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ARTICLE

Improved Cognitive Development Among Preterm

Infants Attributable to Early Supplementation of

Human Milk With Docosahexaenoic Acid and

Arachidonic Acid

Christine Henriksen, PhDa, Kristin Haugholt, MScb, Magnus Lindgren, PhDb,c, Anne Karin Aurvåg, MScd, Arild Rønnestad, MDe,

Morten Grønn, MD, PhDe, Rønnaug Solberg, MDf, Atle Moen, MDg, Britt Nakstad, MD, PhDd, Rolf Kristian Berge, MD, PhDh, Lars Smith, PhDb, Per Ole Iversen, MD, PhDa, Christian Andre´ Drevon, MD, PhDa

aDepartment of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, andbInstitute of Psychology, University of Oslo, Oslo, Norway;cDepartment of

Psychology, Lund University, Lund, Sweden;dDepartment of Pediatrics, Akershus University Hospital and University of Oslo, Akershus Faculty Division, Nordbyhagen,

Norway;eDepartment of Pediatrics Rikshospitalet-Radiumhopitalet Medical Center, Oslo, Norway;fDepartment of Pediatrics, Vestfold Hospital, Vestfold, Norway; gDepartment of Pediatrics, Buskerud Hospital, Buskerud, Norway;hSection of Medical Biochemistry, Institute of Medicine, University of Bergen, Bergen, Norway

The authors have indicated they have no financial relationships relevant to this article to disclose.

What’s Known on This Subject

DHA and AA are important for growth and neurodevelopment of the fetus and preterm infants. The average supply of DHA from human milk or formula is⬍50% of the esti-mated uterine accretion rate.

What This Study Adds

Preterm infants may benefit from supplementation of human milk with DHA and AA in the first month of life.

ABSTRACT

OBJECTIVE.The objective of our study was to evaluate the effect of supplementation with docosahexaenoic acid and arachidonic acid for human milk-fed preterm infants. The primary end point was cognitive development at 6 months of age.

METHODS.The study was a randomized, double-blind, placebo-controlled study among

141 infants with birth weights of⬍1500 g. The intervention with 32 mg of

docosa-hexaenoic acid and 31 mg of arachidonic acid per 100 mL of human milk started 1 week after birth and lasted until discharge from the hospital (on average, 9 weeks). Cognitive development was evaluated at 6 months of age by using the Ages and Stages Questionnaire and event-related potentials, a measure of brain correlates related to recognition memory.

RESULTS.There was no difference in adverse events or growth between the 2 groups. At the 6-month follow-up evaluation, the intervention group performed better on the problem-solving subscore, compared with the control group (53.4 vs 49.5 points). There was also a nonsignificant higher total score (221 vs 215 points). The event-related potential data revealed that infants in the intervention group had signifi-cantly lower responses after the standard image, compared with the control group (8.6 vs 13.2). There was no difference in responses to novel images.

CONCLUSIONS.Supplementation with docosahexaenoic acid and arachidonic acid for very preterm infants fed human milk in the early neonatal period was associated with better recognition memory and higher problem-solving scores at 6 months. Pediatrics2008;121:1137–1145

A

DEQUATE NUTRITION DURINGinfancy and early childhood is essential for optimal

growth, cognitive functioning, and health.1Preterm infants have increased morbidity and mortality rates in

early life and higher prevalence rates of school problems and neurodevelopmental impairments, compared with term

infants.2,3Approximately 50% of preterm infants have psychological complaints, and 25% shows signs of

attention-deficit/hyperactivity disorder.4Low birth weight also is associated with increased risk of cardiovascular diseases and

diabetes mellitus in adulthood.5Some of these disorders may be related to fetal and neonatal nutrient supply.

Present recommendations for preterm infant nutrition are designed to approximate the growth and development of a normal fetus of the same postconceptional age. Docosahexaenoic acid (DHA) and arachidonic acid (AA) are

important for growth and neurodevelopment of the fetus and preterm infants.6During pregnancy, DHA and AA are

transferred to the fetus by specific placental proteins and are incorporated into cell membranes of all tissues of the www.pediatrics.org/cgi/doi/10.1542/ peds.2007-1511

doi:10.1542/peds.2007-1511

This trial has been registered at www.clinicaltrials.gov (identifier NCT00226187).

Key Words

developmental outcomes, fatty acids, human milk, preterm infants, very low birth weight

Abbreviations

DHA— docosahexaenoic acid AA—arachidonic acid NC—negative central ERP— event-related potential VLBW—very low birth weight EEG— electroencephalographic EPA— eicosapentaenoic acid

Accepted for publication Sep 28, 2007

Address correspondence to Christian Andre´ Drevon, MD, University of Oslo, Institute of Basic Medical Sciences, Department of Nutrition, PO Box 1046 Blindern, 0316 Oslo, Norway. E-mail: [email protected]

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body, particularly those of the retina and central nervous system. Preterm infants are prematurely deprived of this supply. The contents of DHA and AA in human milk

vary, depending on the maternal diet.7,8A previous

ran-domized study showed that preterm infants receiving human milk had higher IQ values than did formula-fed infants at 8 years of age, and this was attributed to the

higher content of DHA in human milk.9Most preterm

formulas are now supplemented with DHA and AA to approximately the same levels as found in human milk (0.20%– 0.35% of total fatty acids). Several randomized, clinical trials showed beneficial effects on growth, visual function, and cognitive development, but all of those

studies were performed with formula-fed infants.10–13

Human milk supplies less DHA and AA than the fetus receives in utero. Even if full enteral intake of human milk is achieved, the calculated intake of DHA is only between 13 and 26 mg/day, which is clearly below the

estimated uterine accretion rate of ⬃50 mg/day.14 The

effect of DHA and AA supplementation for human milk-fed, preterm infants is not known.

