The Journal of Nutrition
Nutrient Requirements and Optimal Nutrition
Early Docosahexaenoic Acid Supplementation
of Mothers during Lactation Leads to
High Plasma Concentrations in Very
Isabelle Marc,4–6* Me ´lanie Plourde,5Michel Lucas,6Anca Sterescu,7Bruno Piedboeuf,4
Alexandra Dufresne,4Anne Monique Nuyt,7E´mile Le ´vy,8and Sylvie Dodin6,9
4De ´partement de pe ´diatrie, Centre Hosipitalier de l’Universite ´ Laval, Que ´bec, G1V 4G2, Canada;5Centre de recherche sur le
vieillissement, Institut universitaire de ge ´riatrie de Sherbrooke, Universite ´ de Sherbrooke, Sherbrooke, J1H 4C4; Canada;6Chaire Lucie et
Andre ´ Chagnon pour l’avancement d’une approche inte ´gre ´e en pre ´vention, Universite ´ Laval, Ho ˆpital Saint-Franc ¸ois d’Assise, Que ´bec,
G1L 3L5, Canada;7De ´partement de pe ´diatrie and8De ´partement de nutrition, Centre Hospitalier Universitaire de Sainte-Justine,
Montreal, Qc, H3T 1C5, Canada; and9De ´partement d’obste ´trique et de gyne ´cologie, Universite ´ Laval, Que ´bec, Qc, G1V 0A6, Canada
Very preterm infants are vulnerable to deficiency in DHA. In a longitudinal study, 10 mothers who delivered #29 wk
gestation and planned to breast-feed received DHA (1200 mg/d) until 36 wk after conception. The plasma DHA status was
assessed in their 12 infants (including 2 pairs of twins) from birth to d 49. Fatty acid profiles were measured weekly in
breast milk, and in plasma of mothers and infants at baseline and at d15 and 49. Plasma and breast milk fatty acid
concentrations in the DHA-supplemented group at d 49 were compared with a reference group of very preterm infants
(n = 24, including triplets) whose mothers (n = 22) did not receive DHA during lactation. The infants’ plasma DHA
concentration tended to be greater in the DHA group than in the reference group (P = 0.10) and was greater
when expressed as a percentage of total fatty acids (P = 0.009). At d 49, maternal milk DHA in the DHA group (1.92 6
1.10 mmol/L) was ;12 times higher than in the reference group (0.15 6 0.27 mmol/L) (P , 0.001). The amount of DHA
provided to theinfants increasedfrom wk 1 throughwk 7 in the DHA group(P , 0.001). Althoughenteralintake atwk 7 did
not differ between the DHA group [119 6 51 mL/(kg.d)] and the reference group [113 6 66 mL/(kg·d)], DHA group infants
received 55 6 38 mg/(kg.d) of DHA, and the reference group infants received 7 6 11 mg/(kg·d) (P , 0.001). Early
supplementation with DHA to lactating mothers with low dietary DHA intake successfully increased the plasma DHA
status in very preterm infants.J. Nutr. doi: 10.3945/jn.110.125880.
Very preterm infants with a gestational age , 30 wk are
vulnerable to dietary deficiency, because their growth rate is
faster than at any other period of their life. Moreover, acute
health problems associated with severe prematurity often
compromise or delay enteral intake, being replaced by paren-
teral nutrition during this critical period.
Severely premature infants are at especially high risk of
developing an early deficit in DHA, an important long-chain (n-3)
fatty acid, because 1) the lipid used in parenteral nutrition
provides no preformed DHA; 2) the amount of DHA endoge-
nously synthesized from the precursor (linolenic acid) is low
(1,2); and 3) fat reserves are virtually nonexistent at birth in very
preterm infants. Intrauterine accretion of DHA in tissues during
the last trimester of pregnancy has been estimated at ;60 mg/d
[45 mg/(kgd)] (3,4) but this important phase of in utero DHA
accretion is absent in premature infants (3,5).
