SOCIETY PAPER

Palm Oil and Beta-palmitate in Infant Formula: A Position

Paper by the European Society for Paediatric
Gastroenterology, Hepatology, and Nutrition (ESPGHAN)
Committee on Nutrition

Jiri Bronsky, yCristina Campoy, zNicholas Embleton, §Mary Fewtrell,
ô
Nataša Fidler Mis, jjKonstantinos Gerasimidis, Iva Hojsak, yyJessie Hulst,
zz
Flavia Indrio, §§ôôAlexandre Lapillonne, jjjjChristian Molgaard, yyySissel Jennifer Moltu,
zzz
Elvira Verduci, §§§Rakesh Vora, and ôôôMagnus Domellöf, ESPGHAN Committee on Nutrition

ABSTRACT

Background: Palm oil (PO) is used in infant formulas in order to achieve

palmitic acid (PA) levels similar to those in human milk. PA in PO is What Is Known
esterified predominantly at the SN-1,3 position of triacylglycerol (TAG),
 Palm oil is used as source of fat in infant formula in
and infant formulas are now available in which a greater proportion of PA is
in the SN-2 position (typical configuration in human milk). As there are order to achieve palmitic acid levels comparable to
some concerns about the use of PO, we aimed to review literature on health human milk.
 Palmitic acid in human milk is predominantly at the
effects of PO and SN-2-palmitate in infant formulas.
Methods: PubMed and Cochrane Database of Systematic Reviews were SN-2 position, in palm oil it is predominantly at the SN-
systematically searched for relevant studies on possible beneficial effects or 1,3 position. SN-2-palmitate is used in some formulas
harms of either PO or SN-2-palmitate in infant formula on various health to mimick palmitic acid position in human milk.
outcomes.
Results: We identified 12 relevant studies using PO and 21 studies using SN-2- What Is New
palmitate. Published studies have variable methodology, subject characteristics,
and some are underpowered for the key outcomes. PO is associated with harder  There is insufficient evidence to suggest that palm oil
stools and SN-2-palmitate use may lead to softer stool consistency. Bone effects should be avoided as a source of fat in infant formulas
seem to be short-lasting. For some outcomes (infant colic, faecal microbiota, for health reasons.
lipid metabolism), the number of studies is very limited and summary evidence  Inclusion of high SN-2-palmitate fat blend in infant
inconclusive. Growth of infants is not influenced. There are no studies published formulas may have short-term effects on stool con-
on the effect on markers of later diseases. sistency but cannot be considered essential.
Conclusions: There is insufficient evidence to suggest that PO should be
avoided as a source of fat in infant formulas for health reasons. Inclusion of
high SN-2-palmitate fat blend in infant formulas may have short-term effects
on stool consistency but cannot be considered essential. LIPIDS IN HUMAN MILK AND INFANT
Key Words: colic, constipation, growth, lipids, palm olein, palmitic acid FORMULAS

(JPGN 2019;68: 742–760) L ipids in human milk serve as a major source of energy and
essential fatty acids (FA) for the breastfed infants. They also

Received October 22, 2018; accepted February 4, 2019.

From the Department of Paediatrics, University Hospital Motol, Prague, Exercise and Sports, University of Copenhagen, the Pediatric Nutri-
Czech Republic, the yDepartment of Paediatrics, University of Granada, tion Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen,
Spain, the zNewcastle Neonatal Service, Newcastle Hospitals NHS Trust Denmark, the yyyDepartment of Neonatal Intensive Care, Oslo University
and Newcastle University, Newcastle upon Tyne, UK, the §Childhood Hospital, Oslo, Norway, the zzzDepartment of Pediatrics, San Paolo
Nutrition Research Centre, UCL GOS Institute of Child Health, London, Hospital, Department of Health Sciences, University of Milan, Milan,
UK, the ôDepartment of Gastroenterology, Hepatology and Nutrition, Italy, the §§§Leeds teaching hospitals NHS trust, Leeds, UK, and the
University Children’s Hospital, University Medical Centre Ljubljana, ôôôDepartment of Clinical Sciences, Pediatrics, Umeå University,
Slovenia, the jjHuman Nutrition, School of Medicine, Dentistry and Umeå, Sweden.
Nursing, University of Glasgow, New Lister Building, Glasgow Royal Address correspondence and reprint requests to Jiri Bronsky, MD, PhD,
Infirmary, Glasgow, UK, the Children’s Hospital Zagreb, University Associate Professor of Paediatrics Gastroenterology and Nutrition Unit,
of Zagreb School of Medicine, Zagreb, Croatia, the yyDepartment of Department of Paediatrics, University Hospital Motol, V Uvalu 84,
Paediatric Gastroenterology, Erasmus MC, Sophia Children’s Hospital, 15006, Prague 5, Czech Republic (e-mail: [email protected]).
Rotterdam, The Netherlands, the zzOspedale Pediatrico Giovanni XXIII Supplemental digital content is available for this article. Direct URL citations
University of Bari, Bari, Italy, the §§Paris Descartes University, APHP appear in the printed text, and links to the digital files are provided in the
Necker-Enfants Malades hospital, Paris, France, the ôôCNRC, Baylor HTML text of this article on the journal’s Web site (www.jpgn.org).
College of Medicine, Houston, Texas, the jjjjDepartment of Nutrition, Secretary of CoN: I.H.; Chair of CoN, M.D.

742 JPGN  Volume 68, Number 5, May 2019

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JPGN  Volume 68, Number 5, May 2019 Palm Oil and Beta-palmitate in Infant Formula

facilitate absorption of fat-soluble dietary components and support it was one of the major sources of dietary fats for centuries in most
gastrointestinal function, lipid and lipoprotein metabolism, neuro- of West Africa (11). Palm kernel oil (PKO) is extracted from the
development, and immune function (1,2). Almost 100% of human seeds and edible PO from the mesocarp. PKO has a composition
milk fat is composed by triacylglycerols (TAG). FA in human milk different from that of PO and is mainly used for nonedible purposes
are either saturated (SFA, 35%–40%), monounsaturated (MUFA, (4). Compared with most other vegetable oils, PO contains a high
45%–50%), or polyunsaturated (PUFA, approximately 15%) (1,2). amount of saturated fat (8). Crude palm oil (known also as red palm
Palmitic acid (PA, C16:0) provides the major part of the total SFA oil), contains both compounds beneficial to health (such as TAG,
content and its concentration is kept relatively constant in breast- vitamin E, carotenoids and phytosterols) as well as impurities
feeding mothers (2,3). Human milk TAG are predominantly esteri- (phospholipids, free FA [FFA], gums, and lipid oxidation products).
fied with PA in the SN-2 position and this configuration facilitates Both can be removed by refining processes, but the composition of
absorption in infants after digestion by human pancreatic lipase that is the final product is dependent on the refining method (chemical or
SN-1,3-specific. Nonesterified FA liberated from the SN-1 and SN-3 physical). High-quality PO containing more than 95% neutral TAG,
positions are quite well absorbed if they are unsaturated because of less than 0.5% FFA and a low impurity content is used in the food
their water solubility. On the contrary, poorly absorbed saturated FA, industry. Low-quality oils are used in nonedible industry (6).
such as PA tend to form calcium (Ca) soaps that are excreted in stool PO represents approximately one-third of the world’s vege-
and increase stool hardness. However, pancreatic lipolysis of human table oil production, and its consumption has increased rapidly in
milk TAG with PA esterified predominantly to the SN-2 position the past several decades (8). Malaysia and Indonesia are the main
results in formation of water-soluble palmitoyl-monoglycerol. This producers of PO, but the E guineensis palm tree is now widespread
reduces FA and Ca malabsorption and enables the breastfed infant to throughout the tropical areas of America and South East Asia.
benefit from PA as source of fat (see Fig. 1) (1,2,4–10). Productivity of PO per unit area is 11, 10, and 7 times the yield of
The fat in infant formula comes mainly from vegetable oils. the other main vegetable oils, soybean, sunflower and rapeseed,
Palm oil (PO) is used in order to achieve PA levels similar to those respectively (4). Environmental and economic aspects of PO pro-
in human milk. Recently, there has been an increasing discussion duction (such as rainforest destruction, biofuels, and child-labour)
regarding the use of PO in food products, mostly because of are widely discussed by journalists, consumers, public, and industry
environmental concerns but PO also has potential important health via internet and social media (eg, https://www.theguardian.com/
effects. In PO, PA is esterified predominantly at the SN-1,3 position environment/palm-oil). These aspects are beyond the scope of
of TAG. As the intestinal absorption of SN-1,3-palmitate is not this article.
optimal, there have been attempts to replace it, at least partly, in PO has 2 major fractions. Palm olein (POL; 65%–75%) is the
infant formulas with SN-2-predominant TAG (beta-palmitate), low-melting liquid fraction used mainly in cooking oil for frying
which is the form present in human milk. A number of products and in margarines. The high-melting solid fraction, palm stearin
using either a mixture of fat or commercial synthetic beta-palmitate (30%–35%), is present in shortenings and hydrogenated oils used
(eg, Betapol, INFAT, LipoMilk or Zhejiang Beijia product) in order as butter substitutes in some countries. PO is generally found in
to achieve high SN-2 content are available on the market. Betapol is baked goods, cereals, confectionary fats, frozen meals, ice cream,
produced by interesterifying a tripalmitin-rich PO fraction with a industrial frying fats, margarines, nondairy creamers, salad dres-
mixture of other fats by using the SN-1,3-specific lipase from sings, supplements/vitamins, and other food products (6).
Rhizomucor miehei (code SP-392; Novo Industries, Copenhagen, PO contains 50% SFA, mostly PA (44%) and lower amounts
Denmark). INFAT (Advanced Lipids, Karlshamn, Sweden) is of stearic acid (5%), 40% MUFA, mostly oleic acid, and 10%
produced by a patented enzymatic process, which restructures PUFA, mostly linoleic acid. Thus, PA is the principal constituent of
the fat in a way that mimics the structure of PA in human milk refined PO. FA in PO (as in all vegetable oils) are mainly structured
(SN-2 predominant position). as TAG having oleic acid predominantly located at the SN-2
position, and PA mainly (over 70%–80%) located at the SN-1
and SN-3 positions. As in human milk, PA is also the main SFA
PALM OIL naturally occurring in animal milk fats, often found at the SN-2
PO is the most widely used vegetable oil in the world. It is position (beta-position) of TAG—in cow’s milk in approximately
obtained from an ancient tropical palm tree (Elaeis guineensis) and 40% and in human milk in 60%–80% (3,5–7).