One major impediment for further progress in this field is the lack of reliable valid methods for evaluating cognitive development in infants. Global measures of cognitive development, such as the Bayley Scales of Infant Development and the Brunet-Lezine scale, have often been used in clinical trials. These tests were origi-nally designed to identify infants who developed atypi-cally, and they have limited specificity for outcomes

related to intake of DHA and AA.15Assessment of

event-related potentials (ERPs) represents another method of

investigating cognitive processes among infants.16This is

a noninvasive measure of brain activity derived from standard electroencephalographic (EEG) recordings, which can provide information about changes time-locked to physical or cognitive events. The negative cen-tral (NC) component is a much-studied electrophysio-logical component that is thought to represent important cognitive processes such as attention and recognition memory. The amplitude of the NC component is larger for new, presumably interesting stimuli and decreases as

a stimulus is repeated.17,18

The aim of our study was to evaluate the effect of supplementation with DHA and AA (48 mg/kg per day of each) on human milk-fed, very low birth weight

(VLBW) infants (birth weight: ⬍1500 g) in the early

neonatal period. The primary end point was cognitive development, measured with a global test of develop-ment (Ages and Stages Questionnaire), as well as an ERP index of recognition memory.

METHODS

Study Population

All VLBW infants born between December 2003 and

November 2005 at Rikshospitalet-Radiumhospitalet

Medical Center, Akershus University Hospital, Buskerud Hospital, and Vestfold Hospital in Norway were eligible for inclusion. Infants with major congenital abnormali-ties or cerebral hemorrhage (grade 3 or 4, as determined through ultrasonography) were not included in the

study. Written informed consent was obtained from the parents, and the study was approved by the regional ethics committee. The infants were assigned randomly to either the intervention group or the control group by using computer-generated randomization schedules. The randomization was performed separately for each of the neonatal centers, using blocks of 16 participants, without stratification. Included infants were given pro-gressive study numbers corresponding to the number on the bottles of study oil. All personnel recruiting infants, parents, and hospital staff members were blinded to the group allocation.

DHA and AA Supplementation

The infants received human milk (from either the mother or a donor) from the first or second day after birth. As enteral feeding was increased, the milk was fortified with proteins, minerals, vitamins, iron, and folic acid according to the local routines. In addition, the infants received a daily dose of 0.5 mL of study oil per 100 mL of human milk. The intervention group received a study oil with AA and DHA as triacylglycerol (Martek Biosciences, Columbia, MD). The study oils were dis-persed in a mixture of soy oil and medium-chain triglyc-eride oil (Table 1) at the hospital pharmacy, packed, and numbered according to the randomization list. The con-trol group received the same mixture of soy oil and medium-chain triglyceride oil as the study group but without DHA or AA.

The fatty acid compositions of the human milk and the study oils were analyzed, and the results are given in Table 1. The intervention oil contained 6.9% (wt/wt) DHA and 6.9% (wt/wt) AA, providing 32 mg of DHA and 31 mg of AA in 0.5 mL of study oil added to 100 mL of human milk. This supplementation more than dou-bled the quantities of DHA and AA, compared with unfortified human milk. The added study oil was soni-cated into human milk and given to the infants by gavage feeding. The intervention started when the infant

received most of his or her nutrients enterally (⬎100 mL

of human milk per kg of body weight per day) and continued until the infant was discharged from the hos-pital or the bottle of 100 mL of study oil was empty (at 63 days of age, on average). The last week before dis-charge, when breastfeeding was established, the study oil was given as a fixed dose of 1 mL twice a day. Infants

TABLE 1 Mean Fatty Acid Compositions of Unfortified Human Milk and the Study Oils

Fatty Acid Concentration, mg per 100 mL (% of Total Fatty Acids)

Human Milk (3.7% Fat, by Weight)

Intervention Oil

Control Oil

18:2n⫺6, linoleic acid 485 (12.9) 88 (18.8) 127 (27.1) 20:4n⫺6, AA 17 (0.5) 31 (6.7)

18:3n⫺3,␣-linolenic acid 46 (1.2) 11 (2.3) 16 (3.4) 20:5n⫺3, EPA 7 (0.2)

22:6n⫺3, DHA 26 (0.7) 32 (6.9)

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who were not breastfeeding at the time of discharge changed from donor milk to term formula (most com-monly, Nan 1 [Nestle´, Sandvika, Norway]) during the last days before discharge.