Avoiding a DHA deficit in the first weeks of life remains a
health challenge. Low DHA concentrations in breast milk of
Canadian women are closely related to low DHA in their diets
and to low fish consumption (6–9). In the postnatal period, the
breast milk DHA concentration can be increased either by
providing lactating mothers with DHA supplements or adding
DHA directly to the milk. If provided through breast milk, DHA
1Supported by the SickKids Foundation grant no. CAM06.322. DHA capsules
were provided by Mead Johnson Nutrition Co., Evansville, IN. At the time of this
study, I. Marc was a Scholar of the Canadian Institutes of Health Research (grant
no. MTP85228). Me ´lanie Plourde and Michel Lucas were awarded Postdoctoral
Fellowships from the Fonds de la Recherche en Sante ´ du Que ´bec. None of the
funders were involved in the design of the study, the interpretation of the data, or
the preparation or review of this article.
2Author disclosures: The DHA capsules were provided by Mead Johnson
Nutrition. Michel Lucas has been an invited speaker for Mead Johnson Nutrition.
Otherwise I. Marc, M. Plourde, A. Sterescu, B. Piedboeuf, A. Dufresne, A. M.
Nuyt, E. Levy, and S. Dodin declare no conflicts of interest.
3Supplemental Table 1 and Supplemental Figures 1 and 2 are available with the
online posting of this paper at jn.nutrition.org.
* To whom correspondence should be addressed. E-mail: isabelle.marc@crchul.
ã 2010 American Society for Nutrition.
Manuscript received May 18, 2010. Initial review completed July 19, 2010. Revision accepted October 26, 2010.
Copyright (C) 2010 by the American Society for Nutrition
1 of 6
The Journal of Nutrition. First published ahead of print December 15, 2010 as doi: 10.3945/jn.110.125880.
at Section des Acquistions Univ Laval on January 5, 2011
stability is enhanced and the concentration is regulated by
maternal milk production (10,11). To be associated with
neurodevelopmental advantages in premature babies (12–14),
the DHA fraction of total dietary fatty acids provided for the
growth of premature infants should be as high as 1–1.5% (12).
Attaining this level would involve providing mothers with a
DHA supplement of 1000–1300 mg/d during lactation (15,16).
Given the current recommendations, it is relevant to compare
the estimated DHA needs for normal fetal growth in utero and
the real intake of DHA by the very preterm counterpart (#29 wk
gestation). The purpose of this study was to longitudinally
evaluate the effect of an immediate DHA supplementation of
nursing mothers on the daily DHA intake of their very preterm
infants. We hypothesized that high DHA supplementation is
necessary for an early enhancement of the breast milk DHA
concentration and for a rapid increase in infants’ blood DHA
concentrations in the first weeks of life.
In the present study, lactating mothers of very preterm infants
(#29 wk gestation) in Quebec City were supplemented with
DHA and followed for the first 49 d of life of their babies. The
objectives were to: 1) measure DHA concentration trends in
breast milk and mothers’ and babies’ plasma lipids; 2) assess
dietary DHA intake from birth to d 49 in very preterm babies
receiving breast milk; and 3) compare the plasma DHA
concentration of very preterm breast-fed babies aged 49 d to a
reference group of very preterm infants whose mothers did not
receive DHA supplementation during lactation.
High DHA group recruitment and study design. Mothers who
delivered at gestational age # 29 wk and who planned to breast-feed
their very preterm infants were eligible. At recruitment, mothers were
excluded if they had regularly consumed more than 3 servings/wk of fish
or (n-3) supplements in the last 3 mo, were allergic to fish, were younger
than 18 y or older than 40 y, had a coagulation disorder or took
anticoagulants (warfarin, heparin), had a history of drug or alcohol
abuse, or if they were unable to come back for follow-up visits. Also
excluded were mothers of infants who were small for their gestational
age (#3rd percentile), had chromosomal abnormalities or major con-
genital malformations, had a documented thrombocytopenia (,8 3 107/L),
or had a grade III or IV intraventricular hemorrhage at the time of
inclusion. Mother-infant dyads were met 72 h postdelivery at the
neonatal unit of either recruiting center, i.e. the Centre Me `re-Enfant at
the Centre Hospitalier Universitaire de l’Universite ´ Laval (Universite ´
Laval, Quebec) or Ho ˆpital Sainte-Justine (Universite ´ de Montreal) and
were included in the study between d 3 and 7 (within the first week
Health Canada and the research ethics committees of the recruiting
centers approved the study. All mothers involved in the study gave their
informed written consent. The first visit was scheduled for eligible
women within the first week of the infant’s life. Mothers were given a
dailyDHAdoseof 1200mg(DHASCO, Mead JohnsonNutrition)as two
200-mg DHA capsules 3 times/d for 8–12 wk after birth. The pharmacist
advised mothers to take capsules with water before meals, not to pierce
the capsules, and to avoid consuming hot drink immediately.