M.F. conducted a trial using beta-palmitate, which was funded by Industry and/or consultant and/or speaker for Arla Food, Biogaia, Nestle, Nestle
(Cow & Gate, now Nutricia; in 1995) and has received honoraria for Nutrition Institute, Wyeth, Danone, and Abbott. A.L. received lecture fees
attending 2 Consultancy meetings with Enzymotec (a company involved and/or nonfinancial support from Baxter, Fresenius, Nestle, and Mead
in the manufacture of beta-palmitate for infant formulas). Johnson Nutrition. N.F.M. acknowledges support of the Slovenian Research
The authors report the following conflicts of interest outside the submitted work. Agency (P3–0395: Nutrition and Public Health; L3-8213, L3-7538). C.M.
J.B. reports personal fees and nonfinancial support from AbbVie, Nutricia, reports receipt of grants/research supports from European Commission
Biocodex, personal fees from MSD, Nestlé, Ferring, Walmark. C.C. Innovation Fund Denmark, Nordea-fonden, Arla Foods, Chr. Hansen,
received research funding from ORDESA Laboratories and Abbott USDEC, Gate Foundation. S.J.M. reports receipt of grants/research supports
Nutrition. N.E. reports receipt of grants/research supports from National from DSM Nutritional Products, she served as member of advisory board
Institutes for Health Research (UK), Prolacta, Bioscience (US) and Danone and received payment/honorarium for consultation from Baxter and received
Early life Nutrition. He also served as member of Advisory board for payment/honorarium for lectures from Baxter and Fresenius Kabi. E.V.
Danone Early life Nutrition and received payment/honorarium for lectures reports grant/research support from Nutricia Italia Spa, Nestle Health
from Danone Early life Nutrition, Nestle Nutrition Institute, Baxter, and Science—Vitaflo Italy, FoodAR srl Italy, PIAM Pharma, and Integrative
Fresenius Kabi. K.G. reports personal fees from Nutricia, research grants Care. R.V. reports no conflict of interest. M.D. has received speaker fees
and personal fees from Nestle and Nutricia, and personal fees from Dr Falk. from Baxter, Fresenius, Semper, Abbvie, Nestlé, and research support from
I.H. reports receipt of payment/honorarium for lectures from BioGaia, Baxter and Prolacta.
Nutricia, Nestle, GM pharma, and receipt of payment/honorarium for Copyright # 2019 by European Society for Pediatric Gastroenterology,
consultation from Farmas,Chr Hansen. J.H. reports receipt of grants/research Hepatology, and Nutrition and North American Society for Pediatric
supports from Nutricia Advanced Medical Nutrition Netherlands and Gastroenterology, Hepatology, and Nutrition
Danone Medical care (global). F.I. has participated as a clinical investigator DOI: 10.1097/MPG.0000000000002307

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Bronsky et al JPGN  Volume 68, Number 5, May 2019

FIGURE 1. Digestion and absorption of triacylglycerol and fatty acids in human intestine. Colipase-dependent pancreatic lipase selectively
hydrolyzes the FA at the SN-1 and 3 positions, yielding FFA and the 2-monoglyceride. Unsaturated FFA and monopalmitin are well absorbable.
Saturated FFA (including PA) are involved in the re-synthesis of new TAG and/or formation of Ca2þ or Mg2þ soaps. FA ¼ fatty acids; FFA ¼ free fatty
acids; PA ¼ palmitic acid; Ca ¼ calcium.

POTENTIAL HEALTH EFFECTS OF PALM OIL elevated serum cholesterol levels (14). A systematic review and
AND PALMITIC ACIDS IN ADULTS meta-analysis of 51 dietary intervention trials (many of them
included in the previously mentioned meta-analysis (8) has shown
High-fat diets, particularly those rich in SFA, have been that both favourable and unfavourable changes in blood lipid-
linked to cardiovascular diseases (CVD), obesity, type 2 diabetes related markers of CVD occurred when PO replaced the primary
mellitus (T2DM) and cancer. However, studies on potential dietary fats (rich in stearic acid, MUFA and PUFA or myristic/lauric
unhealthy effects of PO because of the high PA content, are acids), whereas only favourable changes occurred when PO
controversial (6,12,13). replaced trans-FA (15). The same author in a previous review
Moreover, PO is cholesterol-free and POL, containing a concluded that the evidence on dietary PA or PO and the risk of
substantial amount of oleic acid (48%), was considered by some cancer is not convincing and specific studies are limited (4). There
authors as a suitable substitute for olive oil in healthy human diets is 1 study showing promising data on potential anti-inflammatory
(6). PO has also been suggested as an alternative for partially effects of red palm oil and protection against ischemia and reper-
hydrogenated fats in the food supply to reduce transfat intakes fusion injuries of the heart in an intensive care setting that merits
(8). A lower atherogenic power of PO compared with animal fat is further investigation (16). Another extensive review reports con-
also hypothesized, because of the fact that in PO, PA is usually not flicting results regarding all considered outcomes (T2DM, CVD
present at the SN-2 position in TAG and it has been shown in animal and cancer) mainly for methodological reasons (6).
experiments that higher percentages of PA at the SN-2 position are There are data from studies on animals and tissue models
related to the most atherogenic profiles (6). showing potential negative health effects of PO compared with PO-
A meta-analysis of 30 articles including 32 clinical trials nonsupplemented diet, such as reduced insulin sensitivity and
reported that PO significantly increased both low-density lipopro- impaired glucose tolerance, lipotoxicity (negative effect of PA on
tein (LDL) and high-density lipoprotein (HDL) cholesterol when mitochondrial function mediated by oxidative stress), inflammation
compared with vegetable oils low in saturated fat, and that PO in adipose tissue and pancreas, and supposed involvement of PA in
increased HDL cholesterol when compared with transfat-containing regulation of tumour growth (cell proliferation, apoptosis, invasive-
oils (8). The authors of a recent review state that there is not enough ness) (6). On the contrary, there are number of animal studies showing
evidence to conclude that PO is atherogenic and contributes to potentially beneficial effects of PO on lipid profile (14).

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JPGN  Volume 68, Number 5, May 2019 Palm Oil and Beta-palmitate in Infant Formula

OTHER POTENTIALLY BENEFICIAL OR either PO/POL or SN-2-palmitate (beta-palmitate) as a source of fat

HARMFUL COMPOUNDS OF PALM OIL in infant formulas on the following outcomes: composition of stool;
infantile colic; stool frequency and consistency; bone health and
PO is genetic-modification free. Crude PO contains phytoster-
growth; metabolic effects (eg, cardiovascular health, T2DM, hyper-
ols, and is the richest natural source of carotenoids (vitamin A
tension, and lipid profile).
precursors), tocopherols, and tocotrienols (vitamin E compounds)
The database Medline (via PubMed) and Cochrane Database
(6,11,17). The levels of these compounds are affected to various
of Systematic Reviews were searched for keywords for publications
degrees during processing (personal communication, Specialised
up to November 2017—see Appendix 1 (Supplemental Digital
Nutrition Europe [SNE]—an association representing food manufac-
Content, http://links.lww.com/MPG/B600).
turers, including infant formula producers). The final levels of these
compounds in the PO used in the oil blends for infant and follow-on
formulas depends on the formula manufacturers’ specifications to RESULTS
meet the nutritional profile of these foods. It is important to note that In total, we identified 12 relevant studies using PO/POL (5 on
the infant and follow-on formulas fatty acid and vitamin profiles are composition of stool, none on infantile colic, 2 on stool frequency
considered in view of the contribution expected from all ingredients, and consistency, 3 on bone health and growth, and 2 on metabolic
not just PO. Tocotrienols are natural inhibitors of cholesterol synthesis effects) and 21 relevant studies using SN-2-palmitate (8 on com-
and recent studies point to their potential beneficial biological proper- position of stool, 3 on infantile colic, 3 on stool frequency and
ties, such as protection against cancer, cardiovascular diseases, neu- consistency, 5 on bone health and growth, and 2 on metabolic
rodegeneration, oxidative stress, and immune regulation (6,18–20). effects)—see Tables 1 and 2. In the ‘‘Results’’ section, studies are
On the other hand, PO may contain potentially harmful reported according to their primary outcome. Secondary outcomes
substances, such as phospholipids, FFA, gums, and lipid oxidation are also mentioned in Tables 1 and 2 and in the ‘‘Discussion’’ part
products (6). Glycerol-based process contaminants (glycidyl fatty of the manuscript. The majority of the identified studies are either
acid esters [GE], 3-monochloropropanediol [3-MCPD], and 2- industry-supported or performed by employees of formula produ-
monochloropropanediol [2-MCPD], and their fatty acid esters) cers (also mentioned in Tables 1 and 2). The quality of the studies is
are found in PO, but also in other vegetable oils, margarines, variable; some have methodological problems, such as very low
and some processed foods. The substances form during food sample size or the use of multiple interventions (hydrolyzed protein,
processing, in particular, when refining vegetable oils at high oligosaccharides, etc).
temperatures (approximately 200 8C). The European Food Safety
Authority (EFSA) points to potential health concerns (genotoxicity, Palm Oil/Palm Olein Studies
carcinogenicity) of these compounds especially for young age
groups. In their recent report, EFSA points out the fact that the Composition of Stool (Fatty Acid and Calcium
intakes of 3-MCPD, especially in exclusively formula-fed infants, Content, Intestinal Microbiota)
slightly exceeded the stipulated tolerable daily intake of We identified 5 RCTs on this topic (26–30), 1 of them
2 mg  kg  day1 (21). Infant formulas that do not contain PO or composed of 2 subprojects (29) and 2 of them reporting results from
POL have relatively low concentrations of 3-MCPD and glycidyl the same cohort of patients (26,30) (see Table 1). All were per-
esters; however, effective industrial mitigation strategies can sub- formed on relatively small numbers of healthy term infants. All
stantially lower the content in PO/POL-based formula (22). Infants studies consistently reported lower fat and Ca absorption in infants
consuming solely infant formula may be particularly at risk of using PO/POL-based formulas when compared with PO/POL-free
exposure to GE, however, in recent years, because of voluntary formulas. Only 1 study reported equal fat absorption when soy
measures taken by producers, levels of GE in PO and fats have protein-based formula was used, irrespective of its PO content (29).
fallen substantially (https://www.efsa.europa.eu/en/press/news/ One study also described lower LC-PUFA absorption in POL-based
160503a) (23). Oil blends used in infants and young children formula (30). None of the studies reported on intestinal microbiota.
nutrition industry contain levels of contaminants (particularly 3-
MCPD and GE) in line with regulation as low as is technically
possible (SNE, personal communication). Several toolboxes are
Infantile Colic
available and used by the suppliers to mitigate 3-MCPD esters and No relevant study was identified.
GE in oils (eg, BLL toolbox—see https://www.bll.de/de/lebensmit-
tel/sicherheit/unerwuenschte-stoffe-kontaminanten/3-mcpd-und-
glycidyl-fettsaeureester/toolbox-minimierung-3-mcpd-glycidyl). Stool Frequency and Consistency
The EU has also recently implemented stricter regulations for foods
Both a large observational multicentre study and an unblinded
for infants and young children versus general foods (24).
RCT (composed of 2 subprojects—first on breastfed and the second
Some reports show that there may be nonessential trace
on formula-fed infants) have shown less frequent stools and harder
elements and radionuclides present in PO, originating from water
stool consistency in term infants fed/weaned to formula containing
and soil on the palm plantations that may affect the health of
POL when compared with non-POL formula (31,32).
consumers. Data are conflicting, the available literature is limited
and further research is needed, however, to confirm or refute this
suspicion (25). Bone Health and Growth
The aim of this position paper is to review evidence for
Three RCTs were identified—all in healthy term infants with
potential effects of PO and SN-2-palmitate used as source of fat in
several months of follow-up—focused on bone health and growth
infant formula on the health of infants and children. Environmental
(33–35). Two of the studies reported lower bone mineralization
effects of PO production will not be addressed in this article.
(measured by dual-energy X-ray absorptiometry [DEXA]) in the
group of infants fed PO/POL-based formula when compared with
MATERIALS AND METHODS PO/POL-free formula (34,35). Two of the studies used partially
We present the results of relevant studies (RCTs and large hydrolyzed protein-based formula in both intervention and control
observational studies) on possible beneficial or harmful effects of arms (33,34). All 3 studies consistently report no difference in