Data Collection

Maternal characteristics were obtained through inter-views. Growth data on infants were obtained from the medical charts each week during hospitalization. Sam-ples of breast milk were collected from each mother 4 weeks after birth and were analyzed for fatty acid pat-terns through gas-liquid chromatography with flame ionization detection. Nutrient intake was calculated from data on parenteral nutrition, human milk, formu-las, and oral supplements obtained from the medical charts, by using a computerized database (Beregn; De-partment of Nutrition, University of Oslo). All adverse events were recorded on a separate form for each par-ticipant, in the medical charts, throughout the study. In addition, all diagnoses attributable to illnesses during hospitalization were obtained from the medical charts.

Blood Sampling and Analyses

Blood samples (venous or capillary) were obtained from the infant (1 mL) at the time of admission to the study and at discharge. The blood samples were collected in EDTA-containing containers at the start and end of the intervention; they were then centrifuged and stored at

⫺80°C until analyses. The plasma samples were

ana-lyzed for fatty acid patterns through gas-liquid

chroma-tography with flame ionization detection.19

Cognitive Development

Ages and Stages Questionnaire

The primary end point was cognitive development at corrected age of 6 months, which was evaluated with the Ages and Stages Questionnaire, a parent-administered standardized questionnaire originally developed in the

United States.20 This instrument for measuring mental

and motor development includes 30 items designed to assess the infant’s development in the areas of commu-nication, gross motor, fine motor, problem-solving, and personal-social skills. The parents or other caregivers are asked whether the child performs the described behav-ior, with 3 possible responses (yes, sometimes, or not yet). One of the advantages is that the questionnaire requires much less time than instruments that require direct examination. The questionnaire has been trans-lated into Norwegian and validated with Norwegian in-fants.20,21

Event-Related Potentials

We also performed electrophysiological recordings re-lated to recognition memory. A single investigator, who was also blinded to the intervention, tested the infants at a mean age corrected for gestation of 6 months and 4 days. The stimuli included a pseudo-randomized series of colorful images, in which a standard image (a cartoon ball) was shown in 70% of the presentations and novel images (different cartoon toys and animals) were shown

in 30% of the presentations. The novel images were never repeated, and 1 novel image did not follow an-other novel image. This paradigm elicits a negative, long-lasting, ERP deflection that is larger for novel stimuli. This negativity decreases with repetitions, presumably because of recognition. Normal infants quickly recognize the standard cartoon, whereas the novel images

con-tinue to elicit large negative amplitudes.17Therefore, it is

possible to infer memory function from the difference between ERPs recorded in response to a unique image

and those from standard images.22 Our hypothesis was

that the intervention group would show a more-marked decrease of the negative amplitude with repetition of the standard image, compared with the control group, whereas there would be no difference for new images.

During the EEG recordings, the infants were seated on their parents’ laps and the stimuli were presented on

a 30- ⫻ 40-cm computer monitor, in an electrically

shielded, sound-insulated, experimental room. The

reg-istration lasted for ⬃10 minutes. The parents were

in-structed not to speak and not to direct the child’s atten-tion toward the monitor. With the use of an Easycap (Easycap, Herrsching, Germany), 6 active electrodes were attached to standard sites on the head, according to the International 10 –20 System (ie, F3, F4, C3, C4, P3, and P4, referenced to the mastoid bones).

EEG traces were recorded by using Neuroscan soft-ware, and the signals were amplified through a Neuro-scan Nuamps amplifier (Compumedics NeuroNeuro-scan, El Paso, TX) and digitized at a rate of 500 Hz. Continuous EEG traces were scanned for artifacts, and segments

where the EEG signals exceeded 150␮V were excluded

from additional analyses. EEG results were then band-pass filtered from 0.5 to 30 Hz, with a 12-dB roll-off.

Epochs from ⫺100 to 1500 milliseconds were formed

and baseline-corrected by using the prestimulus interval. Averages were calculated separately for the standard and novel stimuli. The mean aggregated amplitude for the frontal and central electrodes in the interval of 400 to 650 milliseconds was used for statistical analyses.

Statistical Analyses

Calculations were performed by using SPSS 14.0 (SPSS Inc, Chicago, IL). Continuous variables are presented as

mean and SD and were tested with t tests, whereas

categorical variables are presented as percentages and

were tested with ␹2 tests. Some data (eg, feeding data

and duration of assisted ventilation) were not normally distributed; those data are presented as medians and interquartile ranges (25th to 75th percentile values) and were tested with nonparametric methods. For repeated measurements such as weight and blood sample mea-surements, analyses of variance were used. Power cal-culations were performed with Ages and Stages Ques-tionnaire scores as the end point. We estimated that 63 participants in each group would be satisfactory to have 80% power to detect a difference of 21 points (corre-sponding to 0.5 SD), with a mean value of 260 points.

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RESULTS

Patient Characteristics

Of a cohort of 222 consecutively born VLBW infants, 141 (64%) were included in the study. Fifty-nine infants did not meet the inclusion criteria, and 22 parents re-fused to participate. Twelve infants were excluded (6 in each group); therefore, 129 infants completed the inter-vention. The reasons for these dropouts were possible

adverse events (n ⫽ 7), prolonged parenteral feeding

(n⫽2), death (n⫽2), congenital abnormalities (n⫽1),

and parents declined (n ⫽1) (Fig 1). Of the 129

com-pleting infants, 62 were in the intervention group and 67 in the control group.

