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Higher dose of docosahexaenoic acid in the neonatal period improves visual acuity of preterm infants: results of a randomized controlled trial^1,2,3,4

¹ From the Women's and Children's Health Research Institute (LGS, RAG, and MM) and Neonatal Medicine (AM), Children, Youth and Women's Health Service, North Adelaide, Australia; Flinders Medical Centre, Bedford Park, Australia (LGS, RAG, and MM); School of Paediatrics and Reproductive Health (LGS and MM) and the School of Agriculture, Food and Wine (RAG), University of Adelaide, Adelaide, Australia

² Neither Nutricia Australia nor Clover Corporation had any role in the design, analysis, or interpretation of this trial.

³ Supported by grants from the National Health and Medical Research Council of Australia (NHMRC), the Channel 7 Children's Research Funds, the University of Adelaide and Senior Research Fellowships from the NHMRC (MM and RAG). Formula for this trial was generously suppled by Nutricia Australia, North Ryde, Australia. Tuna and soy oil capsules were generously supplied by Clover Corporation, Sydney, Australia.

⁴ Reprints not available. Address correspondence to M Makrides, Women's and Children's Health Research Institute, Level 1, Clarence Reiger Building, Children, Youth and Women's Health Service, 72 King William Road, North Adelaide SA 5006, Australia. E-mail: maria.makrides{at}cywhs.sa.gov.au.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: Preterm infants have improved visual outcomes when fed a formula containing 0.2–0.4% docosahexaenoic acid (DHA) compared with infants fed no DHA, but the optimal DHA dose is unknown.

Objective: We assessed visual responses of preterm infants fed human milk (HM) and formula with a DHA concentration estimated to match the intrauterine accretion rate (high-DHA group) compared with infants fed HM and formula containing DHA at current concentrations.

Design: A double-blind randomized controlled trial studied preterm infants born at <33 wk gestation and fed HM or formula containing 1% DHA (high-DHA group) or 0.3% DHA (current practice; control group) until reaching their estimated due date (EDD). Both groups received the same concentration of arachidonic acid. Sweep visual evoked potential (VEP) acuity and latency were assessed at 2 and 4 mo corrected age (CA). Weight, length, and head circumference were assessed at EDD and at 2 and 4 mo CA.

Results: At 2 mo CA, acuity of the high-DHA group did not differ from the control group [high-DHA group ( ± SD): 5.6 ± 2.4 cycles per degree (cpd), n = 54; control group: 5.6 ± 2.4 cpd, n = 61; P = 0.96]. By 4 mo CA, the high-DHA group exhibited an acuity that was 1.4 cpd higher than the control group (high-DHA: 9.6 ± 3.7 cpd, n = 44; control: 8.2 ± 1.8 cpd; n = 51; P = 0.025). VEP latencies and anthropometric measurements were not different between the high-DHA and control groups.

Conclusion: The DHA requirement of preterm infants may be higher than currently provided by preterm formula or HM of Australian women.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Retinal and neural tissues accumulate the n–3 long-chain polyunsaturated fatty acid (LCPUFA), docosahexaenoic acid (DHA) throughout gestation (1). Preterm infants are denied the full intrauterine supply of DHA available to infants born at term; therefore, they depend on diet to supply all the DHA needed for growth and development.

Human milk (HM) provides DHA, but, until the 1990s, preterm infant formulas were devoid of LCPUFAs. Randomized controlled trials (RCTs) comparing visual development of preterm infants fed LCPUFA-enriched formula with unsupplemented formula have reported inconsistent findings. Some RCTs showed improved retinal sensitivity (2) and visual acuity (3–6) in infants fed LCPUFA-enriched formula, yet others reported no differences in visual acuity between infants fed LCPUFA-supplemented and -unsupplemented formula (7, 8). Those different trial results may in part be due to the relatively low doses of DHA in the supplemented formulas (between 0.2% and 0.4% total fatty acids) compared with the amount of total body DHA accumulated during gestation. Total fetal accretion of n–3 LCPUFA was estimated to be 50 mg of n–3 LCPUFAkg^–1d^–1 during the last trimester of gestation (1). To provide preterm infants with a dose of DHA equivalent to that deposited in fetal tissues during gestation, milk needs to provide higher concentrations of DHA than currently available in preterm formulas or in HM from mothers consuming a Western diet.

