Long-chain PUFA supplementation in rural African infants:
a randomized controlled trial of effects on gut integrity, growth, and
Liandre ´ F van der Merwe, Sophie E Moore, Anthony J Fulford, Katherine E Halliday, Saikou Drammeh, Stephen Young,
and Andrew M Prentice
Background: Intestinal damage and malabsorption caused by
chronic environmental enteropathy are associated with growth fal-
tering seen in infants in less-developed countries. Evidence has
suggested that supplementary omega-3 (n23) long-chain PUFAs
(LC-PUFAs) might ameliorate this damage by reducing gastrointes-
tinal inflammation. LC-PUFA supplementation may also benefit
Objective: We tested whether early n23 LC-PUFA supplementation
improves infant intestinal integrity, growth, and cognitive function.
Design: A randomized, double-blind, controlled trial [200 mg DHA
and 300 mg EPA or 2 mL olive oil/d for 6 mo] was conducted in
a population of 172 rural Gambian infants aged 3–9 mo. The primary
endpoints were anthropometric measures and gut integrity [assessed
by using urinary lactulose:mannitol ratios (LMRs)]. Plasma fatty
acid status, intestinal mucosal inflammation (fecal calprotectin),
daily morbidity, and cognitive development (2-step means-end test
and an attention assessment) were secondary endpoints.
Results: PUFA supplementation resulted in a significant increase in
plasma n23 LC-PUFA concentrations (P , 0.001 for both DHA
and EPA) and midupper arm circumference (MUAC) (effect size:
0.31 z scores; 95% CI: 0.06, 0.56; P = 0.017) at 9 mo of age. At 12
mo, MUAC remained greater in the intervention group, and we
observed significant increases in skinfold thicknesses (P # 0.022
for all). No other significant differences between treatment
groups were detected for growth or LMRs at 9 mo or for second-
Conclusions: Fish-oil supplementation successfully increased plasma
n23 fatty acid status. However, in young, breastfed Gambian infants,
the intervention failed to improve linear growth, intestinal integrity,
morbidity, or selected measures of cognitive development. The trial
was registered at www.isrctn.org as ISRCTN66645725.
Clin Nutr 2013;97:45–57.
Chronic environmental enteropathy, which is characterized by
intestinal villous atrophy, crypt hyperplasia, and inflammatory
developing countries (1–7). Repeated exposure to a wide variety
of pathogenic organisms and allergens that are due to the in-
gestion of contaminated weaning foods and water are thought to
initiate this persistent inflammation of the gut, which leads to
intestinal damage and malabsorption (7–12). Mucosal injuries
that result from inflammatory responses are slow or resistant to
healing and repair and leave the gut vulnerable to additional
damage (9, 13). This decreased gut integrity, which is shown by
markedly and consistently raised lactulose:mannitol ratios
(LMRs)4in the dual-sugar permeability test (3, 4, 11), begins in
Gambian infants at w3 mo of age (when weaning foods are first
introduced) and is associated with the faltering in both height
and weight seen in these rural African children (3, 9). There is
evidence that supplementary n23 long-chain PUFAs (LC-
PUFAs) might reduce or delay this damage by reducing gas-
trointestinal inflammation (14–19), but this has not been tested
in an African population.
Meta-analyses of the effects of n23 PUFA interventions on
growth outcomes have been published for high-income countries
and concluded that there is no substantive evidence of a benefit
(20–23). However, the evidence base in respect to infants living
in low-income countries, where growth faltering is of much greater
concern, is exceptionally weak. We could not find any published or
registered trials in low- to middle-income countries that inves-
tigated the effects of LC-PUFA supplementation in infants on
growth or immune modulation.
We performed a double-blind, randomized, controlled, parallel-
group trial that was designed to test the hypothesis that supple-
mentary n23 LC-PUFAs would reduce intestinal damage caused
by chronic enteropathy and reduce the associated growth faltering
1Fromthe Medical Research Council (MRC) International Nutrition
Group (LFvdM, AJF, SEM, and AMP) and Faculty of Infectious and Trop-
ical Diseases (KEH), London School of Hygiene and Tropical Medicine,
London, United Kingdom; the MRC Keneba, Keneba, The Gambia (LFvdM,
AJF, SEM, AMP, and SD); and the MRC Human Nutrition Research, Elsie
Widdowson Laboratory, Cambridge, United Kingdom (SY).
2Supportedby the UK Medical Research Council (MC-A760-5QX00), the
Overseas Research Students Awards Scheme, and the Ernest Oppenheimer
Memorial Trust. Nordic Naturals kindly donated all supplement and control
3Addressreprint requests and correspondence to AM Prentice, Medical
Research Council International Nutrition Group, London School of Hygiene
and Tropical Medicine, Keppel Street, London WC1E 7HT, United King-
dom. E-mail: firstname.lastname@example.org.
4Abbreviationsused: AA, arachidonic acid; FA, fatty acid; LC-PUFA,
long-chain PUFA; LMR, lactulose:mannitol ratio; MRC, Medical Research
Council; MUAC, midupper arm circumference.
ReceivedMay 5, 2012. Accepted for publication October 11, 2012.
Firstpublished online December 5, 2012; doi: 10.3945/ajcn.112.042267.
Am J Clin Nutr 2013;97:45–57. Printed in USA. ? 2013 American Society for Nutrition
in 3–9-mo-old Gambian infants living in the rural area of West
Kiang. Supplementation was started at 3 mo of age in an attempt
to prime the intestinal mucosa and delay or prevent the initiation
of events that lead to gut damage.