There were no significant differences in gender, ges-tational age, weight, length, or head circumference at birth between the 2 groups at inclusion (Table 2). Fur-thermore, there was no significant difference in baseline

characteristics between completing infants (n ⫽ 129)

and those who dropped out (n⫽12; data not shown).

Clinical Events

There was no significant difference in registered adverse events between the 2 groups. There was a trend toward longer duration of nasal continuous positive airway pressure treatment (28 vs 13 days) and oxygen require-ment (13 vs 8 days) in the intervention group, compared with the control group, but the differences were not statistically significant (Table 3). Two infants (birth weight: 705 and 830 g) in the control group died during the study, which was not related to feeding protocols. One infant had major congenital malformations (not

realized at the time of inclusion), and the other experi-enced major respiratory failure.

Diet and Growth

Feeding data existed for 127 of the 129 infants for the whole hospital stay (Table 4). There were no significant differences in energy and nutrient intakes between the 2

FIGURE 1

Trial profile summarizing participation flow, number of assignments, interventions, and follow-up evaluations.

TABLE 3 Clinical Outcomes for the Study Groups During the Hospital Stay

Intervention Group (n⫽68)

Control Group (n⫽73)

Need for respiratory support,n(%) 31 (46) 29 (40) Duration of mechanical ventilation,

median (IQR), d

0 (0–4) 0 (0–3)

Duration of N-CPAP, median (IQR), d 28 (5–43) 13 (2–38) Duration of oxygen support, median

(IQR), d

13 (2–48) 8 (0–39)

No. of blood transfusions, median (IQR) 1 (0–2) 2 (0–2) NEC, treated,n(%)

Suspected 1 (1.5) 0 (0)

Proven 1 (1.5) 2 (3)

Antibiotic treatment, median (IQR), d 4 (0–9) 3 (0–8) Intracranial hemorrhage,n(%)

Grade 1 6 (9) 7 (10)

Grade 2 3 (5) 5 (7)

Grade 3–4 2 (3) 1 (1.5)

Periventricular leukomalacia,n(%)

1 or 2 cysts on 1 side 3 (4.5) 0 (0)

⬎2 cysts or bilateral 1 (1.5) 1 (1.5) Retinopathy,n(%)

Any retinopathy 8 (12) 13 (18)

Treated retinopathy 3 (4) 3 (4)

Died before discharge,n(%) 0 (0) 2 (3) Age at discharge, median (IQR), d 63 (48–91) 63 (50–90)

Data are presented for all infants (n⫽141), including those who were excluded because of adverse events or illness. There were no significant differences between groups. IQR indicates interquartile range; NEC, necrotizing enterocolitis; N-CPAP, nasal continuous positive airway pressure.

TABLE 2 Baseline Characteristics of the Study Population Intervention

Group (n⫽68)

Control Group (n⫽73)

Total No. 68 73

Girls, % 47 44

Boys, % 53 56

Gestational age, median (IQR), wk

28.4 (26.6–30.6) 28.9 (26.8–30.9)

Birth weight, median (IQR), g 1090 (795–1265) 1090 (849–1340) Birth length, median (IQR), cm 35.5 (32.0–37.0) 36.0 (33.0–39.0) Head circumference at birth,

median (IQR), cm

26.9 (25.0–28.0) 26.5 (24.6–28.6)

White, % 79 84

Cesarean section, % 65 67

Maternal age, median (IQR), y 31 (28–34) 32 (29–35) Maternal education, %

⬍9 y 10 11

10–12 y 48 34

⬎12 y 42 55

No maternal smoking during pregnancy, %

79 78

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groups (data not shown), apart from DHA and AA. The intakes of DHA and AA increased in the intervention group after 1 week of age. The nutrient intakes were similar in the 2 groups, apart from DHA (0.86% vs 0.35%) and AA (0.91% vs 0.32%). The mean daily intakes of DHA were 59 mg/kg per day in the interven-tion group and 32 mg/kg per day in the control group

(P⬍.001), and the intakes of AA were 47 mg/kg per day

and 22 mg/kg per day, respectively. There was no sig-nificant difference in growth between the 2 groups (Fig

2). Weight gain (mean⫾SD) was 23.3 ⫾5.2 g/day in

the intervention group and 22.8 ⫾ 4.9 g/day in the

control group. The mean daily length gain was 1.2⫾0.5

mm in the intervention group and 1.3⫾0.7 mm in the

control group. The mean gain in head circumference was

1.2⫾0.7 mm/day in the intervention group and 1.0⫾

0.4 mm/day in the control group.

Plasma Fatty Acid Patterns

At the time of inclusion, there were no significant dif-ferences in plasma fatty acid patterns between the inter-vention group and the control group. During the sup-plementation, plasma DHA concentrations increased by 12% in the intervention group and decreased by 9% in the control group. There was a significant effect of fatty

acid supplementation versus time course (P ⫽ .045,

analysis of variance). Plasma AA concentrations de-creased by 6% in the intervention group and 24% in the control group, and the effect of fatty acid

supplementa-tion versus time course was significant (P⫽.015,

anal-ysis of variance) (Table 5).