We report on a RCT to compare visual development of preterm infants fed milk providing 1% DHA with infants fed DHA at concentrations found in HM of Western mothers and currently marketed preterm formulas (0.3% of total fatty acids). Neonatal nurseries encourage and support feeding of HM milk to provide protection from necrotizing enterocolitis and to foster maternal attachment. Hence, many preterm infants receive a mixed diet of HM and formula in the neonatal period (9, 10). Our trial was designed to increase the dietary supply of DHA in milk fed to preterm infants, with any combination of HM and formula feeding. In the high-DHA group, HM DHA was increased by supplementing lactating mothers with DHA-rich tuna oil, and preterm formula was fortified with extra DHA if formula feeds were required. In the control group, mothers were supplemented with placebo oil capsules and currently marketed preterm formula with added placebo oil. The population of infants was from a wide range of gestational ages and included infants with medical comorbidities common to preterm infants. The mixed HM and formula feeding strategy, as well as the broad eligibility criteria, was intended to improve the generalizability of the trial to the wider population of preterm infants. We hypothesized that preterm infants fed milk with a DHA concentration equivalent to that provided during intrauterine development would exhibit enhanced visual acuity compared with infants fed a lower DHA concentration available through current clinical practice.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects
Families of infants born < 33 wk gestation at the Women's and Children's Hospital of the Child, Youth, and Women's Health Service, Adelaide, Australia, between April 2001 and September 2003 were invited to participate in this double-blind RCT. Infants with major congenital or chromosomal abnormalities were excluded, as were lactating mothers for whom tuna oil was contraindicated (women with blood-thinning disorders or currently taking anticoagulants). Infants were required to be randomly assigned within 5 d of receiving any enteral feeds. Informed written consent was obtained according to the trial protocol, which was approved by the Child, Youth, and Women's Health Service Research Ethics Committee.

Allocation and treatment
Mothers and their infants were randomly assigned to the high-DHA or control intervention by consecutively numbered, opaque sealed envelopes that disclosed the study randomization number and the color code. The randomization sequence concealed in the envelopes was computer-generated by an independent consultant. The randomization schedule was stratified for sex and birth weight < 1250 and 1250 g, 2 factors expected to influence the primary outcome. To augment masking of the groups, the trial had 2 separate color-coded treatment groups and 2 separate color-coded control groups. All participants, as well as medical, nursing, and clinical trial staff, were unaware of the group allocation. Breastfeeding mothers were asked to consume six 500-mg capsules of oil per day, from enrollment through to her term expected delivery date (EDD). The control group capsules contained soy oil (which has no DHA and does not alter the DHA content of HM), whereas the treatment capsules contained tuna oil rich in DHA. The soy and tuna oil capsules were identical in size, color, and shape, and their composition is shown in Table 1. In line with hospital policy, mothers were encouraged to provide HM for as long as possible. A formula with a matching group allocation was supplied if the mother chose not to provide HM or if supplementary milk was required. Trial formula was prepared daily by nursery staff in a dedicated milk preparation room and stored at 4 °C until use. Because formulas contain surplus emulsifiers, trial formula was prepared by gently mixing 2 drops of oil from the allocated capsules into each 60-mL bottle of ready-to-feed formula, which was the standard formula milk used by the neonatal unit. During the intervention period, we regularly collected and stored trial formula from the nursery supply for later analysis of DHA composition. Maternal compliance was evaluated by fatty acid analysis of frozen expressed HM samples that were collected every day for 7 d preceding EDD. The effect of the dietary intervention was assessed by LCPUFA analysis of blood samples collected by heel-prick at EDD. The study described here was the pilot phase of a large, multicenter RCT investigating the effects of high-dose DHA supplementation on neurodevelopment of preterm infants (11).

Visual evoked potentials
Sweep visual evoked potential (VEP) acuity at 4 mo corrected age (CA) was the primary outcome, and sweep VEP acuity at 2 mo CA and VEP latency at 2 and 4 mo CA comprised secondary outcomes. For all VEP recordings infants sat in a darkened room (50 cd/m²) on their caregiver's lap at 50 cm from the monitor. VEP stimuli and data were recorded with the use of ENFANT 4010 software (Neuroscientific Corp, Farmingdale, NY).