One of the consequences of increased gut permeability is the
translocation of antigenic macromolecules, which stimulate and
perpetuate local and systemic inflammatory responses (9). To test
whether n23 LC-PUFA supplementation is associated with
reduced infant systemic inflammation (either via immune-
modulation or by reducing gut leakiness), concentrations of acute-
phase proteins plasma C-reactive protein, a-1-glycoprotein, and
albumin were also assessed. In addition, stool calprotectin was
measured as a marker of intestinal inflammation. General mor-
bidities experienced by infants (eg, diarrhea, vomiting, and fever)
were measured to examine treatment effects in terms of clinical
wellness, and these data contributed to safety monitoring.
In addition, the trial allowed investigations into the effect of
n23 LC-PUFA supplementation on developmental outcomes.
Evidence has suggested that cognitive function in children is
affected by nutritional and health status, particularly during the
rapid-growth phase in the first 2 y of life (24–27), and stunting
during infancy has been related to poor cognitive function in late
childhood (28, 29). Gambian infants may suffer developmental
insults in early life, considering the high rates of stunting and
infections they suffer. LC-PUFAs play a central role in the
normal development and functioning of the brain and central
nervous system, and associations between infant DHA status
and neurodevelopmental outcomes have been shown in several
studies (30–36). Infant LC-PUFA–supplementation studies have
shown mixed results in high-income countries (37), but to our
knowledge, such research in a low-income country setting such
as rural Gambia is lacking.
SUBJECTS AND METHODS
The study was carried out in the West Kiang region of The
Gambia from May 2007 to October 2008. The Gambian climate
is tropical with 2 main seasons that consist of a hot, rainy season
(June to October) and a cooler, dry season (November to May).
80 km2. Keneba is the largest village in this rural area, where
subsistence farming (primarily rice and groundnuts) predominates.
A combination of in utero growth retardation, poor-quality and
frequently contaminated weaning foods, and high levels of in-
fection cause moderately severe growth faltering in almost all
children with an onset at w3 mo postpartum. All infants aged 3
mo who were living in the 16 largest villages of West Kiang and
not enrolled in any other study were eligible to take part in the
current study. In total, 220 infants were assessed for eligibility, of
whom 183 infants were randomly assigned (Figure 1). Infants
with severe congenital abnormalities that could affect growth and
development, infants from multiple births, and infants with known
HIV infection were ineligible for participation.
Potential subjects were identified from the West Kiang De-
a study number by the database system on recruitment. Each study
number had previously been randomly assigned to one of 4
treatment codes (4 rather than 2 codes were used to promote
blinding) represented by 4 simple pictures on the supplements so
that infants were allocated to either the n23 LC-PUFA or the
control group in a 1:1 ratio. The trial statistician implemented
a permuted block random assignment (block size = 16), which
ensured a uniform distribution of treatments across the seasons of
birth. After mothers had given their consent, and their infants
had been recruited, a fieldworker issued them with a card printed
with the appropriate picture. Mothers were asked to bring their
picture-coded cards when their infants were brought to be admin-
istered the supplement. Fieldworkers were also given a treatment
booklet from which to crosscheck for any card swapping. All
infants in the study stayed on the same treatment allocations
throughout the duration of treatment. Participants, staff, and in-
vestigators remained blinded to treatment assignment throughout
the duration of the trial.
Intervention and study procedures
Supplementation started at 3 mo of age and ended at 9 mo
of age when all outcome measurements were made apart from
cognitive function (assessed at 12 mo of age). Field assistants
administered the supplement at a central meeting point in each of
the villages each day. Sterile, graded pastettes were used to
squeeze the oil into the side of the mouth of each infant. Mothers
were asked tobreastfeed their infantsimmediatelyafter the oilhad
been given. Field assistants who administered the dose recorded
The intervention group received 2 mL of highly purified fish
oil, which supplied 200 mg DHA and 300 mg EPA/d. The control
group was given the same volume of olive oil. Both oils were
supplied by Nordic Naturals Inc and contained 1.25% lemon oil
for blinding and 0.5% rosemary extract and d-a-tocopherol as an
antioxidant. On the advice of the trial monitor, the usual to-
copherol concentration of 30 IU/5 mL was reduced to 5 IU/5 mL
as appropriate to this age group. The dosage of 500 mg com-
bined DHA plus EPA/d was designed to achieve a substantial
increase in plasma n23 PUFA to both eliminate any existing
deficiencies and elicit a therapeutic response.
A morbidity questionnaire was administered to mothers or
caretakers on a daily basis to assess diarrhea, vomiting, cough,
might have been related to clotting interference. If a mother felt
that her infant was in need of medical attention, she was free to
take her infant to the Medical Research Council (MRC) clinic in
Keneba to be seen by a doctor or request a visit by a nurse. If the
infant was seen by a nurse or doctor, the diagnosis and treatment
details were recorded.
To reduce intraindividual variance and estimate the reliability
of outcome variables, primary endpoints were taken in triplicate
(on separate days) at baseline and endpoint visits, and the median
of their infant’s stool into a pot provided the evening before they
were due to come to Keneba for the clinic visit and to continue the
collection during the clinic visit if no stool was passed the
previous evening. Stools were thoroughly homogenized before
freeze drying to a constant weight. Mothers expressed w5 mL
breast milk from each breast before their infants received their
first feed at the clinic and again immediately after they had fed
their infants. The 4 breast-milk samples were pooled by mixing
together 1 mL of each sample, and an aliquot of this pooled
sample was stored at 2708C until analysis. An experienced nurse
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n23 LC-PUFA SUPPLEMENTATION IN AFRICAN INFANTS