Cognitive Development

Mental and motor development was measured for 105 infants with the Ages and Stages Questionnaire at the 6-month follow-up evaluation. The intervention group scored higher on the problem-solving subtest than did

the control group (53.4 vs 49.5 points;P⫽.02) (Table

6). There was also a nonsignificantly higher total score (221 vs 215 points).

ERPs were measured for 98 infants at 6 months of age. Two infants had impaired vision and could not participate in this test. Fifteen recordings had to be

dis-carded because the infant was crying (n⫽7) or because

of technical failure of the recording equipment (n⫽8);

therefore, data are presented for 81 infants. Calculations were performed by using the mean amplitude in the interval of 400 to 650 milliseconds after presentations of visual stimuli as standard or novel images (Table 7). Infants in the intervention group had significantly lower (more-negative) amplitudes, compared with the control

group, after the standard image (P⫽.01) (Fig 3A, C, E,

and G and Table 7). Presentations of novel images (de-viants) did not induce any difference between the 2

groups (P ⫽ .14) (Fig 3B, D, F, and H and Table 7).

Similar patterns were seen for frontal and central elec-trodes, as well as left and right hemispherical leads.

DISCUSSION

Our present study is the first to show a beneficial effect on cognitive function of DHA and AA supplementation (48 mg/kg per day of each) for VLBW infants fed human milk. With a parental questionnaire based on the tradi-tional test paradigm (Ages and Stages Questionnaire), the intervention group obtained a significantly higher problem-solving score than did the control group. There was also an indication toward a higher total score in the

TABLE 4 Enteral Feeding Data for the Study Groups Intervention Group

(n⫽62)

Control Group (n⫽65)

Enteral feeding started, %

First day 71 85

Second day 29 15

Received PN, % 95 97

Duration of PN, median (IQR), d 6 (2–13) 5 (2–13) Age reached full feedings, median (IQR), d 7 (6–10) 7 (7–10) Type of feeding (%)

Human milk only 77 75

Mixed (human milk and formula) 23 25

Full feedings were 150 mL/kg per day. There were no significant differences between groups. PN indicates parenteral nutrition; IQR, interquartile range.

0 500 1000 1500 2000 2500 3000 3500

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Gestational age (weeks)

Weight (g)

Intervention Control FIGURE 2

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intervention group, without reaching statistical signifi-cance. We found a clear beneficial effect on recognition memory in the intervention group, as indicated by ERP measurements after visual stimuli.

Earlier studies of DHA and AA supplementation for VLBW infants were conducted with formula-fed or par-tially formula-fed infants, giving doses of important fatty acids equivalent to the content in human milk. Most studies showed little or only modest effect of DHA

sup-plements on cognitive function,23 which may be

ex-plained in part by low dosages and methodologic prob-lems in the earliest studies, such as low statistical power and lack of reliable end points. Another possibility is that the previously observed beneficial effect on IQ was at-tributable to other differences between human milk and formula (eg, energy, protein, or antioxidants). However, our present study supports the hypothesis that DHA and/or AA are major beneficial components, because these fatty acids represent the main difference between the groups.

Previous studies tested formulas without DHA/AA, compared with different concentrations of these fatty

acids.23 In our present study, both groups received

hu-man milk containing some DHA and AA, and the inter-vention group received additional DHA/AA supplemen-tation. Our design is different from that of previous studies, which makes direct comparisons difficult. We found a small partial difference between groups by using a traditional assessment of mental and motor develop-ment (Ages and Stages Questionnaire). The Ages and Stages Questionnaire consists of 5 subparts, measuring a

wide range of infant development (ie, communication, motor development, problem-solving, and social devel-opment), and we did not expect that DHA and AA would have an effect on all of these parameters. There is grow-ing evidence that DHA and AA have specific functions

related to memory and problem-solving.24The result of

our present study might be interpreted to support this hypothesis, because we observed a highly significant difference between groups by using an ERP index of recognition memory. Our results add to the evidence that choice of end point measurement is crucial in these

types of intervention studies.15

The strength of our present study is the multidisci-plinary approach combining aspects of neonatology, nu-trition, biochemistry, and neuropsychology. In addition to tests of mental and motor development, we used ERPs to examine processes related to recognition memory. The method is also suitable for young infants, because no complex linguistic or behavioral responses are required. Another advantage is that recognition memory may

pre-dict later IQ better than traditional tests.25 The ERP

method also makes it possible to obtain specific informa-tion about timing and patterns of brain activities. Atyp-ical ERP responses after auditory stimuli were reported previously for preterm infants, and these have been

interpreted as signs of cognitive dysfunction.22,26Atypical

ERP responses after visual stimuli also were reported for infants at high risk for neurodevelopmental

impair-ments.27 The present study is the first to compare ERP

patterns in infants receiving 2 different nutritional reg-imens in the neonatal period.