Maternal supplementation stopped at term (i.e. 36 wk postconcep-
tion) regardless of the gestational age of the child at birth. Mothers’
compliance with the intervention was monitored by the use of a diary and
The very preterm newborns were unable to breast-feed at birth. Their
mothers extracted milk with an electrical pump (Lactina, Medela) from
both breasts using a sterile glass suction cup. Freshly extracted human
milk was given to the very preterm infants whenever it was available.
Last-dated bottles of frozen milk were used otherwise. If breast milk
production was insufficient, the very preterm infants were fed formula
according to the decision made by the medical staff. Formula DHA
initiated within48 h in stable infants at1 mLevery 4 h ifbirthweightwas
,1000 g or 2 mL every 4 h if birth weight was .1000 g. Feeding
progression was attempted at a rate of 20 mL/(kg·d) and was guided by
diet tolerance. Feeding intolerance was defined as gastric residuals of over
50% of the previous feed, in 2 of 3 consecutive feeds, or persistent
abdominal distension, vomiting, or diarrhea. Very preterm infants who
were clinically unstable or receiving indomethacin may have had a delay
in the feeding progression prescribed by the treating physician regardless
of whether they had a feeding intolerance.
Blood samples were obtained from the mothers and infants in the first
and at follow-up on d 15 (wk 3) and 49 (wk 7). On the same day each
week, a sample of breast milk was collected.
Reference group. To compare plasma DHA concentrations of the
infants fed DHA-enriched milk from their mothers taking DHA
supplements (DHA group) with a reference group, we enlisted mothers
who had also given birth #29 wk of gestational age but who did not
receiveDHA supplementation (reference group).Women inthe reference
group were recruited with the same inclusion and exclusion criteria as
the DHA group. However, in the reference group, a single blood sample
from the mother and infant as well as a single breast milk sample were
collected at d 49 (wk 7 postnatal).
Measurements. Sociodemographic indicators, maternal medical char-
acteristics, and obstetrical history were collected in both groups.
Maternal fish consumption the month before delivery and before d 49
postbirth were determined by a validated questionnaire (17). Newborn
outcomes were collected from their hospital chart. Additional standard-
ized information on the newborn clinical follow-up was obtained from
the Canadian Neonatal Network Database, a national database used to
track neonatal outcomes (18).
The amount of daily enteral intake (fluids including formula and
breast milk)was takenfrom thebaby’schart. Enteralintakewas assessed
in detail daily in the DHA group for the entire study period but only
during wk 7 of life among the reference group. The mean total intake per
week was calculated for each of the first 7 wk of life. The mean weekly
DHA intake was calculated using the daily fluid (formula and/or breast
milk) intake during the week and the DHA concentrations of the fluids.
Data were normalized to each infant’s mean body weight during that
week. Milk DHA content was calculated using the DHA concentrations
in the breast milk and/or formulas provided to the infants. Breast milk
concentrations were measured sequentially each week, but the formula
milk concentrations were those reported by the company.
DHA analysis. Plasma and milk total lipids were extracted into a 2:1
chloroform:methanol solution by using heptadecanoate as an internal
standard. The total lipids were then saponified with 1 mol/L methanolic
KOH followed by transmethylation of the FFA to FAME using 14%
methanolic BF3. FAME were analyzed using a gas chromatograph
(Agilent model 6890) equipped with a 50-m BPX-70 fused capillary
column (SGE, 0.25-mm i.d., 0.25-mm film thickness). Splitless mode
injection and flame ionization detection were performed at 2508C. The
oven temperature program was 508C for 2 min, increased to 1708C at a
rate of 208C/min, and held there for 15 min, then increased to 2108C at a
rate of 58C/min and held there for 7 min. The inlet pressure of the carrier
gas (He) was 233 kPa at 508C. The identity of the individual fatty acids
was determined from the retention times of standard mixtures of fatty
acids (NuChek 68A, NuChek 411, and NuChek 455; NuChek Prep) and
a custom mixture of SFA standards.