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 TABLE 1. List of studies evaluating formulas with palm oil/palm olein as source of fat
PO/POL studies

First author, Ref. Study Type of  Duration of

Clinical outcome year No. Country design Sponsor sponsoring Study design Population intervention Intervention Comparison Primary outcome Secondary outcomes

Composition of Leite et al, (26) Brazil Blinded Abbott E, G Feeding 2 formulas for 33 healthy term 14 days followed by a Formula containing POL Formula not NoPALM group had higher both NoPALM group had softer
stool (FA and 2013 RCT, 14 days in a tolerance infants (68– 4 day hospital ward (44% of total fat), containing POL, Ca absorption (%) and retention stool consistency and
calcium [Ca] crossover period, followed by a 159 days metabolic balance PKO (21.7%), and PKO or canola oil (%) than PALM group, but higher fat absorption (%)
content, 4-day metabolic of age) study canola oil (18.5%) as (NoPALM) absorption was not significant than PALM group. Ca
intestinal balance period in 17 of predominant fats when Ca intake was used as a intake was higher in
microbiota) the male subjects (PALM) covariate NoPALM versus PALM-
fed infants (P < 0.001).
Formula and human milk
intakes, growth, formula
acceptability and adverse
events were comparable
between both groups
Nelson et al, (27) USA Blinded Abbott/Ross S, G Comparison of fat and 10 healthy infants 72–96 hours POL (45% of fat) Formula without POL formula-fed infants had lower Stool consistency not
1998 RCT, Ca absorption of POL- (22–192 days containing formula POL fat and Ca absorption and higher determined in this study
crossover containing formula of age) fat and Ca excretion. The
versus formula difference in percent fat
without POL. Fat and absorption was explained by
Ca levels in the 2 significantly (P < 0.05) lower %
formulas were similar absorption of palmitic (16:0) and
stearic (18:0) acids
Nelson et al, (28) USA RCT, Abbott/Ross S, G Effect of POL- 11 term infants 72–96 hours Formula with mixture Formula with mixture Both fat and Ca was less well Stool consistency not
1996 crossover predominant formula (27–161 days of 53% POL and of 60% soy oil and absorbed in infants using determined in this study
on fat and Ca of age) 47% soy oil 40% coconut oil experimental formula,
absorption. Half of presumably because of the
infants admitted for formation of insoluble Ca soaps
72-hour metabolic of unabsorbed PA. The
studies and half of difference in excretion of fat was
them performing stool explained by the difference in
collection at home excretion of PA
Ostrom et al, (29) USA Two blinded Abbott E, S, G ‘‘Casein hydrolysate 22 healthy, 72 hours Casein hydrolysate- CHF or SPF infant Ca and fat absorption was less in Secondary outcomes are
2002 RCTs, study’’ and ‘‘soy full-term infants based (CHF) or soy formulas without infants fed CHF with PO reported only for the soy-
crossover protein study’’ protein-based (SPF) POL compared with CHF without PO, protein study: Infants
comparing fat and Ca infant formulas with (P < 0.01), but fat and Ca intake averaged 1 to 2 stools per
absorption in infants POL did not differ between the 2 day in both groups. Mean
fed either casein groups. For infants fed SPF, fat rank stool consistency was
hydrolysate-based or and Ca intake did not differ 3.4 þ/- 0.2 for PO and 3.2
soy protein-based between the feeding groups. þ/- 0.2 for no PO group.
infant formulas with Mean Ca absorption was also The percentage of stools
or without POL significantly less when infants that were formed was
were fed SPF with PO than when significantly greater when
fed SPF without PO (P < 0.05). infants were fed PO
Fat absorption did not differ formula than no PO
between the two SPFs. PO, as formula (57% vs 28%;
the predominant fat, is P < 0.05). Percent of
associated with significantly feedings with spit-up and
lower absorption of Ca from vomit did not differ
infant formulas in which Ca salts significantly between
are the source of Ca. groups
Souza et al, (30) Brazil DB-RCT, Abbott E, G Feeding 2 formulas for 33 healthy term 14 days followed by a 4- Formula containing POL Formula not NoPALM-fed infants had higher The absorption percentage of
2017 crossover 14 days in a tolerance infants (68–159  3 day hospital ward (44% of total fat), containing POL, fat absorption (96.55% vs palmitic acid (C16:0) did
period, followed by a days of age) metabolic balance PKO (21.7%) and PKO or canola oil 95.50%, respectively; not differ significantly, but

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4-day metabolic study canola oil (18.5%) as (NoPALM) P ¼ 0.023), DHA and ARA this acid was excreted at
balance period in 17 of predominant fats absorption, calcium (Ca) significantly higher
the male subjects (PALM) retention and nonsignificantly concentrations in the
also Ca absorption (58.00% vs PALM (29.42 mg/kg/day)
40.9%, P ¼ 0.104 when Ca than in the NoPALM
intake was used as a covariate) (12.28 mg/kg/day).
Adverse events did not
differ between groups
(p > 0.05). Stool
consistency not determined
in this study.
 TABLE 1. Continued
PO/POL studies

First author, Ref. Study Type of  Duration of

Clinical outcome year No. Country design Sponsor sponsoring Study design Population intervention Intervention Comparison Primary outcome Secondary outcomes