The NC component was shown previously to be larger with novel stimuli, compared with familiar or repeated

stimuli.28The NC component is likely to be affected by an

interaction of arousal, attention, and memory

mecha-TABLE 5 Plasma Fatty Acid Patterns According to Study Group

Fatty Acid Concentration, Mean⫾SD, mg/mL P

Intervention Group (n⫽62) Control Group (n⫽67)

Baseline Discharge Baseline Discharge

n⫺3 fatty acids

18:3,␣-linoleic acid 17.5⫾14.6 15.3⫾7.2 13.0⫾8.8 15.7⫾10.9 NS

20:5, EPA 17.2⫾8.0 18.0⫾9.8 17.6⫾6.7 17.1⫾8.9 NS

22:6, DHA 63.1⫾20.5 70.8⫾21.3 64.5⫾20.6 58.9⫾20.7 .045a

n⫺6 fatty acids

18:2, linoleic acid 526.4⫾195.1 528.5⫾106.1 482.90⫾168.3 528.6⫾146.9 NS 20:4, AA 202.5⫾44.9 190.2⫾54.0 205.4⫾50.1 156.9⫾35.7 .015a

NS, not significant.

aDifferences in supplement group from baseline to discharge by analysis of variance.

TABLE 6 Ages and Stages Questionnaire Scores at 6 Months of Age in the Study Groups

Score, Mean⫾SD Pa

Intervention Group (n⫽50)

Control Group (n⫽55)

Total 221⫾32 215⫾39 NS

Communication 45.4⫾7.9 46.6⫾9.1 NS

Gross motor 33.3⫾11.5 30.9⫾11.1 NS

Fine motor 45.2⫾10.7 45.8⫾14.3 NS

Problem-solving 53.4⫾7.0 49.5⫾9.5 .02 Personal-social 43.2⫾12.8 42.2⫾12.3 NS

attests; NS indicates not significant.

TABLE 7 ERPs at 6 Months of Age in the Study Groups

Image ERP, Mean⫾SD,␮V P

Intervention Group (n⫽39)

Control Group (n⫽42)

Standard ⫺8.9⫾7.8 ⫺13.2⫾7.2 .01

Novel ⫺17.4⫾9.6 ⫺19.6⫾11.9 .37

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nisms.28 Ideally, these contributions should be

decom-posed, which would have called for a much larger num-ber of channels, as well as a more-complex paradigm. This was not feasible. For our purposes, it was not critical to separate components of the modulation of NC ampli-tude. Instead, we used recognition in this context as a term that encompassed pure memory and attention components. This renders the response to the repeated

standards the measure of central interest in our study. Attention and recognition are both essential for learning and information processing. The stability of the present findings needs to be demonstrated, and we intend to monitor the participants later in childhood.

One limitation of our present study was low statistical power for detecting differences by using the Ages and Stages Questionnaire, increasing the probability of type Frontal, left side (F3) registration after standard image

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Latency (ms)

Amplitude (microvolt)

intervention control

Frontal, right side (F4) registration after deviant images

A

B

D

C

Central, left side (C3) registration after standard image

-30

-25

-20

-15

-10

-5

0

-100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500

-100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500

Latency (ms)

Amplitude (microvolts)

intervention control

Central, left side (C3) registration after deviant images

-30

-25

-20

-15

-10

-5

0

Latency (ms)

Amplitude (microvolt)

intervention control

Central, right side (C4) registration after standard image

-30

-25

-20

-15

-10

-5

0

Latency (ms)

Amplitude (microvolts)

intervention control

Central, right side (C4) registration after deviant images

-30

-25

-20

-15

-10

-5

0

Latency (ms)

Amplitude (microvolts)

intervention control

H

F

G

E

FIGURE 3

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2 errors. There may be a real difference between groups that we were unable to detect. We estimated that we would need at least 126 participants (63 subjects in each group), but only 105 completed the 6-month question-naire. Another limitation is the subject’s attention with the ERP method. Although the method is noninvasive, the infants need to be relatively calm and awake. A substantial number of participants needed to be ex-cluded because the infants were crying and/or refusing to wear the electrodes. This problem is shared by many tools for measuring cognitive development in infants. Crucially, in the present study, the numbers of records that needed to be rejected were similar in the 2 groups. The study oil was well tolerated and absorbed. Al-though we used higher doses of DHA and AA, compared with other studies, we noticed a decline in plasma con-centrations of AA in both groups, which suggests that the dose of AA still may be too small. An alternative explanation is that a decline in AA concentrations is normal. We did not notice any negative effect in clinical events during the supplementation. There was a nonsig-nificant trend toward a longer duration of assisted ven-tilation and greater oxygen requirements in the inter-vention group, compared with the control group. This

was also noticed in 1 other study,12 but not in

oth-ers.10,11,13,29,30

The effect of DHA supplementation on infant growth has been controversial. Some early trials among preterm infants reported that supplement-treated infants had lower weight gain and were shorter than

non–supple-ment-treated infants.31,32This difference was thought to

be a consequence of altered proportions between eico-sapentaenoic acid and AA but, when both DHA and AA were added to formulas, impaired growth was no longer

noted.23In our study, we used a 50:50 mixture of DHA

and AA, and we confirmed earlier studies by not detect-ing any negative effect of supplementation on weight gain or growth.

