acid/high-oleic acid peanut oil, together with a vegetable oil high in linolenic acid.

 

Ready-to-Use-Therapeutic-Foods (RUTF) are lipid- and carbohydrate-rich paste-like foods that have been developed for the purpose of providing a nutrient-complete diet to malnourished children, and to assist in their rehabilitation. The use of RUTFs has seen significant implementation on a global scale in the last 15 years. RUTFs are used in at least 50 countries, and are now produced by several organizations. RUTFs are composed of several of the following ingredients in emulsified form; one or more vegetable oils, such as peanut, palm and soybean oil, purified phospholipid (lecithin), carbohydrates such as powdered sugar and corn syrup, milk powder, a vitamin premix, and some emulsifying agent. RUTF is mostly packaged in light-impermeable sachets and has a low water content to minimize microbial growth, allowing preservation for several months in tropical conditions. The use of RUTF is primarily intended for outpatient care of severely malnourished children who have unimpaired appetite and are otherwise medically stable.

Acute malnutrition in infants and children remains a grave problem worldwide, causing more than half a million preventable deaths each year (~35% of deaths in children under 5 years globally). The most severe form of acute malnutrition in children is defined as having a weight-for-height Z-score of <3 according to WHO growth standards, or less than 70% of the median National Center for Health Statistics (NHCS)/WHO reference values (both are measures of visible wasting), or the presence of e - Hsieh Jones 1nutritional edema (kwashiorkor; which can represent up to 50% of malnutrition cases). The availability of RUTF is one of the essential interventions known to improve the health outcomes of children globally. The United Nations post-2015 development agenda foresees further implementation of RUTF usage to increase the coverage of malnourished children globally, of which currently only around 15% are being reached.

e - Hsieh Jones

Photo by I. Trehan

Children do not only need diets containing the necessary nutrients and energy to prevent malnutrition, or help recover from it – they also need those nutrients that support optimal functional development of tissues. This is of particular relevance to the central nervous system, as apparent normal body growth can be accomplished but optimal neurological development may lag or is irreversibly compromised when nutrients that support brain development are not present in an infant’s or child’s diet. Sufficiency in the dietary intake of essential fatty acids is an important aspect for normal brain development. In RUTFs that are being used to date, the composition has no rational design with respect to essential fatty acid composition and content, and broad ranges of omega-6 and omega-3 fatty acids can be found. Ample evidence gathered in the last decades has indicated that children have a substantial need for omega-3 LCPUFA, with DHA in particular known to be important for brain development. Omega-3 LCPUFA are obtained from breast milk and from foods that contain preformed EPA/DHA. Besides being lipid-rich, RUTFs developed to date have no precise guidelines to ensure sufficiency in omega-3 LCPUFA provision.

Since the lipid portion of current RUTFs is provided nearly entirely by vegetable oils (groundnut and seed oils), the level of the omega-6 PUFA precursor linoleic acid (LA) is in substantial excess to estimated nutritional needs (around 2% of energy in adults). RUTFs used currently favor a dominant intake of omega-6 PUFA and very little, if any, omega-3 PUFA. Alpha-linolenic acid (ALA) is present in low levels in some of the vegetable oils used for RUTF manufacturing. Depending on the dose, this ALA may support some endogenous EPA biosynthesis. However, the further conversion to DHA in humans has been demonstrated as extremely low and most probably insufficient to satisfy accretion rates in children. High LA levels will likely inhibit any ALA conversion, since both fatty acids share the same elongation and desaturation pathways. In addition, given the high overall PUFA content in current RUTF (mainly linoleic acid (LA) up to ~10 weight percent of RUTF paste, and 25% of the fatty acid content), omega-3 LCPUFA biosynthesis from precursor ALA may be effectively shut down when combined precursor PUFA content (LA plus ALA) in the diet exceeds a certain energy percentage (for example around 3%). In other words, there is a worthy opportunity to adjust the fatty acid content of RUTFs to provide the correct amounts of specific fatty acids and/or facilitate precursor fatty acid conversion in children recovering from malnutrition.

It is possible that by markedly lowering the content of LA in RUTFs, improvements in omega-3 status may be achieved. In addition, improvements in omega-3 status could possibly be attained by increasing ALA content, and likely by the direct inclusion of preformed omega-3 LCPUFA. How changes in RUTF composition affect fatty acid status in malnourished children that might help improve their clinical and neurological outcome is unknown. Exactly what the best strategies would be to achieve this is the topic of some very interesting new research. Two recent studies have taken a step in this direction by investigating the changes in fatty acid status of malnourished children in Malawi and Kenya following the ingestion of RUTF with purposefully adjusted fatty acid compositions.