Stool frequency Alarcon (31) USA Observational Abbott E, G Assessment of 6999 healthy term 2 weeks Non-POL formula Formula containing On the basis of subanalysis of There were no statistically
and consistency et al, 2002 multicentre gastrointestinal infants (28–98 days 45% of POL; other results: less frequent stools and significant differences
controlled study tolerance (including of age) formula; human harder stool consistency (both between Non-POL and
stool frequency and milk P < 0.001) in infants fed formula POL-formula group for the
consistency) of a new containing 45% of POL when incidence of GI intolerance
infant milk formula in compared with non-POL indicators. Regurgitation
healthy term infants formula not analysed according to
POL vs Non-POL.
Lloyd et al, (32) USA Unblinded Abbott/Ross E To compare the 82 healthy term 2 weeks Cow milk-based formula Cow milk-based Healthy term breastfed infants No significant differences in
1999—part 1 RCT tolerance of 2 breastfed infants with a whey:casein formula with a weaned to POL-based formula weight gain, spit-up or
commercially ratio of 60:40 and a fat whey:casein ratio of had less frequent stools, fewer vomit between feeding
available powder blend of 45% palm 48:52 and a fat brown stools and more yellow groups
infant formulas that olein, 20% soy, 20% blend of 42% stools, and firmer stools than did
differ in composition. coconut, and 15% higholeic safflower, infants fed control formula
Measures of tolerance high-oleic sunflower 30% coconut, and without POL
in exclusively oils 28% soy oils;
breastfed infants contained
weaned to an infant nucleotides
formula were
evaluated
Lloyd et al, (32) USA Unblinded Abbott/Ross E To compare the 87 healthy term 2 weeks Cow milk-based formula Cow milk-based Healthy term formula-fed infants No significant differences in
1999—part 2 RCT tolerance of 2 formula-fed with a whey:casein formula with a randomised to POL-based weight gain, spit-up or
commercially infants ratio of 60:40 and a fat whey:casein ratio of formula experienced vomit between feeding
available powder blend of 45% palm 48:52 and a fat significantly firmer stools than groups
infant formulas that olein, 20% soy, 20% blend of 42% controls
differ in composition. coconut, and 15% higholeic safflower,
Measures of tolerance high-oleic sunflower 30% coconut, and
in exclusively oils 28% soy oils;
formula-fed infants contained
were evaluated nucleotides
Bone health Borschel (33) USA Blinded Abbott E, G Effect of partially 209 healthy 4 months 100% partially 100% partially There were no significant Infants fed PO-free pHF had
and growth et al, 2014 multicentre hydrolyzed whey- term infants hydrolyzed whey hydrolyzed whey differences between groups in significantly softer stools
RCT based infant formula formula containing formula containing weight, length, HC, or weight, than those fed the PO-pHF
with and without POL 41% high-oleic 46% POL; 26% soy length or HC gains. except at 4 months of age.
on growth of healthy safflower oil; 27% oil; 20% coconut No statistically significant
term infants coconut oil; 29% soy oil; 6% high-oleic differences in the number
oil; 1.5% mono- and safflower or high- of stools per day between
diglycerides; 0.4% oleic sunflower oil; groups during the study.
ARA, 0.15% DHA 0.64% ARA; 0.32% Throughout the study,
DHA infants fed PO-free formula
had predominantly green
stools
Borschel (34) USA Multicentre Abbott E, G Effect of 2 study 74 term infants 56 or 84 days Partially hydrolyzed Partially hydrolyzed Infants fed the EF exhibited Infants fed the EF had softer
et al, 2012 DB-RCT formulas on tolerance, (0–8 days cow’s milk whey cow’s milk whey significantly greater serum 25- stools compared with
BMC and serum of age) protein þ high-oleic- protein þ POL, soy, OH vitamin D levels at 2 months infants fed CF. Incidence of
vitamin D safflower, soy, and coconut, high- of age and significantly greater spit-up/vomiting associated
concentration in coconut oils (EF) oleic-safflower, and BMC (assessed by DEXA) at with feeding did not differ
healthy term infants high-oleic- 3 months compared with infants between groups. No
sunflower oil (CF). fed CF differences were observed
The CF had less Ca in formula tolerance or
and phosphorus anthropometric
than the EF. The measurements
vitamin D3 content
was similar in both

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formulas
Koo et (35) USA DB-RCT Abbott/Ross E, G Effect of POL containing 128 healthy term 6 month Formula containing PO/ Milk-based formula Bone mineral content (BMC) and There were no significant
al, 2003 formula on bone infants (0–2 weeks coconut/soy/high- without PO bone mineral density (BMD) differences between both
mineralization in of age) oleic sunflower oils containing high- measured by dual-energy X-ray groups in weight, length,
infants (45/20/20/15% oil) oleic safflower/ absorptiometry (DEXA) were head circumference, or
(PMF) coconut/soy oils not different at baseline but formula intake throughout
(40/30/30% oil) infants fed PMF had the study
(MF) significantly lower BMC and
BMD at 3 and 6 months than
infants fed MF
 TABLE 1. Continued
PO/POL studies

First author, Ref. Study Type of  Duration of

Clinical outcome year No. Country design Sponsor sponsoring Study design Population intervention Intervention Comparison Primary outcome Secondary outcomes

Metabolic effects Fuchs (36) USA RCT Carnation G Effect of dietary fat on 104 healthy infants Until 12 months One of 2 nearly identical Whole cow milk or a Mean daily intakes of total fat, Ponderal, linear, and head
et al, 1994 Nutritional cardiovascular risk (4–6 months of age (except of minor standard infant saturated fat, monounsaturated circumference growth was
Products factors in infancy. of age) differences in formula (48%– fat, and cholesterol as well as equivalent among feeding
micronutrients) lower 49% of energy as mean serum total cholesterol groups
fat follow-up formulas fat from butterfat or was significantly higher in the
(36% kcal from a fat a soy-coconut oil infants fed cow milk, whereas
blend of POL, corn, blend, respectively) mean LDL and apo B were lower
and safflower oils) in the infants fed the follow-up
formulas. Infants consuming the
infant formula or whole cow
milk demonstrated greater
increases in mean serum total
cholesterol, LDL, and apo B by
12 months of age compared with
infants ingesting follow-up
formula
Innis (37) Canada Multicentre Mead E, G Effect of infant formula 172 term infants 3 months Formula containing Formula containing Plasma and red-blood-cell No significant differences in
et al, 1997 RCT Johnson containing POL on (0–14 days POL, high oleic coconut and soy oil phospholipid DHA, AA, body weight, length, or
phospholipid and lipid of age) sunflower, coconut, (10.3% 16:0 18:6% cholesterol. and apolipoprotein head circumference, which
profile, growth and and soy oil (22.2% 18:1, 34.2% 18:2n- B (apo B) were significantly could be attributed to breast
visual acuity in term 16:0, 36.2% 18:1, 6, 4.7% 18:3n-3); lower in the formula- than feeding or formula feeding
infants 18% 18:2n-6, 1.9% breastfed group breastfed infants. There were no were found at 1,2, or
18:3n-3) differences in visual acuity 3 month of age
among the breastfed and
formula-fed infants. No
significant relations were found
between DHA and visual acuity,
or AA and growth within or
among any of the infant groups.
The only difference between the
2 formulas was lower TAG level
in non-POL group at day 90
(P ¼ 0.014), but there was no
difference in TAG levels when
compared with breast milk
group in any of the formula
groups

apo B ¼ apolipoprotein B; ARA ¼ arachidonic acid; CF ¼ control formula; CHF ¼ casein hydrolysate-based formula; LDL ¼ low-density lipoprotein cholesterol; no PALM ¼ palm oil/palm olein-free formula; PALM ¼ palm oil/palm
olein-based formula; PKO ¼ palm kernel oil; PO ¼ palm oil; POL ¼ palm olein SPF ¼ soy protein-based formula, TAG ¼ triacylglycerols.

Type of sponsoring: E ¼ one of co-authors of the study was employee of the industry; S ¼ study product supplied by industry; G ¼ study supported by grant from/sponsored by industry; U ¼ unclear role of sponsor.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 TABLE 2. List of studies evaluating formulas with SN-2-palmitate as source of fat

SN-2-palmitate (beta-palmitate) studies

First author, Ref. Study Type of Duration of


Clinical outcome year No. Country design Sponsor sponsoring Study aim Population intervention Intervention Comparison Primary outcome Secondary outcomes

Composition of stool Bar-Yoseph (38) China Blinded RCT Enzymotec E, G Effect of SN-2 palmitate 171 term infants 6 weeks Infant formula in Infant formula Significantly lower stool No significant differences
(fatty acids [FA] and et al, 2016 on FA excretion in up to 14 days which 43% of the containing a dry weight, fat and PA were observed in any
calcium [Ca] content, term formula-fed of age PA was esterified to standard vegetable stool content in the of the anthropometric
intestinal microbiota) infants the SN2 position oil mixture (13% of SN2-palmitate measurements at
(INFAT) the PA at SN-2 formula-fed group baseline or at any visit
position); breastfed compared with the during the study
group control formula-fed
group. Breastfed
infants had a
significantly lower
stool dry weight, fat
content, and saponified
fat excretion compared
with formula-fed
infants
Carnielli et al, 1995: (39) Netherlands Blinded RCT, Nutricia G Effect of dietary TAG - 7 preterm 1 week Formula containing Formula containing Infants fed with SN-2- Plasma differences were
subanalysis of study crossover FA positional infants 76.1% of PA at the 87.3% of PA at the palmitate formula had consistent with
Carnielli et al, 1995 distribution on plasma SN-2 position SN-1,3 positions higher percentages of enhanced absorption of
(40) lipid classes and their (Betapol) PA in plasma sterol PA from the SN-2
FA composition in esters, TAG, and FFA, compared with the SN-
preterm infants and lower linoleic acid 1,3 positions
in TAG than control
formula
Carnielli et al, 1995 (40) Netherlands Blinded RCT, Nutricia G Effect of SN-2 12 preterm (28–32 weeks 2 weeks Formula with PA Formula with PA SN-2-predominant TAG Fecal output was not
crossover predominant formula of gestation) infants at esterified mainly at esterified mainly at was associated with an significantly different
on fat and mineral a postnatal age of SN-2 position of SN-1,3 position of improvement in the by treatment. No
balance 38  7 days TAG (Betapol) TAG absorption of myristic, differences were found
palmitic, and stearic in urine production or
acids and of mineral mean intestinal transit
balance. time
Carnielli et al, 1996 (41) Netherlands Blinded Nutricia G Effect of SN-2 27 healthy term male 5 weeks Formula beta (24% Formula intermediate Fat absorption was the Infants fed the beta
RCT predominant formula infants (0–5 weeks palmitic acid, 66% (24% palmitic acid, highest in infants fed formula produced a
on fat, fatty acid, and of age) esterified to b- 39% esterified to the the beta formula, smaller amount of
mineral balance position; Betapol) b-position) and intermediate in those feces than regular
regular formula fed with the formula group.
(20% palmitic acid; intermediate formula, Consistency and the
13% esterified to the and lowest in infants color of the feces was
b-position) receiving the regular significantly different
formula. Fecal Ca among the groups. In
excretion was the beta group, 2
significantly lower in infants had soft feces, 6
the beta group than in had runnysoft feces,
the other 2 groups and none had hard
stools. All had yellow

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feces
 TABLE 2. Continued
SN-2-palmitate (beta-palmitate) studies

First author, Ref. Study Type of Duration of


Clinical outcome year No. Country design Sponsor sponsoring Study aim Population intervention Intervention Comparison Primary outcome Secondary outcomes