For sweep VEP acuity, infants were presented with a horizontal sinusoidal grating pattern of constant luminance reversing at 12 Hz. Each 10-s stimulus swept in roughly linear increments from 0.26 to 8.43 cycles per degree (cpd) at 2 mo CA. At 4 mo CA the visual stimulus was initially set at 0.51–8.43 cpd; however, after testing the first 31 infants from the trial it was clear that a number of infants exhibited acuities higher than 8.43 cpd, hence the spatial frequency of the stimulus was increased from 1.0 to 13.6 at 4 mo CA. Data from the first 31 infants were not included in the acuity results (n = 16 control, n = 15 treatment group). These infants did not differ in sex, birth weight, or gestational age from infants tested with the appropriate stimulus. Responses to approximately 10 sweeps were collected, depending on infant fatigue. The electrode montage included 2 active electrodes (O₁ and O₂) placed at 30% left and right of a central reference electrode placed over the occipital cortex, with a grounded electrode at the central vertex. Impedance was matched in active channels, usually at <5 . Frequencies between 1 and 100 Hz were amplified 10 K through 2 AC amplifiers (model PC511; Grass Technologies, Astro-Med Inc, West Warwick, RI). To reduce user manipulation of acuity data we developed software to assist with the analysis of acuity data based on the description published by Norcia et al (13). The software was written in the MATLAB program (version 6.0.0.88 release 12; The Mathworks Inc, Natick, MA). Acuity was estimated from an automatically generated regression line passing through the linear portion of the amplitude compared with spatial frequency function to 0 V. Data included in the regression equation were subject to the following signal and phase conditions; one point had a signal-to-noise ratio (SNR) > 3 plus 2 further points with SNR > 1.5; continuously constant or lagging phase. The SNR was calculated from amplitude of the signal divided by the mean of the noise at 14 Hz. Phase was calculated from the raw data multiplied by the sine and cosine components of the stimulus at the reversal rate. An infant's best performance estimated from either a single sweep or the vector average of 3 sweeps was considered to be the limit of acuity.

VEP latency stimuli were 2 high contrast (90%) checkerboard patterns reversing at 2 Hz for 30 s with visual angles subtending 96 and 69 min of arc at 2 mo CA, and 69 and 48 min of arc at 4 mo CA. Duplicate responses to each check were recorded from an active electrode placed at the occipital cortex, a reference electrode at the central hairline on the forehead and an earth electrode at the central vertex. Latencies are reported (in ms) as the time to the first positive peak of the response (P1 or P100).

Anthropometry
Infant weight, length, and head circumference (HC) were measured at EDD and at 2 and 4 mo CA. Infant weight without clothing was measured on a calibrated electronic balance to the nearest 5 g. Recumbent length was measured to the nearest 1 mm on an infant length board (O'Leary; Ellard Instrumentation, Monroe, WA) according to standard procedures with the head in the Frankfort plane (14). HC was taken as the largest occipitofrontal circumference and measured to the nearest 1 mm with the use of nonstretchable tape.

Sample size
On the basis of the primary outcome of VEP acuity, a sample size of 50 infants per group was necessary to detect a 2-cpd improvement in VEP acuity of infants between the groups with 95% confidence and 90% power. We aimed to enroll 70 infants per group to accommodate up to 20% loss to follow-up.

Statistical analyses
Statistical analyses were performed with the use of SPSS for WINDOWS (version 11.0.0; SPSS Inc, Chicago, IL), with probability < 0.05 considered significant. Primary analyses were conducted on intention-to-treat group comparisons followed by covariate adjustment for birth weight and sex. Preplanned subgroup analyses comparing VEP acuity between the treatment and control groups were limited to randomization strata and the primary endpoint (at 4 mo CA). Secondary analyses comparing VEP acuity at 4 mo CA between the treatment and control groups included infants predominantly fed HM at the end of the intervention period (80% of diet). Categorical variables were compared by chi-squared tests; continuous normally distributed variables were compared by independent samples t tests and nonparametric continuous variables by Mann-Whitney U tests. In chi-squared comparisons, the Yates correction for continuity statistic was used to prevent overestimation of the significance, and the Fischer's exact probability test was applied when examining variables of low incidence. In exploratory analyses, Pearson's correlations were used to examine the relation between erythrocyte phospholipid fatty acids and weight, length, and HC. Statistical analyses were performed blinded to group assignment, and the code was broken only after all analyses of primary and secondary outcomes were completed.