Statistical analysis. The primary outcome was the DHA concentration
in infant plasma on d 49 postnatal. Values in the text are means 6 SD.
Mean comparisons between groups at d 49 were performed using
Wilcoxon’s-Mann-Whitney nonparametric tests. In the DHA group, the
nonparametric Friedman test was used for testing trends over time for
DHA concentration in breast milk and in the plasma of mothers and
their infants as well as for infants’ absolute DHA intake per day and
relative to body weight. Mixed regression models with repeated
2 of 6Marc et al.
at Section des Acquistions Univ Laval on January 5, 2011
measureswere usedtodetermineassociations between2 trendsovertime
in the DHA group. Statistical analyses were conducted with the SAS v9.2
program for Windows (SAS Institute). Differences between groups and
associations were considered significant at P # 0.05 (bilateral).
Participants in the DHA and reference group were recruited in
parallel from July 2007 to December 2008. During this period,
a total of 59 mothers were eligible for participation (Supple-
mental Fig. 1). Among them, 33 were approached. Ten
mothers agreed to participate and were included in the DHA
group with their 12 very preterm infants (2 pairs of twins). A
total of 23 women refused to participate for the following
reasons: no interest in research, refusal to undergo blood
sampling, anxiety and the perceived need to focus on their
baby’s health, lack of time, or too many responsibilities. For
the reference group, a total of 26 women were approached for
participation at d 49 (wk 7 postnatal) and of these, 22 mothers
(and their 24 infants, including triplets) were enlisted. In 13
preterm infants, d 49 postbirth matched within 1 wk to the
36-wk corrected age.
Compared with the reference group, mothers from the DHA
group had a similar BMI before pregnancy and were of similar
age at delivery (Table 1). Daily consumption of fish meals (90 g)
1 mo before pregnancy did not differ between mothers in the
DHA (0.2 6 0.1) and reference (0.3 6 0.2) groups, nor did it
differ in the month before d 49 in the DHA (0.1 6 0.1) and
reference (0.2 6 0.3) groups.
The growth trends for weight, length, and head circumfer-
ence over the study period in the DHA group did not differ from
the reference group (data not shown). Anthropometric mea-
surements and the incidence of neonatal complications in the
DHA group did not differ at wk 7 from the reference group
Over the study period, total milk intake (formula + breast
milk) in the DHA group (5550 6 2930 mL) was similar to the
reference group (5270 6 2890 mL). All infants were completely
or predominantly fed human milk. Breast milk, as a percentage
of total intake, did not differ between the DHA (87%) and
reference (72%) groups. Direct breast-feedings were still un-
common at wk 7 in the DHA group (0.2 6 0.6) as well as in the
reference group (0.1 6 0.2) and were excluded from the total
amount of milk fed to the infants. Enteral intake at wk 7 did not
differ between the DHA group [119 6 51 mL/(kg·d)] and the
reference group [113 6 66 mL/(kg·d)].
The infants’ plasma DHA concentration at d 49 tended to be
greater in the DHA group than in the reference group (Fig. 1B)
(P = 0.10) and was greater when expressed as a percentage of
total fatty acids (P = 0.009) (Supplemental Fig. 2). At d 49,
mothers’ plasma DHA concentration in the DHA group was
higher than those in the reference group (P , 0.001) (Fig. 1A).
Similarly, babies’ plasma DHA concentration at d 49 in the
DHA group was higher than those in the reference group (P ,
0.001) (Fig. 1B).
Human milk DHA concentration in supplemented mothers
increased to 5-fold the baseline value within the first week of
DHA supplementation (Fig. 2A). At d 49, maternal milk DHA in
the DHA group (1.92 6 1.10 mmol/L) was ~12 times higher
than in the reference group (0.15 6 0.27 mmol/L) (P , 0.001)
(Fig. 2A). When expressed as a percentage of total fatty acids at
wk 7, maternal milk DHA in the DHA group reached 1.2 6
0.6% compared with 0.1 6 0.2% in the reference group (P ,
0.001) (Supplemental Table 1).