Lambidou et al, 2016 (42) Germany RCT No industry U Fecal excretion of FA 40 term infants 6 weeks Infant formula with Breastfed infants; Breastfed infants showed The results for the safety
sponsor soaps and total FA in increased SN-2 infants fed regular lower fecal excretion parameters body
declared infants fed with regular palmitate formula of FA soaps and total weight and head
infant formula, SN-2 FA than infants fed circumference showed
palmitate enriched with regular infant no differences among
formula and breastfed formula. However, the groups
infants increasing SN-2
palmitate in infant
formula did not reduce
stool total FA soaps,
palmitate soaps and
total FA
Lopez-Lopez (43) Spain Blinded RCT Fundacio’ Bosch i G The influence of dietary 36 term 2 months Group B—formula Group A— human Feeding with SN-2- The anthropometric
et al, 2001 Gimpera, PA-TAG position on infants ‘‘a’’ (19% PA in milk (66% PA in predominant formula parameters were not
Laboratorios the FA, Ca, and Mg SN-2-position) for SN-2-position) reduced significantly significantly different
Ordesa, CeRTA contents of at term 2 months and Group the contents of total FA between the 3 groups
newborn faeces C - formula ‘‘a’’ and PA in faeces. throughout the study
during the first Faecal calcium in
month and with groups A and C had
formula ‘‘b’’ (44.5% diminished at 1 month
PA in SN-2- whereas in group B, it
position) during the remained virtually
second month unchanged
(Betapol)
Lucas et al, 1997 (44) UK Blinded RCT Wyeth/Unilever E, S Effect of infant formula 24 preterm infants 3 weeks Formula containing 2 comparison diets SN-2 palmitate No differences between
containing synthetic (less than 1500 g and 74% of SN-2 (8.4% and 28% SN- predominant formula diet groups were found
structured TAG on less than 35 weeks of palmitate (Betapol) 2 palmitate, improved palmitate for steady state gains in
palmitate, total fat, and gestation) respectively) absorption, reduced the weight, length, or head
Ca absorption and Ca formation of insoluble circumference during
soap formation in the Ca soaps in the stool the whole period on the
gut and improved Ca assigned diets. The
absorption. infant’s sex was found
to be unrelated to PA
absorption, other
individual or total FA
absorption, soap
excretion or fractional
Ca absorption.
Yaron et al, 2013 (45) Israel RCT Enzymotec E, G Effect of high SN-2- 36 term infants 6 weeks High SN-2-palmitate Breastfed (BF group) The HBP and BF groups At 6 weeks, no significant
palmitate infant formula (HBP and low SN-2- had higher differences in weight
formula on the group; 44% beta- palmitate (LBP Lactobacillus and and length were
intestinal microbiota of palmitate from group, 14% beta- bifidobacteria counts observed between the 2
term infants structured PO) palmitate, based on than the LBP group formula-fed groups;
(INFAT) not standard unmodified (P < 0.01). The however, the head
containing pre- or PO; N ¼ 8) formula Lactobacillus counts at circumference was
probiotics not containing pre- 6 weeks were not lower in the HBP group
or probiotics significantly different than in the BF group

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between the HBP and (P ¼ 0.019). z scores
BF groups for weight, length, and
head circumference
were found to be within
the normal growth
range
 TABLE 2. Continued
SN-2-palmitate (beta-palmitate) studies

First author, Ref. Study Type of Duration of


Clinical outcome year No. Country design Sponsor sponsoring Study aim Population intervention Intervention Comparison Primary outcome Secondary outcomes

Infantile colics Litmanovitz et al, 2014 (46) Israel DB-RCT Enzymotec E Effect of high beta- 63 healthy 12 weeks Formula with high SN- Regular formula with a The percentage of crying Stool frequency and
palmitate formula on term infants 2-palmitate (HBP) standard vegetable infants in the LBP consistency was
crying in term infants (INFAT) oil mix (LBP); group was significantly comparable in both
breastfed (BF) higher than that in the formula groups. The
infants HBP and BF groups BF infants had
both at weeks 6 and 12 significantly higher
(both P < 0.05). The stool frequencies and
infants fed HBP had softer stools than the
significantly shorter infants in both the
crying durations when formula groups at both
compared with LBP 6 and 12 weeks
group (P ¼ 0.047). postnatal. At 12 weeks,
a significant reduction
in hard stools was
observed for the HBP
group but not the LBP
group
Savino et al, 2003 (47) Italy Observational Unknown U Effect of high SN-2- 604 infants with minor 2 weeks Formula containing None Rreduction in frequency Reduction in frequency of
prospective palmitate formula on gastrointestinal fructo- and galacto- of colic (P < 0.005) regurgitation (P <
multicentre minor feeding problems fed up to oligosaccharides, occurred 0.005) and increase in
uncontrolled study problems 90 days of age by study partially hydrolyzed the daily number of
formula proteins, low levels stools in constipated
of lactose, high SN- children (P < 0.005)
2-palmitate and occurred
higher density
Savino et al, 2006 (48) Italy Single-blinded Numico G Effect of partially 267 infants below 2 weeks Partially hydrolyzed Standard formula and Reduction of crying None reported
RCT hydrolyzed formula, 4 months of age formula, with high simethicone episodes (both after 1
with high SN-2- SN-2-palmitate and 2 weeks) in infants
palmitate content and a content and a fed experimental
mixture of galacto and mixture of galacto formula when
fructo- and fructo- compared with
oligosaccharides on oligosaccharides standard formula and
reduction of crying simethicone
episodes related to (P < 0.0001)
infantile colic
Stool frequency and Bongers et al, 2007 (49) Netherlands DB-RCT, Nutricia G Evaluation of a new 38 constipated term 3 weeks þ Formula containing Whey-based control Feeding with formula Throughout the study,
consistency crossover infant formula in term infants (3–20 weeks of cross-over high concentration formula (11.5% SN- containing high there were no serious
infants with age) follow-up of SN-2 palmitate 2 palmitate) partly concentration of SN-2- adverse effects in
constipation (41%), a mixture of mixed with a palmitate significantly either group. Both
prebiotic formula based on increased defecation formulas were well
oligosaccharides hydrolyzed whey frequency (but there tolerated. Weight gain
and partially protein was no difference to was similar in both
hydrolyzed whey standard formula [SF]) feeding groups
protein and had a trend to
softer stool consistency
when compared with
SF. No difference was

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found in painful
defecation or the
presence of an
abdominal or rectal
mass between the 2
groups
 TABLE 2. Continued
SN-2-palmitate (beta-palmitate) studies

First author, Ref. Study Type of Duration of


Clinical outcome year No. Country design Sponsor sponsoring Study aim Population intervention Intervention Comparison Primary outcome Secondary outcomes

Nowacki et al, 2014 (50) USA DB-RCT Nestlé E, G Effect of infant formulas 165 healthy term infants 4 weeks Formula containing Control formula (CF); Stool consistency score at The parent assessment of
containing high SN-2 (25–45 days of age) high SN-2 palmitate formula containing day 28 of the SN-2 and GI tolerance was
palmitate with or plus 3 g/L of high SN-2 palmitate OF group was lower similar across all
without oligofructose prebiotic (SN-2); human than CF and SN-2 groups and the GI
on stool fatty acid oligofructose (SN- milk-fed group (P < 0.0001), but burden of each of the
soaps, stool 2þOF) (HM) higher than the HM-fed study feedings was
consistency and group (P < 0.0001), low. All FF infants had
gastrointestinal moreover, SN-2 group urine osmolality and
tolerance in term was not different from specific gravity values
infants CF. SN-2 group had within the normal
lower stool palmitate range
soaps compared with
CF (P ¼ 0.0028) and
SN-2 þ OF group had
reduced stool palmitate
soaps, total soaps and
Ca compared with both
CF and SN-2 (all
P < 0.0001). The HM-
fed group had lower
stool palmitate soaps,
total soaps and Ca (all
P < 0.0001 for each
comparison) than all
formula-fed groups
Yao et al, 2014 (51) USA DB-RCT Nestlé/Wyeth E, G Effects of high SN-2 300 healthy term 8 weeks High SN-2 palmitate Bovine milk-based At week 8 the SN-2 group At weeks 4 and 8, no
palmitate infant infants (7–14 formula (40% beta- term formula with a had 46% less stool soap differences were
formulas with and days of age) palmitate) 100% vegetable fat palmitate (P < 0.001) observed in GI
without oligofructose (Betapol); SN-2þ3 blend; human milk- and softer stools than tolerance among any of
on stool composition, g/L OF—a high SN- fed group (HM) controls. Addition of the feeding groups
stool characteristics, 2 palmitate formula resulted in even fewer after adjusting for
and bifidogenicity supplemented with formed stools versus baseline scores. Mean z
3.0 g/L oligofructose controls. HM group scores for weight-for-
(OF); SN-2þ5 g/L had lowest stool Ca at age, length-for-age,
OF—a high SN-2 week 8, OF groups had head circumference-
palmitate formula lower Ca than SN-2 for-age, and weight-
supplemented with group. both SN-2 for-length were similar
5.0 g/L OF (P < 0.05) and SN-2 across all feeding
with OF groups groups
(P < 0.01) had
significantly higher
fecal bifidobacteria
concentrations than
controls at week 8, not
differing from HM-fed
infants

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 TABLE 2. Continued
SN-2-palmitate (beta-palmitate) studies

First author, Ref. Study Type of Duration of


Clinical outcome year No. Country design Sponsor sponsoring Study aim Population intervention Intervention Comparison Primary outcome Secondary outcomes