In the first study, Hsieh and colleagues made use of a custom-made “high-oleic” RUTF (HO-RUTF) made with peanut oil from a high-oleic acid peanut cultivar. This research was carried out by researchers from the College of Medicine, University of Blantyre, Malawi, and colleagues at the Department of Pediatrics, Washington University, St. Louis, MO, Cornell University, Ithaca, NY and College of William and Mary, Williamsburg, VA, in the US. High-oleic peanut oils contain significantly higher levels of oleic acid (up to 80%) and 5-7 fold lower levels of LA than found in common peanut cultivar groundnut oils. Furthermore, replacing part of the palm oil and peanut oil used in standard RUTF, omitting any soybean oil, and using ALA-rich linseed (flax) oil (up to 8%) led to a HO-RUTF with markedly increased levels of ALA and reduced levels of LA. Compared to currently used standard RUTFs, the total PUFA content was similar, but the LA content was reduced from 8.9 g/100 g (21.3% of fatty acids) to 4.4 g/100 g (13.1 % of fatty acids). ALA content was increased from 0.17 g/100 g to 4.4 g/100 g (0.4 and 13.1 %, respectively). Achieving a 1:1 ratio of LA to ALA in the new HO-RUTF, this offered the possibility to compare the effect of a more balanced essential fatty acid intake on fatty acid status in malnourished children with that of a standard RUTF that contained 53 times more LA than ALA.

The effectiveness of the HO-RUTF was determined in a double-blind placebo controlled randomized intervention study in 141 Malawian children with acute normal (uncomplicated by other diseases) malnutrition. Some 44% of the children had edematous malnutrition. The children (75% girls, age range of six months to five years), were assigned at random to either the RUTF group (n=70) or the HO-RUTF group (n=71). RUTF and HO-RUTF were given daily to children, with help from their caretakers who were well instructed by nurses. All study personnel and care-takers were blinded to the two types of RUTF. Besides fatty acid content, both RUTF and HO-RUTF had a similar nutrient content, with 175 kcal/kg provided to each child every day. The principal objective of the trial was to assess the effect of the therapeutic foods on the level of EPA and DHA in plasma phospholipids, measured at baseline and after four weeks. Families were provided with enough RUTF for two week periods, and the children visited a study clinic every two weeks. RUTF was provided for as long as children needed it until recovery, up to three months after the start of the trial. At study visits, the investigators measured the recovery from malnutrition (mid-arm circumference >12.4 cm without edema), the child’s health and growth status, and eating habits.

e - Hsieh Jones 2In both groups about half of the children recovered from malnutrition. Overall no differences in clinical outcome were noted: rates of recovery, death, and the number of children who remained malnourished were similar. The children who had received HO-RUTF had a significantly better weight-for-height at the time they recovered from malnutrition, although still marginally below average weight-for-height. The levels of EPA, docosapentaenoic acid n-3 (DPA n-3), and DPA n-6 did not change in children on standard RUTF. However, their DHA levels had decreased from 3.2 to 2.4%, indicating that the standard RUTF received during the four-week period did not support circulating DHA levels. In contrast, in the children on HO-RUTF, the levels of EPA and DPA n-3 increased, and DHA levels remained at the level observed at study onset. Apparently, HO-RUTF supported the endogenous formation of omega-3 LCPUFA, and protected the levels of DHA from decreasing during recovery from malnutrition. Compared to children receiving RUTF, HO-RUTF also induced a lowering of arachidonic acid (AA) levels, indicating that less LA was transformed to DHA or that AA was displaced from plasma phospholipids by the increased levels of omega-3 LCPUFA.