CONCLUSIONS

Supplementing human milk with DHA and AA led to increased plasma concentrations of DHA and AA in the early neonatal period. At the 6-month follow-up evalu-ation, infants who received DHA and AA had better problem-solving skills and discriminated better between familiar and unfamiliar objects, compared with the con-trol group. This function is essential for focusing atten-tion, learning, and information processing. It remains to be seen whether this type of intervention may have long-term effects on cognitive function, school perfor-mance, and rates of attention-deficit/hyperactivity dis-order in later childhood.

ACKNOWLEDGMENTS

Financial support was provided by the Norwegian Foun-dation for Health and Rehabilitation, the Johan Throne Holst Foundation for Nutrition Research, the Freia Med-ical Research Foundation, the Research Council of Nor-way, and the Thematic Program on Perinatal Nutrition, Faculty of Medicine, University of Oslo. Martek Bio-sciences kindly provided the study oils.

We are grateful to the staff members at the 4 NICUs and to Ane Westerberg for assistance with analysis of the dietary records.

REFERENCES

1. Dewey K, Lutter C.Guiding Principles for Complementary Feeding of the Breastfed Child. Washington, DC: World Health Organiza-tion, Division of Health Promotion and ProtecOrganiza-tion, Food and Nutrition Program; 2006

2. Elgen I, Johansson KA, Markestad T, Sommerfelt K. A non-handicapped cohort of low-birthweight children: growth and general health status at 11 years of age.Acta Paediatr. 2005; 94(9):1203–1207

3. Mikkola K, Ritari N, Tommiska V, et al. Neurodevelopmental outcome at 5 years of age of a national cohort of extremely low birth weight infants who were born in 1996 –1997.Pediatrics. 2005;116(6):1391–1400

4. Indredavik MS, Vik T, Heyerdahl S, Kulseng S, Fayers P, Brubakk AM. Psychiatric symptoms and disorders in adoles-cents with low birth weight.Arch Dis Child Fetal Neonatal Ed. 2004;89(5):F445–F450

5. Guerra A, Rego C, Vasconcelos C, Silva D, Castro E, Guimaraes MJ. Low birth weight and cardiovascular risk factors at school age.Rev Port Cardiol.2004;23(3):325–339

6. Carlson SE, Neuringer M. Polyunsaturated fatty acid status and neurodevelopment: a summary and critical analysis of the literature.Lipids.1999;34(2):171–178

7. Harris WS, Connor WE, Lindsey S. Will dietary omega-3 fatty acids change the composition of human milk?Am J Clin Nutr. 1984;40(4):780 –785

8. Helland IB, Saarem K, Saugstad OD, Drevon CA. Fatty acid composition in maternal milk and plasma during supplemen-tation with cod liver oil.Eur J Clin Nutr.1998;52(11):839 – 845 9. Lucas A, Morley R, Cole TJ, Lister G, Leeson-Payne C. Breast milk and subsequent intelligence quotient in children born preterm.Lancet.1992;339(8788):261–264

10. O’Connor DL, Hall R, Adamkin D, et al. Growth and develop-ment in preterm infants fed long-chain polyunsaturated fatty acids: a prospective, randomized controlled trial. Pediatrics. 2001;108(2):359 –371

11. Innis SM, Adamkin DH, Hall RT, et al. Docosahexaenoic acid and arachidonic acid enhance growth with no adverse effects in preterm infants fed formula.J Pediatr.2002;140(5):547–554 12. Fewtrell MS, Abbott RA, Kennedy K, et al. Randomized, dou-ble-blind trial of long-chain polyunsaturated fatty acid supple-mentation with fish oil and borage oil in preterm infants. J Pediatr.2004;144(4):471– 479

13. Clandinin MT, Van Aerde JE, Merkel KL, et al. Growth and development of preterm infants fed infant formulas containing docosahexaenoic acid and arachidonic acid. J Pediatr. 2005; 146(4):461– 468

14. Innis SM. Essential fatty acid transfer and fetal development. Placenta.2005;26(suppl A):S70 –S75

15. Cheatham CL, Colombo J, Carlson SE. N⫺3 fatty acids and cognitive and visual acuity development: methodologic and conceptual considerations.Am J Clin Nutr.2006;83(6 suppl): 1458S–1466S

16. Thomas KM. Assessing brain development using neurophysi-ologic and behavioral measures.J Pediatr.2003;143(4 suppl): S46 –S53

17. Reynolds GD, Richards JE. Familiarization, attention, and rec-ognition memory in infancy: an event-related potential and cortical source localization study. Dev Psychol. 2005;41(4): 598 – 615

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In: de Haan M, Johnson MH, eds.The Cognitive Neuroscience of Development. Hove, England: Psychology Press; 2003:19 – 42 19. Bjørneboe A, Smith AK, Bjørneboe GE, Thune PO, Drevon CA.