Bone health Civardi et al, 2017 (52) Italy DB-RCT Heinz Italia E, S, G Effect of infant formula 51 term 135 days Formula enriched with Standard formula (SF) Infants fed the Infants fed the
and growth S.p.A. enriched with neonates galacto- based on vegetable experimental formula experimental formula
functional compounds oligosaccharides (7 oils (including soya had comparable growth had higher increase of
on safety, growth, and g/L), SN-2- oil) and whey (length, weight, head bifidobacteria faecal
support to healthy gut palmitate (PA was protein (enriched in circumference) to the counts.
microbiota 60% of total FA, alphalactalbumin) group receiving Gastrointestinal
whose 39% were standard formula adverse effects,
esterified at the SN-2 intestinal gas, bowel
position) and cramp,s and the mean
acidified milk number of stools per
(representing 50% day were comparable
of the whole milk in between the 2 groups
the formula)
Fewtrell et al, 2013— (53) UK Unblinded MRC UK and EU; G Long-term effects of Traceable subjects 10 years Formula containing Standard formula Previously breastfed The control formula
unblinded follow-up follow-up original RCT (54) formula containing from original cohort 50% SN-2 palmitate containing 12% SN- children had lower subjects had
of RCT by Kennedy of RCT sponsored by synthetic TAG on bone (57 formula-fed (Betapol) 2 palmitate. Both lumbar spine BMD significantly higher
et al, 1999 (54) Nutricia mineralization and 34 breastfed) formulas contained SDS (by 0.44, weight SDS than the
evaluated by DEXA similar salts, P ¼ 0.03), but size- breastfed subjects, with
including Ca salts. adjusted bone mass did intermediate values for
The control formula not differ. There were the high SN-2 group.
had slightly less fat no significant There were neither
(39 vs 42 g/L); differences in bone significant differences
breastfed group mass between the between the groups in
formula-fed groups the number of children
who reported a
previous fracture, nor
in estimated current
daily Ca intake
Kennedy (54) UK DB-RCT Nutricia S Effects of formula 323 healthy term 3 months Formula containing Standard formula Infants fed formula The stools of infants
et al, 1999 containing synthetic neonates 50% SN-2 palmitate containing 12% SN- containing 50% SN-2 receiving the high–
TAG on stool (Betapol) 2 palmitate. Both palmitate had higher SN-2 formula
biochemistry, stool formulas contained (but similar as breast- contained less total FA
characteristics, and similar salts, fed infants) whole- (P ¼ 0.013), however
bone mineralization including Ca salts. body BMC, evaluated there were no
The control formula by DEXA, softer stools significant differences
had slightly less fat at 6 and 12 wk, and a for the nonsoap FA. A
(39 vs 42 g/L); lower proportion of greater proportion of
breastfed group stool soap FA than the mothers using the
infants fed standard high–SN-2 formula
formula. were concerned about
runny stools and
reported more colic at
the age of 3 wk.
Duration of crying was
not significantly
different. Among the
formula-fed infants,

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there were no
significant differences
in anthropometry
throughout the study.
There were no
significant differences
in respiratory tract
infections, visits to the
family doctor, hospital
outpatient visits, or
hospital admissions.
 TABLE 2. Continued
SN-2-palmitate (beta-palmitate) studies

First author, Ref. Study Type of Duration of


Clinical outcome year No. Country design Sponsor sponsoring Study aim Population intervention Intervention Comparison Primary outcome Secondary outcomes

Litmanovitz (55) Israel DB-RCT Enzymotec E Effect of high beta- 83 term infants 3 months High SN-2 palmitate Regular formula (14% The mean bone SOS Anthropometric data
et al, 2013 palmitate formula on formula (43% of PA of PA on SN-2 (speed of sound during study visits
bone strength in term on SN-2 position; position; LBP measured by showed no significant
infants HBP group) group) based on quantitative differences between
(INFAT) based on standard vegetable ultrasound) of the HBP the 2 formula groups.
standard vegetable oil mix of PKO, group was significantly There was a 2-fold
oil mix of PKO, rapeseed oil, higher than that of the difference in maternal
rapeseed oil, sunflower oil, and LBP group (P ¼ 0.049) smoking between the 2
sunflower oil, and PO or structured PO; and comparable with formula groups (not
PO or structured PO breastfed group that of the breast-fed statistically
group significant)—in further
analysis not found to
affect the change in
bone SOS.
Schmelzle (56) Germany DB-RCT Numico E, G Evaluation of nutritional 154 term infants 3 months Infant formula (NF) Standard formula (SF) During the first 6 weeks, The NF stools had a
et al, 2003 efficacy and (0–2 weeks containing partially not containing NF girls gained more higher proportion of
bifidogenicity of a new of age) hydrolyzed whey hydrolysed protein weight and head bifidobacteria at
infant formula protein, modified or prebiotic circumference than the 6 weeks compared with
containing partially vegetable oil with a oligosaccharides SF girls. These velocity the SF stools, and they
hydrolyzed protein, a high (41%) SN-2- differences were not were softer. Both
high beta-palmitic acid palmitate content, maintained throughout formulas were well
level, and prebiotic the 12-week study tolerated
nondigestible oligosaccharides, period
oligosaccharides and starch
Metabolic effects Nelson et al, 1999 (57) Canada RCT Ross S, G Effect of positional 87 full term 4 months Experimental formula Standard formula (SF) Infants fed EF, SF, or There were no significant
distribution of fatty infants (EF) (fatty acid (48% of total fat as breast milk had 15.8%, differences in the
acids in infant formula composition similar POL, 26% as 8.3%, and 28.0% 16:0 weight, length, or HC
triacylglycerols on to SF, but made with soybean oil, 14% as in the chylomicron between the 3 groups
plasma lipoprotein synthesized TAG high-oleic acid sun- triacylglycerol 2 during the whole
fatty acids with 30% SN-2- flower oil, and 12% position (P < 0.05). follow-up (120 days)
palmitate) as coconut oil); Infants fed EF had
(Betapol1) breastfed group significantly lower
HDL-cholesterol and
apo A-1 and higher apo
B concentrations than
SF group
Innis et al, 2013 (58) Canada RCT No industry sponsor U Effect of dietary TAG Healthy infants 120 days Formula containing Formula containing Higher formula SN-2 led None reported
declared rich in SN-2 palmitate (120 days 25%–27% 16:0 with 25–27% 16:0 with to lower n-9-MUFA,
on post-prandial of age) 29% 16:0 at the 5% 16:0 at the TAG but higher n-6-PUFA
lipoprotein and TAG SN-2 position SN-2 position; and n-3-PUFA in the
unesterified fatty acids Breastfed group infant plasma, higher
in term infants 18:0 in LDL TAG, and
higher apo B and lower
apolipoprotein A-1
(apo A-1).

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apo B ¼ apolipoprotein B; FA ¼ fatty acids; HBP ¼ high beta palmitate formula; LDL ¼ low-density lipoprotein cholesterol; PA ¼ palmitic acid; RCT, randomized controlled trial.

Type of sponsoring: E ¼ one of co-authors of the study was employee of the industry; S ¼ study product supplied by industry; G ¼ study supported by grant from/sponsored by industry; U ¼ unclear role of sponsor.
JPGN  Volume 68, Number 5, May 2019 Palm Oil and Beta-palmitate in Infant Formula

anthropometric measurements between PO/POL group and PO/ Bone Health and Growth
POL-free group.
Four RCTs (one of them with unblinded follow-up) in
Metabolic Effects healthy term infants were identified (52–56). Two of the studies
were focused on bone health and both have shown short-term
No relevant intervention studies were found focused primar- positive effects of SN-2-palmitate formula on bone parameters—
ily on the effect of PO/POL-containing formula on predictors bone mineral content (BMC) and mean bone speed of sound (SOS)
(markers) of metabolic diseases (cardiovascular health, T2DM, at week 12 (54,55), however, unblinded follow-up of 28% of the
hypertension, etc) in infants and children. Two RCTs were identi- original cohort until 10 years of age did not show long-term
fied that focused on lipid profile in healthy infants with several persistence of this effect (53). The other 2 studies focused on
months of follow-up (36,37). A lower serum TAG level at day 90 in anthropometric parameters and did not show any significant differ-
the non-POL group when compared with the POL-group was found ence at week 12 and/or 135 days of follow-up, respectively,
in the first study but there was no difference in TAG levels when between SN-2-palmitate and control formulas. The experimental
compared with a human milk group in any of the formula groups formula in both studies was enriched also with prebiotic oligosac-
(37). In the other study, infants consuming POL-based follow-up charides, and in one of the studies also contained partially hydro-
formula had lower increases in mean serum total cholesterol, LDL, lyzed protein, in the other study acidified milk (52,56).
and apo B by 12 months of age compared with infants ingesting the
standard infant formula or whole cow milk (36). Metabolic Effects
SN-2-palmitate (Beta-palmitate) Studies No relevant intervention studies focused primarily on the
effect of SN-2-palmitate formula on predictors (markers) of meta-
Composition of Stool (Fatty Acid and Calcium bolic diseases (cardiovascular health, T2DM, hypertension, etc) in
Content, Intestinal Microbiota) infants and children were found. Two studies on healthy term
Altogether 8 RCTs were identified on this topic (38–45), 3 infants that focused on lipid profile were identified.
of them on preterm infants (39,40,44), the rest on term infants The first RCT showed higher (closer to breastfed group)
(see Table 2). The study by Carnielli et al (39) was a subanalysis content of C16:0 FA in the SN-2 position of chylomicron TAG in
of a study previously published by the same group (40). The infants fed SN-2-palmitate formula when compared with standard
studies have consistently shown that a higher SN-2-palmitate formula (57). In the other study, higher formula SN-2 led to lower n-
proportion in formula is associated with improved absorption of 9-MUFA, but higher n-6-PUFA and n-3-PUFA in the infant plasma,
Ca and fat, including palmitate. Only 1 study, presented as a higher C18:0 in LDL TAG, and higher apo B and lower apolipo-
congress abstract only, did not show any reduction in stool total protein A-1 (apo A-1) (58).
FA soaps, palmitate soaps, and total FA when increasing SN-2
palmitate in infant formula (42). One study has shown higher DISCUSSION
Lactobacillus and Bifidobacteria counts in the stool in high SN- In cow milk and infant formulas, PA predominantly found in
2-palmitate group when compared with low SN-2-palmitate the SN-1 and SN-3 positions is hydrolyzed by pancreatic lipase and
group (45). the resulting free PA may form Ca-FA complexes, which are poorly
absorbed—this was previously confirmed by experiments in
Infantile Colic rodents and piglets (54,59–65). The overall efficacy of fat absorp-
tion gradually increases both in preterm and term infants postnatally
One DB-RCT, 1 single-blinded RCT, and a large uncon- reflecting the functional development of the gut (66).
trolled observational study were identified, all in term infants (46– Several studies have shown that PO, as the predominant fat
48). The DB-RCT tested the effect of SN-2-palmitate alone (46), source, or PA present predominantly on SN-1,3 position, may
whereas the other studies used multiple interventions—partially negatively influence absorption of Ca and FA from infant formulas
hydrolysed SN-2-palmitate formula containing fructo-oligosac- (26–30), and SN-2 palmitate positioning has generally an opposite
charides and galacto-oligosaccharides (47,48). All studies have effect (38,40,41,43–45). One study presented as a congress abstract
shown a reduction of crying episodes/frequency of colic, when did not show any effect of SN-2 palmitate on reduction in stool total
SN-2-palmitate formula was used. FA soaps, palmitate soaps, and total FA (42). Despite varying
quality of the studies, there is generally convincing evidence of
Stool Frequency and Consistency differences in PA digestion and absorption related to positioning of
PA on the TAG. No clinical conclusions can be directly made from
Three DB-RCTs were identified, all in term infants (49–51). these findings, but such changes may be relevant to underlying
All of the studies used not only SN-2-palmitate, but also prebiotic physiological mechanism for some clinical conditions, such as
oligosaccharides as the intervention, moreover, one of them used infantile colic or constipation and explain the observed effects
partially hydrolyzed protein formula (49). The first study showed on bone health. Moreover, different structure of TAG in infant
significantly increased defecation frequency and a trend to softer formulas may influence intestinal microbiota, but the number of
stools in the intervention arm, but there was no difference compared studies is limited and no clinically relevant conclusions are possible
with standard formula (49). The second study did not show any at the moment (45,51,52,56).
difference from the control group when only SN-2-palmitate for- There are 2 RCTs published so far on the effect of high SN2-
mula was used, however, the stool consistency score was signifi- palmitate formula on crying episodes in infantile colic (46,48). The
cantly lower at day 28 when both SN-2-palmitate and oligofructose- first study did not only evaluate the effect of SN-2-palmitate as the
enriched formula was used (50). In the third study, the SN-2- study formula also contained hydrolyzed protein, a mixture of
palmitate group had significantly softer stools than controls at galacto- and fructo-oligosaccharides, and had different whey/casein
week 8. Addition of oligofructose resulted in even fewer formed ratio and carbohydrate content than control formula. Simethicone
stools (51). was added to standard formula in the control group. Whether the