	RESULTS

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Study sample
One hundred forty-three preterm infants were enrolled in the trial, with 74 randomly assigned to the treatment group and 69 to the control group (Figure 1). During the intervention period, 2 infants from each group were withdrawn and 1 (treatment group) died. At 2 mo CA, 13 infants (7 treatment, 6 control) did not attend follow-up and 11 infants (7 treatment, 4 control) did not attend at 4 mo CA (Figure 1).

View larger version (27K): [in this window] [in a new window]   FIGURE 1. Flow of participants through trial. 1Two infants from both groups were withdrawn from the trial at their parents’ request before receiving the intervention. 2One infant from the treatment group died of necrotizing enterocolitis before the end of the intervention period. This infant was included in "received allocated intervention" because the infant received the docosahexaenoic acid–supplemented intervention. 3Two infants in the treatment group and 3 infants in the control group who did not attend at 2 mo corrected age returned for the appointment at 4 mo corrected age.

Table 2

Infant erythrocyte phospholipid DHA was significantly higher, and the n–6 fatty acids linoleic acid and AA were significantly lower in the treatment group than in the control group (Table 3). This finding showed the bioavailability of the intervention.

Table 4

VEP latencies were not significantly different between the control and treatment groups at 2 or 4 mo CA (Table 4). Maturation of the latency response, as indicated by faster time to peak response, was observed in both groups between 2 and 4 mo CA (P < 0.0005).

Anthropometry
Weight, length, and HC were not significantly different between the treatment and control groups at EDD or 2 or 4 mo CA (Figure 2). A sex-by-diet interaction was observed, indicating that the response to diet differed between males and females (P = 0.04). Further investigation of sex subgroups showed that females fed high-dose DHA were heavier and longer than were control females at 4 mo CA (weight, treatment: 6139 ± 873 g, n = 32; control: 5693 ± 815 g, n = 37; 95% CI: –842, –19; P = 0.04; length, treatment: 60.8 ± 2.6 cm; control: 59.3 ± 2.8 cm, 95% CI: –2.7, –0.13; P = 0.03; HC, treatment: 41.5 ± 1.0 cm; control: 41.1 ± 1.0 cm; 95% CI: –0.8, 0.2; P = 0.2). In males, growth measures did not differ between groups. No consistent relations were observed between erythrocyte phospholipid polyunsaturated fatty acids and weight, length, and HC at 4 mo CA across all infants.

View larger version (6K): [in this window] [in a new window]   FIGURE 2. Infant anthropometry at enrollment, at the end of the intervention period, and at 2 mo corrected age (CA) and 4 mo CA. Weight, length, and head circumference of the treatment group (shaded boxes) and control group (white boxes) at enrollment, at estimated due date (EDD), at 2 mo CA, and at 4 mo CA are shown. Boxes show median and upper and lower quartiles at end with whiskers extending to the 10th and 90th percentiles. Independent t tests showed no significant differences between the treatment and control groups for any anthropometric measurements. A sex-by-diet interaction (P = 0.04) showed differential effects of the intervention on sex, in which the subgroup of females fed the high-dose DHA were heavier and longer than those fed the control intervention, but no differences were observed in the males (see text for details).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

Within the male and female subgroups, visual acuity improved with high-dose DHA treatment, but only the male subgroup achieved significance because of the greater mean difference. Acuity in the female subgroup was consistent with the direction of the overall analysis, and we did not find any evidence of differential effects between sex and diet; therefore, the nonsignificant finding in the females is likely to be due to the limited sample size of the subgroup. Consistent with other research, we found no effect of DHA supplementation on VEP acuity at 2 mo CA followed by subsequent improvement at 4 mo CA (6). This is difficult to explain but may indicate differential sensitivity of acuity measures at these ages.