Full enteral feeds [.100 mL/(kgd)] were reached ~4 wk of
age. The amount of DHA provided to the infants was greater
Characteristics of the mothers1
Gravid $ 1, n (%)
Parity $ 1, n (%)
Abortion $ 1, n (%)
Years of schooling $ 13, n (%)
Worked before pregnancy, n (%)
Living with a partner, n (%)
Smoked during pregnancy, n (%)
Vitamin supplement during pregnancy, n (%)
Caucasian, n (%)
Economic status, n (%) well off
27.2 6 4.3
26.8 6 3.8
26.9 6 4.1
24.6 6 7.3
1Values are means 6 SD or n (%).
2Information missing for n = 4 (DHA) and 8 (reference).
Characteristics of the infants1
Gestational age, wk
Birth weight, kg
Birth head circumference,2cm
Sex, n (%)
Received $1 transfusion, n (%)
Diagnosis, n (%)
Respiratory distress syndrome
Patent ductus arteriosus
Suspected maternal infection4
Suspected secondary infection
Intraventricular hemorrhage, n (%)
Received oxygen at 36 wk, n (%)
Died, n (%)
Weight at wk 7,5kg
Length at wk 7,6cm
Head circumference at wk 7,7cm
27.6 6 1.5
1.01 6 0.30
25.6 6 1.6
27.7 6 1.1
1.05 6 0.20
26.1 6 3.5
1.7 6 0.5
43.1 6 3.0
30.0 6 1.7
1.7 6 0.4
42.9 6 2.6
29.0 6 2.1
1Values are means 6 SD or n (%).
2Information missing for n = 3 (DHA) and 4 (reference).
3Information missing for n = 1 (reference).
4Information missing for n = 1 (DHA).
5Information missing for n = 1 (DHA) and 3 (reference).
6Information missing for n =6 (DHA) and 4 (reference).
7Information missing for n =5 (DHA) and 4 (reference).
Docosahexaenoic acid for very premature infants3 of 6
at Section des Acquistions Univ Laval on January 5, 2011
in the DHA group (P , 0.001) (Fig. 2B). Although infants
from both groups had similar enteral intake at d 49, the DHA
group infants received 55 6 38 mg/(kg·d) of DHA and the
reference group infants received 7 6 11 mg/(kg·d) (P , 0.001)
In the DHA group, the linear trend over time for DHA
concentrations in mothers’ plasma was associated with the trend
of DHA concentration in milk (P = 0.027). However, there was
no significant association between trends in the plasma DHA
concentration of very preterm infants and their DHA intake.
Few women reported inconveniences related to the intake of
DHA. Two women reported such discomforts as eructation with
fishy aftertaste, digestive discomfort, and night sweats. Compli-
ance was good. At wk 7, 70% of the women were taking all 6
capsules/d for at least 6 d/wk. Women reported an intake of
5.6 6 0.4 (1120 6 80 mg) and 4.7 6 2.0 pills (940 6 400 mg) at
wk 2 and 7, respectively (P-trend . 0.05).
Our study showed that a dietary DHA supplement given during
lactation (1200 mg/d) (1) raises the breast milk DHA concen-
tration in mothers who have prematurely delivered (gestational
age # 29 wk) and (2) raises DHA concentrations in plasma of
breast-fed very premature infants. DHA intake was ~7 times
higher in babies fed milk from their mothers who were
supplemented with DHA throughout the first 7 wk of life,
probably because the milk DHA concentration was almost 12
times higher than in the reference group at wk 7. Moreover,
plasma DHA concentrations in mothers and babies were 2–3
times higher in the DHA group compared with the reference
group. Our results are supported by positive trends observed
over time in DHA concentrations in breast milk and babies’
plasma lipids in the DHA-supplemented group. Therefore,
providing a DHA supplement to mothers succeeded at increas-
ing the plasma DHA status of their very preterm infants.
This outcome is particularly important in the context of severe
prematurity, because the infants were born before the 3rd
trimester, a critical period of growth that is highly susceptible to
nutritional insult (19,20). For births before wk 30 of gestation,
only ;10% of the normal amount of fat is present (21). As a
result, the low fat stores (and, presumably, low DHA stores) leave
very preterm infants vulnerable to DHA deficiency. Therefore,
DHA in very preterm infants has to be provided by diet.
Our study is original in that we determined DHA intakes in
very preterm infants based on their current feeding in the first
weeks of life in association with longitudinal assessments of
DHA in maternal milk as well as mothers’ and infants’ plasma.