Effect of dietary supplementation with n⫺3 fatty acids on clinical manifestations of psoriasis.Br J Dermatol.1988;118(1): 77– 83

20. Janson H, Squires J. Parent-completed developmental screen-ing in a Norwegian population sample: a comparison with US normative data.Acta Paediatr.2004;93(11):1525–1529 21. Richter J, Janson H. A validation study of the Norwegian

version of the Ages and Stages Questionnaires.Acta Paediatr. 2007;96(5):748 –752

22. Black LS, deRegnier RA, Long J, Georgieff MK, Nelson CA. Electrographic imaging of recognition memory in 34 –38-week gestation intrauterine growth restricted newborns.Exp Neurol. 2004;190(suppl 1):S72–S83

23. Simmer K, Patole S. Long-chain polyunsaturated fatty acid supplementation in preterm infants.Cochrane Database Syst Rev. 2004;(1):CD000375

24. Willatts P, Forsyth JS. The role of long-chain polyunsaturated fatty acids in infant cognitive development.Prostaglandins Leu-kot Essent Fatty Acids.2000;63(1–2):95–100

25. McCall RB, Carriger MS. A meta-analysis of infant habituation and recognition memory performance as predictors of later IQ. Child Dev.1993;64(1):57–79

26. Fellman V, Kushnerenko E, Mikkola K, Ceponiene R, Leipala J, Naatanen R. Atypical auditory event-related potentials in preterm infants during the first year of life: a possible sign of cognitive dysfunction?Pediatr Res.2004;56(2):291–297 27. deRegnier RA, Georgieff MK, Nelson CA. Visual event-related

brain potentials in 4-month-old infants at risk for neurodevel-opmental impairments.Dev Psychobiol.1997;30(1):11–28 28. Richards JE. The development of visual attention and the

brain. In: de Haan M, Johnson MH, ed.The Cognitive Neuro-science of Development. Hove, England: Psychology Press; 2003: 73–98

29. Vanderhoof J, Gross S, Hegyi T, et al. Evaluation of a long-chain polyunsaturated fatty acid supplemented formula on growth, tolerance, and plasma lipids in preterm infants up to 48 weeks postconceptional age. J Pediatr Gastroenterol Nutr. 1999;29(3):318 –326

30. Fewtrell MS, Morley R, Abbott RA, et al. Double-blind, ran-domized trial of long-chain polyunsaturated fatty acid supple-mentation in formula fed to preterm infants.Pediatrics.2002; 110(1):73– 82

31. Carlson SE, Cooke RJ, Werkman SH, Tolley EA. First year growth of preterm infants fed standard compared to marine oil n⫺3 supplemented formula.Lipids.1992;27(11):901–907 32. Carlson SJ, Ziegler EE. Nutrient intakes and growth of very low

birth weight infants.J Perinatol.1998;18(4):252–258

POVERTY IS POISON

“‘Poverty in early childhood poisons the brain.’ That was the opening of an

article in Saturday’s Financial Times, summarizing research presented last

week at the American Association for the Advancement of Science. As the article explained, neuroscientists have found that ‘many children growing up in very poor families with low social status experience unhealthy levels of stress hormones, which impair their neural development.’ The effect is to impair language development and memory—and hence the ability to escape poverty—for the rest of the child’s life. So now we have another, even more compelling reason to be ashamed about America’s record of failing to fight poverty. L.B.J. declared his ‘War on Poverty’ 44 years ago. Contrary to cynical legend, there actually was a large reduction in poverty over the next few years, especially among children, who saw their poverty rate fall from 23 percent in 1963 to 14 percent in 1969. But progress stalled thereafter: American politics shifted to the right, attention shifted from the suffering of the poor to the alleged abuses of welfare queens driving Cadillacs, and the fight against poverty was largely abandoned. In 2006, 17.4 percent of chil-dren in America lived below the poverty line, substantially more than in 1969. And even this measure probably understates the true depth of many children’s misery.”

Krugman P.New York Times. February 18, 2008

(10)

DOI: 10.1542/peds.2007-1511

2008;121;1137

Pediatrics

Berge, Lars Smith, Per Ole Iversen and Christian André Drevon

Rønnestad, Morten Grønn, Rønnaug Solberg, Atle Moen, Britt Nakstad, Rolf Kristian

Christine Henriksen, Kristin Haugholt, Magnus Lindgren, Anne Karin Aurvåg, Arild

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Supplementation of Human Milk With Docosahexaenoic Acid and Arachidonic

Improved Cognitive Development Among Preterm Infants Attributable to Early

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DOI: 10.1542/peds.2007-1511

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Pediatrics

Berge, Lars Smith, Per Ole Iversen and Christian André Drevon

Rønnestad, Morten Grønn, Rønnaug Solberg, Atle Moen, Britt Nakstad, Rolf Kristian

Christine Henriksen, Kristin Haugholt, Magnus Lindgren, Anne Karin Aurvåg, Arild

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Figure

TABLE 1Mean Fatty Acid Compositions of Unfortified Human Milkand the Study Oils
TABLE 2Baseline Characteristics of the Study Population
TABLE 4Enteral Feeding Data for the Study Groups
TABLE 5Plasma Fatty Acid Patterns According to Study Group
+2

References

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