Our trial was focused on DHA because it is the major n–3 LCPUFA present in retinal and neural tissues. The high concentration of DHA in membranes of retinal photoreceptors and neurons is indicative of the importance of DHA in membrane-associated functions, including signal transduction, neurotransmission, and neurogenesis (15). However, the clinical relevance of enhanced visual acuity with high-dose dietary DHA in the present trial is not clear because most infants from both groups achieved an acuity considered to be normal. Studies with infants born at term have shown that lower n–3 LCPUFA status in early life was related to poorer stereoacuity and letter matching in childhood (16) and to poorer attentional control (increased distractibility) (17), which together indicates that the effects of early LCPUFA nutrition may persist over time and influence multiple areas of development. Just as evidence from our trial suggests current practices about n–3 LCPUFA nutrition may be inadequate to support optimal development of the visual system, similar-sized benefits were also observed in recognition memory and problem-solving tests (18), suggesting that other developmental domains may also be vulnerable to DHA nutrition. Further assessments across multiple domains and into early childhood are necessary to identify the optimal concentration of dietary DHA for preterm infants.

Transient VEP latency responses did not differ between high- and standard-dose DHA groups, indicating comparable myelination of the visual pathway. Although no other LCPUFA intervention trials involving preterm infants have assessed transient latencies to checkerboard stimuli, 3 trials have reported latencies to flash stimuli (8, 19, 20). In 2 of those trials, no significant differences in latencies were found between infants fed LCPUFA-supplemented and unsupplemented formula (8, 19). Although improved flash VEP latencies were reported in one trial, the sample size was small and the trial was not analyzed according to the intention-to-treat principle, which may have reduced the validity of the observation (20).

The relation between dietary LCPUFA, fatty acid status, and infant growth remains controversial, particularly with the balance of dietary DHA and AA. The concentration of DHA in HM fed to the treatment group was 1% and AA was 0.4%, whereas control milk provided 0.3% DHA and 0.4% AA. The higher concentration of DHA in erythrocyte phospholipids of treated compared with control infants indicates that the extra DHA present in milk was bioavailable. Although the infants from both groups received equivalent amounts of AA, infants in the treatment group had a lower erythrocyte phospholipid AA than did infants in the control group. Despite the difference in erythrocyte AA status between the high-DHA group and the control group, no overall effect of the intervention on growth measurements was observed.

LCPUFA trials in formula-fed preterm infants have reported inconsistent findings in terms of infant growth. Although some trials have found no differences in growth measurements between infants fed LCPUFA-supplemented formula compared with no LCPUFA supplementation (21–23), other trials have reported both increased (7, 24) and reduced (25–27) growth. A systematic review and meta-analysis of LCPUFA trials in preterm infants concluded that LCPUFA-supplemented formula may enhance anthropometric measures of preterm infants at 2 mo of age (28) compared with infants fed formula with no LCPUFA; however, growth of males and females were not examined separately. In the present trial, the increases in the weight and length of females fed the high-dose DHA intervention compared with the control intervention are consistent with the overall findings of the systematic review (28). However, differences in growth measures only in the female subgroup should be interpreted with caution because of the reduced sample size.

In summary, we have described a unique DHA intervention trial in preterm infants fed HM and formula. Our novel approach of involving lactating mothers was readily accepted by women and was easily incorporated into clinical management. By incorporating both HM and formula into the intervention strategy, we have widened the population under investigation, designed a trial comparing 2 distinct dietary doses of DHA, and examined the unexplored area of dietary DHA for preterm infants fed HM. Furthermore, we have involved infants from a broad range of gestational ages and clinical conditions in which many of the typical diseases of prematurity were present. Hence, our trial findings offer generalizability to the wider population of preterm infants and suggest that the amount of DHA fed to preterm infants in HM and formula may not be sufficient for optimal visual development.

	ACKNOWLEDGMENTS

 
We thank the families and their infants for their participation. We also thank Heather Garreffa, Jenni O'Hare, Ros Lontis, Louise Goodchild, Dr Brett Jeffrey, Sherry Randhawa, Prof Algis Vingrys, and Dr Bang Bui for their clinical, administrative, and technical support.

The author's responsibilities were as follows—MM, RAG, and AM: designed the trial; LGS and AM: collected data under the supervision of MM; RAG: responsible for the fatty acid analyses; LGS: developed the visual testing methods, analyzed the data, and wrote the manuscript under the supervision of MM and RAG; MM and RAG: secured the funding and contributed to the interpretation of the data; all authors approved the final version. None of the authors had a personal or financial conflict of interest. In the past, MM and RAG have conducted clinical trials funded by the formula industry. They have no financial interest in the production and sales of infant formula or nutritional supplements.

	REFERENCES

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

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