The combination of low DHA concentrations of breast milk
with low milk intake has as a consequence a very low DHA
intake in the early weeks of life. Our study documented that
when a high dose of DHA (1200 mg/d) is provided to lactating
mothers, this intervention effectively increases and sustains
DHA intake in very preterm newborns within the first 3 wk after
birth as long as the percentage of total intake that is breast milk
is high (70–80%). Furthermore, the timing of enteral feeding
also plays a role in the amount of DHA provided to these very
preterm infants. Very preterm infants should not be supple-
mented with milk extracted during the first week following
delivery because of its low DHA concentration. Priority should
be given to the extracted milk with the highest DHA concen-
tration, independent of the time of extraction.
DHA in breast milk depends largely on maternal diet and
ranges worldwide from 0.06 to 1.4% of total fatty acids (22).
Given the high rate of breast-feeding (;80% of total intake) and
increasing the milk DHA to 1% after 3 wk of supplementation,
the optimal concentration expected to improve brain DHA
accretion in the first months of life as well as very preterm infant
neurodevelopment was achieved (21,23,24). Recent data sug-
gest, however, that preterm requirements might be higher,
because a milk DHA concentration of 2% of total fatty acids
may be needed for plasma DHA of preterms to plateau (25,26).
There are large daily variations in the breast milk DHA
concentration of an individual mother as well as among mothers
(15,22,27). Our strategy of feeding DHA to infants through the
mother’s milk was based on the physiological regulation of the
DHA concentration in maternal milk, with a plateau being
reached within 2–3 wk of DHA supplementation, as also
reported in previous studies (15,28). It appears that the curves
for DHA appearance and plateauing in milk of the women in our
study who delivered very preterm infants are quite similar to
observations by Henderson et al. (29) in breast milk of women
were not supplemented with DHA during lactation (A) and their
preterm infants (B) from 1–7 wk after birth. Values are means 6 SD,
n = 10 (DHA) and 21 (reference). *Different from reference, P , 0.01.
Plasma DHA concentrations in mothers who were or
4 of 6Marc et al.
at Section des Acquistions Univ Laval on January 5, 2011
who delivered term infants and consumed 720 mg/d of DHA.
The effects at d 49 of supplementation of lactating women on
the infants’ plasma DHA increase is also similar to those
observed in term infant erythrocytes at d 21 in the study of
Henderson et al. (29). Because no intermediate values are
available between d 15 and 49, we cannot determine whether
plasma DHA concentrations of premature infants reached
saturation at d 49. Our study duration might also be too short
to evaluate if a plateau is achieved. On another hand, we cannot
rule out the possibility that this lack of a plateau may be
explained by the extraordinary needs for DHA of the very
preterm babies for the brain and for storage in adipose tissue.
We did not assess the effects of high DHA supplementa-
tion on the production of reactive species derived from the
peroxidation of (n-3) fatty acids in the mothers (30,31). High
levels of DHA have been shown to readily undergo peroxida-
tion, but further studies are needed to focus on the clinical
importance of such lipid peroxidation for the mother. Conse-
quently, before introducing this type of routine practice, the
potentially higher susceptibility of DHA peroxidation in the
mother with such high intake should be studied.
Our intervention did not affect growth, as determined by
weight, length, and head circumference, or the incidence of
immediate neonatal adverse outcomes. These results must be
interpreted with caution, because our study was not designed to
specifically address these outcomes.
Our study has a number of limitations. We had a small sam-
ple size, because recruitment was difficult due to high parental
stress in the period immediately after delivery. Nonetheless, we
observed significant differences at d 49 between the DHA-
supplemented group and the reference group. Although partic-
ipants were recruited in the same period of time (temporal
controls), they were not randomized. In addition, we did not
have longitudinal blood samples from the mothers and babies
in the reference group. Finally, even though the number of
infants who received blood transfusions was similar in both
groups, we cannot exclude that the transfusions may have been a
nondietary source of DHA and therefore influenced the plasma
Our results suggest that supplementing mothers with DHA is
a feasible and efficacious way of providing DHA to premature
infants with low birth weight (#29 wk of gestational age) in the
early weeks of life, even before they reach full enteral feeding
[140 mL/(kg·d)]. Our results emphasize the need for recommen-
dations addressing dietary DHA intake during lactation for
mothers of very preterm infants, because the DHA concentra-
tion in the milk from mothers not consuming fish during this
period probably does not meet the infants’ dietary requirements
for this nutrient.