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Bronsky et al JPGN  Volume 68, Number 5, May 2019

clinical effect was because of the PO content is, therefore, unclear always be perceived positively by mothers. In the study by Kennedy
(48). In the second study, the formulas differed only in SN-2- et al (54), a greater proportion of the mothers using the high SN-2
palmitate content and a reduction in crying was observed. No pre- or formula were concerned about runny stools at the age of 3, 6, and 12
probiotics were used (46). Possible beneficial effects on infant colic weeks. The difference was not seen in the small group of infants
and other minor gastrointestinal problems were described in a large who had started solids by 12 weeks but continued to receive the
observational prospective trial; however, the study formula con- study formula. According to a recent consensus paper, a partially
tained fructo- and galacto-oligosaccharides, partially hydrolyzed hydrolyzed infant formula with prebiotics and SN-2-palmitate may
proteins and low levels of lactose apart from the SN-2-palmitate, be considered as a dietary intervention for functional constipation in
and there was no control group (47). These findings are promising, formula-fed infants (67).
but more data from well-designed RCTs are needed in order to draw For the effect of PO/POL on bone health, the same patho-
conclusions on the effect of SN-2-palmitate in infant colic. In some physiological background as for stool consistency changes was
of the studies not primarily focused on colic, minor GI problems suggested (formation of Ca-FA complexes leading to poor Ca
(spit up, vomiting, ‘‘GI intolerance’’) were evaluated as secondary absorption). In an animal model, levels of intestinal calbindin-
outcomes (29,31,32,34). No difference was found between inter- D9k (vitamin D-dependent Ca-binding protein) mRNA expression
vention and control group in any of the studies. Moreover, mea- was higher in piglets fed PO-based formula when compared with
surement of the primary outcome in trials focused on infant colic is formula with SN-2 predominant synthetic TAG (72). BMC, bone
often subject to discussion as it is very difficult to find an objective area (BA), and cortical BA in femur were lower (P ¼ 0.002,
measurement for ‘‘crying episodes’’ and researchers have to rely on P ¼ 0.005, and P ¼ 0.02, respectively) in piglets fed human milk
subjective evaluation by parents using various questionnaires. fat substitute with a modified TAG structure holding C16:0 pre-
According to a recent consensus paper, limited data suggest that dominantly in the SN-2-position compared with a control (63).
infant formula with a partial hydrolysate, galacto-oligosaccharides/ In healthy infants, average BMC and bone mineral density
fructo-oligosaccharides and added SN-2-palmitate may be of ben- (BMD) significantly increases during infancy, and body size is the
efit in reducing infantile colic in formula-fed infants in cases where dominant predictor of bone mineral status (73). Reference values of
cow’s milk protein allergy is not suspected (67). body composition obtained by DEXA both in preterm and term
Previously, it was reported that formula-fed infants have neonates were published (73–75); however there is a large variation
harder stools than breastfed infants. Ca and FA soaps were the in published normative data for BMC and BMD of both human
dominant factors significantly related to stool solids and hardness milk-fed and formula-fed infants (76).
score across the breastfed and formula-fed groups (68). Vandenplas Jones et al (77) have shown in a longitudinal observational
and Salvatore (69) in their review on functional gastrointestinal cohort study (N ¼ 330) a positive association between breast-feed-
disorders in infants state that harder stools are frequent in infants fed ing in early life (particularly for 3 months or longer) and bone mass
formula containing POL or PO as the main source of fat. A large in 8-year-old children born at term. Schanler et al have shown that
observational study and a RCT with 2 sub-studies were published on although predominantly formula-fed preterm infants had signifi-
this topic (having stool frequency or consistency as primary out- cantly greater BMC values at 16, 25, and 52 weeks, if the predomi-
come) suggesting that POL content in infant formulas may be nantly human-milk fed infants continue to receive human milk,
responsible for this phenomenon (31,32). However, in the observa- radius BMC will ‘‘catch-up’’ to that of similar infants given formula
tional study, the 2 formulas differed also in other components (ratio in the posthospitalization period (78). On the contrary, some studies
of other oils, Ca and nucleotides content) (31). Also in the RCTs, find that human milk-fed infants have lower bone accretion than do
tested and control formulas differed in other aspects (eg, whey:- formula-fed infants (with greater bone accretion when the mineral
casein ratio, content of nucleotides) (32). content of formula is higher).
A recent meta-analysis of RCTs indicated that infants fed Inclusion of PO in infant formula may be responsible for
POL-free formulas had significantly softer stools (difference in reduced bone mineral accretion, but other factors play a role, like
Mean Rank Stool Consistency score 0.355, 95% CI of 0.472 to maternal nutritional status (vitamin D, Ca) during pregnancy, type
0.239, P < 0.001) than infants fed POL-predominant formulas. of infant feeding, Ca and phosphorus content of infant formula,
However, stool frequencies were similar between both groups infant vitamin D supplementation, diet, and physical activity during
(P ¼ 0.6). Studies included in the meta-analysis had many differ- the toddler and preschool years (79). A small RCT on 67 infants
ences in study design, infant age, formula types, and composition. indicates that during the first 6 months, bone mass accretion is lower
The meta-analysis did not include clinical data from infants fed in infants fed human milk or low-mineral (Ca and phosphorus)
human milk or SN-2-palmitate (70). Stool frequency and/or con- formula compared with infants fed moderate-mineral formula.
sistency was also mentioned as a secondary outcome in other However, the human milk-fed group had greater bone mass accre-
studies (26,29,33,34). Conclusions from these studies generally tion during the second 6 months and by 12 months of age, there were
support the hypothesis that PO/POL content in formula may be no differences among the feeding groups (80).
associated with harder stools. A RCT by Koo et al (35) showing that infants fed PO-based
Several studies on the effect of SN-2-palmitate on stool formula had significantly lower BMC and BMD at 3 and 6 months
consistency or frequency have been published (49–51). The study than PO-free formula was challenged in 2004 by Clandinin et al (76)
by Bongers et al (49) did not show significant difference in the because of lack of inclusion of a human milk control group. Infants
effect of SN-2 formula on stool frequency in constipated infants. fed human milk have BMC and BMD values well below either of
However, the authors used 3 different interventions at once (par- the 2 study formulas and all are well within published normative
tially hydrolyzed protein, SN2-palmitate, and prebiotics) and the values at both 3 and 6 months of age (the same is valid for the PO-
study was considered to be underpowered for its outcomes (71). based formula group after intervention). This questions the clinical
Two studies showed positive effect of SN-2-formula on stool significance of the data, as it is not clear whether bone mineral
consistency, which seemed to be enhanced by adding prebiotic accretion higher than that found in breastfed infants is beneficial
oligofructose (50,51). Stool consistency or frequency is also (76). Another RCT has shown higher BMC and greater 25-OH
reported as one of the outcomes in other studies on Ca/FA balance, vitamin D serum levels in children fed PO-free formula when
bone health and growth, with conflicting results on the effect of SN- compared with PO formula. However, the PO formula contained
2-palmitate (40,41,46,47,52). Moreover, softer stools may not less Ca than the PO-free formula (34). A retrospective study that