In the second study, a decrease in DHA levels in children recovering from malnutrition was also observed. This study was carried out by Jones and colleagues at the KEMRI-Wellcome Trust Research Programme in Kilifi, Kenya, together with colleagues at the Centre for Global Health Research, Imperial College, London, and several other institutes in the UK and Ireland. This study focused on children with severe acute malnutrition (uncomplicated by other diseases) who were treated in an on-site outpatient therapeutic feeding program of a rural Kenyan referral hospital. Children (age 6 to 60 months, approximately 50% girls) were randomly assigned to three groups. Twenty children per group received either a daily dose of standard RUTF, a flax oil-RUTF, or a flax oil-RUTF plus fish oil (1 ml daily containing both EPA and DHA) during four months. There were no significant differences between the three groups in a range of variables at baseline. The objective was to determine how an RUTF enriched with ALA (by addition of linseed/flax oil), or with both ALA and EPA/DHA (from fish oil) would affect the PUFA status of children with severe malnutrition, in comparison to a standard RUTF. The flax oil-RUTF contained 3.3 energy % (en%) ALA compared to a standard RUTF with 0.7 en% ALA, and nearly similar levels of LA (7.9% vs 8.2 en%). The children and study personnel were blinded to the two RUTF preparations, with reportedly indistinguishable organoleptic properties. RUTF doses were determined according to national guidelines and given until recovery, followed by supplemental use of the RUTFs as 50% of dietary intake alongside food eaten at home until the end of the four months. The treatment with fish oil together with flax oil-RUTF was provided as an open-label administration, with the oil squeezed directly from a ruptured gelatin capsule into the children’s mouths.

No difference in growth rates between the children in the three groups was noted over the treatment period. Recovery was accompanied by increases in insulin growth factor-1 and hemoglobin levels in all groups. DHA levels in RBC membranes significantly decreased after four weeks of outpatient support with standard RUTF, from marginally low baseline levels of 5.2% to ~4%. In the children receiving flax oil-RUTF alone the DHA level similarly decreased. In children also receiving fish oil, DHA levels in RBC membranes increased over time to a level around 6-8%. Only supplementation with fish oil increased EPA levels. Flax oil-RUTF did not change the overall omega-6 to omega-3 ratio compared to baseline, whereas this ratio increased with standard RUTF and decreased with the fish oil supplementation to flax oil RUTF. In summary, in this group of children with severe malnutrition the addition of flax oil to a standard RUTF did not protect DHA levels from decreasing during rehabilitation. Only the addition of fish oil increased EPA and DHA in RBCs. The improvement in omega-3 status in the children receiving fish oil was not associated with marked changes in the levels of circulating markers of inflammation and T-cell function.

Both studies also addressed organoleptic acceptability and oxidative stability of the RUTFs. Scoring of taste/likeability and assessment of the consumed quantities of a fixed weight of RUTF led to the conclusion that children liked the new RUTFs equally well to standard RUTF pastes, and there was no difference in intake reported. Peroxidation of PUFA content is considered important to remain within certain limits. The study by Jones measured peroxide levels in the standard and flax oil-RUTF products after one year storage and found 29.7 and 17.9 meq/kg of paste, respectively. Although both were above limits recommended for newly manufactured batches (<10 meq/kg UNICEF), there was no effect on palatability as tested.

The view that the addition to RUTFs of an ALA-rich oil alone can contribute to maintaining DHA levels in malnourished children is unsupported, consistent with more than 20 studies yielding similar results in normally nourished adults. The replacement of groundnut oils with a high-oleic groundnut or seed oil alone, may bring about favorable changes in omega-3 LCPUFA status. The value of “high-oleic” oils in this context lies in their low LA content. Concomitant to lowering LA content, the extent to which a significant increase in ALA is needed for support of DHA levels by novel RUTF preparations remains to be addressed. Availability of high-oleic groundnut oils obtained from cultivars that can be grown locally where they are needed will provide a valuable new RUTF ingredient. High-oleic peanut oils can offer additional favorable properties such as enhanced resistance to oxidation.

e - Hsieh Jones 3Interestingly, the fact that a high-oleic/high-ALA RUTF supports DHA levels is somewhat surprising as total PUFA levels remain elevated, which would be expected to down-regulate conversion of ALA to omega-3 LCPUFA. This observation, at least made here in children, suggests that additional components in the high-oleic oil stimulate increased fractional conversion rates of ALA to DHA. Indications have recently been obtained in animal studies that other dietary fatty acids, such as short-chain saturated fatty acids, can promote the conversion of ALA to omega-3 LCPUFA. As shown in the study by Jones, the more direct approach to administer preformed DHA, such as present in a fish oil or an omega-3 concentrate, in addition to a standard RUTF, can also serve to provide sufficient DHA during the recovery of malnourished children. Whether the more direct approach or a reformulation of RUTFs will be practical to implement will likely depend on local conditions. Cost and lability of DHA may be limiting factors. In any case, reducing LA to levels more similar to natural foods is supported by the Hsieh study.