Emphasis in future studies should be placed on providing
sufficient DHA intake in the first weeks of life to quickly and
safely meet the requirements for optimal growth and neuro-
development in very preterm infants. With this information, a
larger trial is needed to assess whether improved plasma DHA
concentrations within the first weeks have a beneficial effect on
clinical outcomes in very premature infants.
We thank Louise St-Pierre, Sonia Lagace ´, and Estelle Valle ´e for
their assistance in following participants to the study and
collecting data as well as milk and blood samples. We thank
Richard Poulin for language revision of the manuscript. I.M.,
M.L., B.P., S.D., and E.L. designed the study; I.M., A.S., B.P.,
and A.M.N. conducted the research; M.P. conducted biological
analyses; I.M. was responsible for the analyses and all authors
were involved in the interpretation of the data; A.D. conducted
the statistical analysis and plotted the figures; I.M. prepared the
first draft of this article and all authors contributed to writing
and reviewing the paper; and I.M. had the chief responsibility
for its final content. All authors read and approved the final
1. Carnielli VP, Simonato M, Verlato G, Luijendijk I, De Curtis M, Sauer
PJ, Cogo PE. Synthesis of long-chain polyunsaturated fatty acids in
preterm newborns fed formula with long-chain polyunsaturated fatty
acids. Am J Clin Nutr. 2007;86:1323–30.
not supplemented with DHA during lactation (A) and DHA intake in
their preterm infants from 1–7 wk after birth (B). Values are means 6
SD, n = 10 mothers and 12 infants in the DHA group and n = 14
mothers and 22 infants in the reference group. *Different from
reference, P , 0.01.
Milk DHA concentration in mothers who were or were
Docosahexaenoic acid for very premature infants5 of 6
at Section des Acquistions Univ Laval on January 5, 2011
2.Plourde M, Cunnane SC. Extremely limited synthesis of long chain
polyunsaturates in adults: implications for their dietary essentiality and
use as supplements. Appl Physiol Nutr Metab. 2007;32:619–34.
Clandinin MT. Brain development and assessing the supply of polyun-
saturated fatty acid. Lipids. 1999;34:131–7.
Clandinin MT, Chappell JE, Leong S, Heim T, Swyer PR, Chance GW.
Intrauterine fatty acid accretion rates in human brain: implications for
fatty acid requirements. Early Hum Dev. 1980;4:121–9.
Martinez M. Tissue levels of polyunsaturated fatty acids during early
human development. J Pediatr. 1992;120:s129–38.
Innis SM. Perinatal biochemistry and physiology of long-chain polyun-
saturated fatty acids. J Pediatr. 2003;143:S1–8.
Chen ZY, Pelletier G, Hollywood R, Ratnayake WM. Trans fatty acid
isomers in Canadian human milk. Lipids. 1995;30:15–21.
Lucas M, Asselin G, Plourde M, Cunnane SC, Dewailly E, Dodin S. n-3
Fatty acid intake from marine food products among Quebecers:
comparison to worldwide recommendations. Public Health Nutr.
Jensen RG. Lipids in human milk. Lipids. 1999;34:1243–71.
10. Simmer K, Patole S. Longchain polyunsaturated fatty acid supplementa-
tion in preterm infants. Cochrane Database Syst Rev. 2004;CD000375.
11. Fleith M, Clandinin MT. Dietary PUFA for preterm and term infants:
review of clinical studies. Crit Rev Food Sci Nutr. 2005;45:205–29.
12. Lapillonne A, Jensen CL. Reevaluation of the DHA requirement for the
13. Beyerlein A, Hadders-Algra M, Kennedy K, Fewtrell M, Singhal A,
Rosenfeld E, Lucas A, Bouwstra H, Koletzko B, et al. Infant formula
supplementation with long-chain polyunsaturated fatty acids has no effect
on Bayley developmental scores at 18 months of age: IPD meta-analysis of
4 large clinical trials. J Pediatr Gastroenterol Nutr. 2010;50:79–84.