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JPGN  Volume 68, Number 5, May 2019 Palm Oil and Beta-palmitate in Infant Formula

related DEXA performed at 4 years of age (N ¼ 178) with type of of fat in formula does not seem to play a role. In another study,
infant feeding identified by history has shown no significant plasma lipid percentages of C18:1 and C18:2n-6 were higher in
differences in BMC or BMD (P ¼ 0.51 and 0.89, respectively) piglets fed formula with medium chain triglyceride or coconut oil
among children who had exclusively consumed human milk rather than formulas with C16:0 (from PO or synthesized triglycer-
(n ¼ 57), an infant formula containing no PO (n ¼ 56) or an infant ide containing predominantly sn-2 C16:0), or sow milk, although
formula containing PO (n ¼ 65) during the first 4 months of life the formulas contained similar C18:1 and C18:2n-6 (88).
(81). This study was criticized because of its methodology (retro- In the study by Innis et al, only TAG levels at day 90 were
spective nature not controlling for many potential confounders, lower in POL-free formula than in POL formula; however, neither
possible variability in measurement, and underpowered sample of the groups had different TAG levels when compared with breast-
size) (82). The authors’ reply to this criticism was that their study fed infants. Moreover, the study was primarily focused on the effect
was designed to detect a difference of 0.52 SD of bone mineral of n-6 and n-3 FA on growth, visual acuity, and lipid profile in
content between feeding groups (82). A systematic review by Koo infants. Thus, no direct conclusions can be made on metabolic
et al included 9 publications with non-PO and PO comparison effects of POL by itself (37). The RCT by Fuchs et al has shown that
groups in infants between 28 and 42 weeks of gestational age and up older infants fed lower fat formula have adequate total energy intake
to 192 days at study onset. The standardized results were consis- and normal growth and that the fat composition of the diets
tently significantly (P < 0.05) positive in favour of the feeding with influenced serum lipid and lipoprotein profiles. The design of
non-PO formulas with respect to increased intestinal fractional the study, however, does not allow any POL-specific conclusions,
absorption of fat, PA and Ca and significantly higher BMC. The and POL as source of dietary fat may not necessarily be fully
authors conclude that avoidance of PO or its substitution with responsible for the above-mentioned metabolic changes (36).
synthetic TAG in infant formulas can prevent this detrimental Results of an RCT by Nelson and Innis (57) suggest that at least
effect (83). 50% of the dietary SN-2-palmitate is conserved through digestion,
Although a large RCT has shown possible short-term effects absorption, and chylomicron TAG synthesis in breastfed and for-
of SN-2-rich formula on bone health in infants (54), in an open-label mula-fed infants. In another study by Innis et al (58), postprandial
extension of part of the original cohort, no significant effect was lipoprotein and unesterified FA levels in term infants were different
shown by DEXA at 10 years of age (53). Thus, it is questionable if in children fed SN-2-predominant formula compared with low-SN-
the effect of high-SN-2 is long lasting. Another RCT has shown that 2 formula.
palmitic structural distribution may influence (with borderline
statistical significance) mean bone speed of sound (SOS; a measure
of bone density, microarchitecture, cortical thickness, and elastic- SUMMARY
ity) in term infants (55). In contrast, it has been suggested that SOS Despite available data on potential benefits of SN-2-palmi-
changes during infancy may be independent of the type of early tate and potential nonbeneficial effects of PO/POL used in infant
diet (84). formulas (3,89,90), the current evidence remains inconsistent and
A meta-analysis by Yu et al (85) (article in Chinese, only does not allow definite conclusions to be drawn. Published studies
abstract evaluated by authors of this position paper) analyzed the have variable methodology, differ in subject characteristics, and
effect of infant formula containing PA at the SN-2 position, formula some of them are underpowered for the key outcomes. Many of the
containing PA at the SN-1, 3 positions and formula without PA on studies combine different interventions, such as partially hydro-
nutrient absorption, BMC, and and stool consistency in infants. lyzed protein, prebiotic oligosaccharides, and in some studies
Absorption of fat and Ca was lower, faecal excretion of Ca was experimental and control formula differ in other aspects-like protein
higher, the BMC was reduced, and the incidence of hard stools was source and composition, carbohydrates, or mineral content.
increased when the infant formula provided PA at the SN-1 and SN- Changes in Ca and PA absorption have been reported that may
3 positions as compared with formula with PA at the SN-2 positions represent the physiological background for some clinical situations,
or without PA. However, the authors stress that the conclusions such as infantile colic, constipation, or lower BMC and BMD. PO/
should be used with caution because of the limited quality of POL seem to be associated with harder stools, on the contrary, SN-
evidence (85). 2-palmitate use may lead to softer stool consistency. Bone effects
Published studies that did not include growth as primary seem to be short-lasting. For some of the outcomes (infant colic,
outcome (26,33–38,43–45,51,52,54–57) did not show any signifi- faecal microbiota, lipid metabolism), the number of studies is very
cant differences between PO/POL/SN-2-palmitate base formulas limited and summary evidence inconclusive. There are no studies
and controls. In an animal experiment, a small but significant published on the effect of PO/POL/SN-2 in infant formulas and
improvement in most growth parameters was found in the rats long-term outcomes/markers of later diseases (CVD, T2DM, obe-
fed beta-palmitate-based diet when compared with controls (86). sity, hypertension, cancer, or long-lasting changes in lipid profile).
No human intervention studies focused primarily on the Growth and infant health-related quality of life seems not to be
effect of PO/POL/SN-2-containing formula on biomarkers of met- influenced irrespective of PO/POL/SN-2 content of the formula
abolic diseases (cardiovascular health, T2DM, hypertension, etc) as (91). The majority of the studies are supported by (or performed by
the primary outcome in infants and children were identified. Scarce employees of) infant formula producers. Moreover, in several
data are available on lipid metabolism both from animal and studies, high SN-2 palmitate formula remains inferior to breast
human studies. feeding. Thus, because of the lack of high-quality evidence and
One study using a piglet model showed that mRNA levels of inconsistency in the findings of the studies presented here, current
hepatic hydroxymethylglutaryl coenzyme A (HMG-CoA) reduc- guidelines do not mandate the inclusion of high SN-2 palmitate in
tase, and 7alpha-hydroxylase (C7H) are higher (P < 0.05) and infant formulas (92,93). EFSA successively rejected 2 health claim
plasma total, HDL, and apo B-containing cholesterol are lower petitions for beta-palmitate in 2011 and 2014, respectively
(P < 0.05) in formula-fed versus milk-fed piglets, irrespective of the (3,94,95). There are also other potential health benefits of high
formula TAG source (POL vs synthesized SN-2 predominant dietary SN-2 palmitate suggested in animals, like reduced
TAG). There was no difference in LDL receptor mRNA levels gut inflammation in a colitis model and altered tissue endocanna-
(87). This study shows that important components of lipid metabo- binoid concentrations (7,96,97) that warrant further scientific
lism are altered by early diet in an animal model, but POL as source attention.

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Bronsky et al JPGN  Volume 68, Number 5, May 2019

CONCLUSIONS AND RECOMMENDATIONS 12. Berraaouan A, Abid S, Bnouham M. Antidiabetic oils. Curr Diabetes
On the basis of the available data, the ESPGHAN Committee Rev 2013;9:499–505.
on Nutrition: 13. Teng KT, Chang CY, Chang LF, et al. Modulation of obesity-induced
inflammation by dietary fats: mechanisms and clinical evidence. Nutr J
1. concludes that inclusion of high SN-2-palmitate fat blend in 2014;13:12.
infant formulas may have short-term effects on stool 14. Odia OJ, Ofori S, Maduka O. Palm oil and the heart: a review. World J
Cardiol 2015;7:144–9.
consistency because of reduced formation of calcium soaps,
15. Fattore E, Bosetti C, Brighenti F, et al. Palm oil and blood lipid-related
but cannot be considered essential, markers of cardiovascular disease: a systematic review and meta-
2. concludes that there is insufficient evidence to suggest that PO/ analysis of dietary intervention trials. Am J Clin Nutr 2014;99:1331–50.
POL should be avoided as a source of fat in infant formulas for 16. Bengmark S. Nutrition of the critically ill - emphasis on liver and
health reasons, pancreas. Hepatobiliary Surg Nutr 2012;1:25–52.
3. recommends that all producers of infant formulas take measures 17. Souganidis E, Laillou A, Leyvraz M, et al. A comparison of retinyl
to minimize levels of glycerol-based process contaminants in palmitate and red palm oil beta-carotene as strategies to address Vitamin
infant formulas. A deficiency. Nutrients 2013;5:3257–71.
18. Ahsan H, Ahad A, Siddiqui WA. A review of characterization of
tocotrienols from plant oils and foods. J Chem Biol 2015;8:45–59.
The ESPGHAN Committee on Nutrition recommends fur- 19. De Silva L, Chuah LH, Meganathan P, et al. Tocotrienol and cancer
ther research on: metastasis. Biofactors 2016;42:149–62.
20. Meganathan P, Fu JY. Biological properties of tocotrienols: evidence in
1. possible long-term health effects of PO/POL/SN-2-palmitate- human studies. Int J Mol Sci 2016;17:pii: E1682.
based infant formulas in well-powered RCTs, 21. Update of the risk assessment on 3-monochloropropane diol and its fatty
2. presence of nonessential trace elements and radionuclides in acid esters. EFSA 2018;16:5083.
PO, 22. Leigh J, MacMahon S. Occurrence of 3-monochloropropanediol esters
3. potential health benefits of high dietary SN-2 palmitate and glycidyl esters in commercial infant formulas in the United States.
suggested in animals, such as reduced gut inflammation in a Food Addit Contam Part A Chem Anal Control Expo Risk Assess
colitis model and altered tissue endocannabinoid concentra- 2017;34:356–70.
tions, 23. Scientific opinion on the risks for human health related to the presence
of 3- and 2monochloropropanediol (MCPD), and their fatty acid esters,
4. the potential beneficial/harmful effects of other compounds in and glycidyl fatty acid esters in food. EFSA 2016;14:426.
PO, like tocotrienols. 24. EFSA panel on dietetic products naa Commission Regulation (2018/
290) of 26 February 2018 amending Regulation (EC) No 1881/2006 as
regards maximum levels of glycidyl fatty acid esters in vegetable oils
and fats, infant formula, follow-on formula and foods for special
DISCLAIMER medical purposes intended for infants and young children. EFSA
ESPGHAN is not responsible for the practices of physicians 2018;61:64.
and provides guidelines and position papers as indicators of best 25. Olafisoye OB, Oguntibeju OO, Osibote OA. Trace elements and radio-
practice only. Diagnosis and treatment is at the discretion nuclides in palm oil, soil, water, and leaves from oil palm plantations: a
review. Crit Rev Food Sci Nutr 2017;57:1295–315.
of physicians.
26. Leite ME, Lasekan J, Baggs G, et al. Calcium and fat metabolic balance,
and gastrointestinal tolerance in term infants fed milk-based formulas
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