The studies highlighted here are complementary and signal the progress in RUTF development. RUTFs can be improved to attain a better fatty acid status to, in principle, support neurological development in children enrolled in therapeutic feeding programs. Such improved RUTF formulations are palatable, and may find applicability under conditions where fish oil capsules cannot be taken as a complementary dietary intervention, or a rehabilitation diet containing fish cannot be provided. For readers further interested in this topic, an informative commentary on both studies has been published by several specialists.

 

Hsieh JC, Liu L, Zeilani M, Ickes S, Trehan I, Maleta K, Craig C, Thakwalakwa C, Singh L, Brenna JT, Manary MJ. High-oleic ready-to-use therapeutic food maintains docosahexaenoic acid status in severe malnutrition. J. Pediatr. Gastroenterol. Nutr. 2015;61(1):138-143. [PubMed]

Jones KD, Ali R, Khasira MA, Odera D, West AL, Koster G, Akomo P, Talbert AW, Goss VM, Ngari M, Thitiri J, Ndoro S, Knight MA, Omollo K, Ndungu A, Mulongo MM, Bahwere P, Fegan G, Warner JO, Postle AD, Collins S, Calder PC, Berkley JA. Ready-to-use therapeutic food with elevated n-3 polyunsaturated fatty acid content, with or without fish oil, to treat severe acute malnutrition: a randomized controlled trial. BMC Med. 2015;13:93. [PubMed]

 

Worth Noting

Blanchard H, Pédrono F, Boulier-Monthéan N, Catheline D, Rioux V, Legrand P. Comparative effects of well-balanced diets enriched in α-linolenic or linoleic acids on LC-PUFA metabolism in rat tissues. Prostaglandins Leukot. Essent. Fatty Acids 2013;88(5):383-389. [PubMed]

Brenna JT, Akomo P, Bahwere P, Berkley JA, Calder PC, Jones KD, Liu L, Manary M, Trehan I, Briend A. Balancing omega-6 and omega-3 fatty acids in ready-to-use therapeutic foods (RUTF). BMC Med. 2015;13(117):1-4. [PubMed]

Derbyshire EJ. A review of the nutritional composition, organoleptic characteristics and biological effects of the high oleic peanut. Int. J. Food Sci. Nutr. 2014;65(7):781-790. [PubMed]

Gibson RA, Muhlhausler B, Makrides M. Conversion of linoleic acid and alpha-linolenic acid to long-chain polyunsaturated fatty acids (LCPUFAs), with a focus on pregnancy, lactation and the first 2 years of life. Matern. Child Nutr. 2011;7 Suppl 2:17-26. [PubMed]

Gibson RA, Neumann MA, Lien EL, Boyd KA, Tu WC. Docosahexaenoic acid synthesis from alpha-linolenic acid is inhibited by diets high in polyunsaturated fatty acids. Prostaglandins Leukot. Essent. Fatty Acids 2013;88(1):139-146. [PubMed]

High-oleic peanut cultivar development: http://pmil.caes.uga.edu/research/UGA203/index.html

Peanut & Mycotoxin Innovation Lab / USAID supported study: http://pmil.caes.uga.edu/news/articles/2015/MalnutritionInterventionsUpdate.html

KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya: http://www.kemri-wellcome.org/

Lassi ZS, Mallick D, Das JK, Mal L, Salam RA, Bhutta ZA. Essential interventions for child health. Reprod. Health 2014;1 (Suppl. 1):1-12. [PubMed]

MSF – Management of Moderate Acute Malnutrition with RUTF: http://www.doctorswithoutborders.org/news-stories/special-report/management-moderate-acute-malnutrition-rutf-niger

Nutriset: http://www.nutriset.fr/en/about-nutriset/nutriset-timeline.html

Ready-to-Use Therapeutic Foods: UNICEF. Ready-to-Use Therapeutic Food: Current outlook. May 2014. http://www.unicef.org/supply/files/RUTF_Supply_Update__May_2014.pdf.

World Health Organization – Malnutrition: http://www.who.int/maternal_child_adolescent/topics/child/malnutrition/en/

World Health Organization. Guideline: Updates on the Management of Severe Acute Malnutrition in Infants and Children. ISBN-13: 978-92-4-150632-8 2013. http://www.ncbi.nlm.nih.gov/books/NBK190328

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