14. Innis SM. Fatty acids and early human development. Early Hum Dev.
15. Makrides M, Neumann MA, Gibson RA. Effect of maternal docosa-
hexaenoic acid (DHA) supplementation on breast milk composition.
Eur J Clin Nutr. 1996;50:352–7.
16. Gibson RA, Neumann MA, Makrides M. Effect of increasing breast
milk docosahexaenoic acid on plasma and erythrocyte phospholipid
fatty acids and neural indices of exclusively breast fed infants. Eur J Clin
17. Lucas M, Asselin G, Merette C, Poulin MJ, Dodin S. Validation of an
FFQ for evaluation of EPA and DHA intake. Public Health Nutr.
18. Lee SK, McMillan DD, Ohlsson A, Pendray M, Synnes A, Whyte R,
Chien LY, Sale J. Variations in practice and outcomes in the Canadian
NICU network: 1996–1997. Pediatrics. 2000;106:1070–9.
19. Dobbing J, Sands J. Quantitative growth and development of human
brain. Arch Dis Child. 1973;48:757–67.
20. Godfrey KM, Barker DJ. Fetal nutrition and adult disease. Am J Clin
21. Cunnane SC, Francescutti V, Brenna JT, Crawford MA. Breast-fed
infants achieve a higher rate of brain and whole body docosahexaenoate
accumulation than formula-fed infants not consuming dietary docosa-
hexaenoate. Lipids. 2000;35:105–11.
22. Brenna JT, Varamini B, Jensen RG, Diersen-Schade DA, Boettcher JA,
Arterburn LM. Docosahexaenoic and arachidonic acid concentrations
in human breast milk worldwide. Am J Clin Nutr. 2007;85:1457–64.
23. Makrides M, Gibson RA, McPhee AJ, Collins CT, Davis PG, Doyle LW,
Simmer K, Colditz PB, Morris S, et al. Neurodevelopmental outcomes
of preterm infants fed high-dose docosahexaenoic acid: a randomized
controlled trial. JAMA. 2009;301:175–82.
24. Sarkadi-Nagy E, Wijendran V, Diau GY, Chao AC, Hsieh AT, Turpeinen
A, Nathanielsz PW, Brenna JT. The influence of prematurity and long
chain polyunsaturate supplementation in 4-week adjusted age baboon
neonate brain and related tissues. Pediatr Res. 2003;54:244–52.
25. Henriksen C, Haugholt K, Lindgren M, Aurvag AK, Ronnestad A,
Gronn M, Solberg R, Moen A, Nakstad B, et al. Improved cognitive
development among preterm infants attributable to early supplementa-
tion of human milk with docosahexaenoic acid and arachidonic acid.
26. Smithers LG, Gibson RA, McPhee A, Makrides M. Effect of two doses
of docosahexaenoic acid (DHA) in the diet of preterm infants on infant
fatty acid status: results from the DINO trial. Prostaglandins Leukot
Essent Fatty Acids. 2008;79:141–6.
27. Caspi A, Williams B, Kim-Cohen J, Craig IW, Milne BJ, Poulton R,
Schalkwyk LC, Taylor A, Werts H, et al. Moderation of breastfeeding
effects on the IQ by genetic variation in fatty acid metabolism. Proc
Natl Acad Sci USA. 2007;104:18860–5.
28. Fidler N, Sauerwald T, Pohl A, Demmelmair H, Koletzko B.
Docosahexaenoic acid transfer into human milk after dietary supple-
mentation: a randomized clinical trial. J Lipid Res. 2000;41:1376–83.
29. Henderson RA, Jensen RG, Lammi-Keefe CJ, Ferris AM, Dardick KR.
Effect of fish oil on the fatty acid composition of human milk and
maternal and infant erythrocytes. Lipids. 1992;27:863–9.
30. Calzada C, Colas R, Guillot N, Guichardant M, Laville M, Vericel E,
Lagarde M. Subgram daily supplementation with docosahexaenoic acid
protects low-density lipoproteins from oxidation in healthy men.
31. Guillot N, Caillet E, Laville M, Calzada C, Lagarde M, Vericel E.
Increasing intakes of the long-chain omega-3 docosahexaenoic acid:
effects on platelet functions and redox status in healthy men. FASEB J.
6 of 6 Marc et al.
at Section des Acquistions Univ Laval on January 5, 2011