Five new, eligible, completed trials have been added in this update. Results of the new trials confirm that there are no significant benefits or risks of LCPUFA supplementation of formula for preterm infants.
Not enough evidence to show the effect of supplementing baby formulas for preterm babies with fat supplements to improve early sight development and intelligence.
Babies fed with breast milk are believed to have more mature sight skills and a higher IQ (Intelligence Quota) than babies fed with formula. It has been suggested that low levels of longchain polyunsaturated fatty acids (LCPUFA) found in formula, may contribute to the lower IQ levels and sight skills. Some formulas are available with added LCPUFA. The review of trials found the evidence does not support the claim that preterm infants have improved visual and intellectual development if their formula is supplemented with LCPUFA. LCPUFA supplementation does not significantly influence the growth of preterm infants.
The n-3 and n-6 essential fatty acids alpha linolenic acid (ALA) and linoleic acid (LA) are the precursors of the n-3 and n-6 longchain polyunsaturated fatty acids (LCPUFA). Controversy exists over whether LCPUFA are essential nutrients for preterm infants who may not be able to synthesise sufficient amounts of LCPUFA to satisfy the needs of the developing brain and retina.
The aim of this review is to assess whether supplementation of formula with LCPUFA is safe and of benefit to preterm infants.
Development
Most of the trials have used Bayley Scales of Infant Development
(BSID) at 12 to 24 months postterm and shown no significant effect following
supplementation. Meta-analysis of BSID of three studies (Fewtrell 2002,
O'Connor 2001, van Wezel 2002) shows no significant effect of supplementation
on development. Carlson 1993 and Carlson 1996 demonstrated lower novelty
preferences (possibly predictive of lower intelligence) in the supplemented
compared with the control group. The investigators however concluded that
supplemented infants may have more rapid visual information processing given
that they had more looks and each look was of shorter duration.
Growth
Most trials have reported no significant effect of LCPUFA supplementation
on growth of preterm infants. Two trials (Carlson 1993, Carlson 1996) suggest
that LCPUFA supplemented infants grow less well than controls, possibly
due to a reduction in AA levels which occurs when n-3 supplements are used
without n-6 supplements. Recent trials with addition of AA to the supplement
have reported no significant effect on growth. Fewtrell 2002 reported mild
reductions in length and weight z scores at 18 months. Contrary to these
results, the meta-analysis of five studies (Uauy 1992, Carlson 1996, Hansen
1997, Vanderhoof 1999, Innis 2002) showed increased weight and length at
two months post-term in supplemented infants.
Side effects
Uauy 1992 reported no significant effect of LCPUFA supplementation on
bleeding time and red cell membrane fragility.
Dietary fat in infancy is fundamental for the provision of energy for rapid growth, fat soluble vitamins and essential fatty acids. However, the type of fat required is controversial and interest has recently focused on the importance of LCPUFA such as docosahexaenoic acid (DHA) and arachidonic acid (AA). These fatty acids are found in high proportions in the structural lipids of cell membranes, particularly those of the central nervous system, and their accretion primarily occurs during the last trimester of pregnancy and the first year of life (Clandinin 1980).
During pregnancy DHA and AA cross the placenta to the fetus. Postnatally these fatty acids are supplied in breast milk which contains a full complement of all PUFA including precursors and metabolites. However, most infant formulae contain only the precursor essential fatty acids (EFA), ALA (omega 3 precursor) and LA (omega 6 precursor) from which formula-fed infants must synthesise their own DHA and AA respectively. The absence of LCPUFA in formula may be further exacerbated by inhibition of incorporation of endogenously produced LCPUFA by the high concentrations of LA currently in most formulae. Biochemical studies in both term and preterm infants indicate that formula-fed infants have significantly less DHA and AA in their erythrocytes relative to those fed breast milk (Clark 1992). This suggests that infant formulae containing only LA and ALA may not be effective in meeting the full EFA requirements of infants.
Biochemical studies of LCPUFA are clinically relevant as dietary fatty acid supply may affect physiological function. In non-randomised, observational studies, term infants fed breast milk have been found to have more mature visual acuities and higher DHA levels than those receiving formula. Further, their acuities were positively correlated with erythrocyte DHA levels (Makrides 1993).
Evidence to suggest that breast fed infants have a longterm IQ advantage over those who have been fed formula has been evident in the literature for many years (Rogers 1987; Morrow-Tlucak 1988; Lucas 1992; Temboury 1994). As most of these studies are not randomised, the majority of comparisons between breast fed and formula-fed infants are confounded by genetic and socioeconomic factors. These studies do not relate their findings to fatty acid supply. However, some reports suggest that the low levels of LCPUFA, such as DHA, found in formula-fed infants may contribute to the lower IQ scores reported in formula-fed infants (Rogers 1987; Bjerve 1992; Neuringer 1986).
There are few prospective studies investigating the effect of DHA supply on long-term development. Randomised trials comparing standard formula and supplemented formula are necessary to address the issue of whether LCPUFA are essential nutrients in infancy before supplementation of formula with LCPUFA becomes routine, at considerable cost without the longterm risks and benefits being determined.
The aim of this review is to assess whether supplementation of formula with LCPUFA is safe and of benefit to preterm infants. The main areas of interest are the effects of LCPUFA supplementation on the visual function, development and growth of preterm infants.
Only randomised clinical trials with at least six weeks of follow-up were considered.
Trials involving enterally-fed preterm (<37 weeks gestation) infants were considered.
Different LCPUFA supplements were included as different oils have been used to increase the DHA levels in the plasma and erythrocytes of infants e.g. fish, fungal and egg phospholipid.
Trials with clinical outcomes (visual development, general development, growth) were included. Trials reporting biochemical outcomes were not included.
Trials were identified by MEDLINE (October 2003), Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2003), conference proceedings, and by checking reference lists of relevant articles.
Data collection forms were compiled and completed independently by the
two reviewers. Authors for four of the studies were contacted in writing
to clarify or provide missing data and a response was received from one
(O'Connor & Auestad).
Abbreviations used in this review include: LCPUFA longchain polyunsaturated
fatty acids, n- omega, LA linoleic acid, ALA alpha linolenic acid, AA
arachidonic acid, DHA docosahexaenoic acid, EFA essential fatty acids,
GA gestational age, BW birthweight, VEP visual evoked potential, ERG electroretinogram,
ACP acuity card procedure, FPL forced preferential looking, PDI psychomotor
developmental index, MDI mental developmental index, RBC red blood cell,
PCA postconceptional age, TBARS thiobarbituric acid reactive substances.
Eleven randomised studies assessing the clinical effects of feeding formula supplemented with LCPUFA were identified. Published data were inadequate to include one of the trials (Donzelli 1996). Details of the patients and methods of the eleven trials included in this review are summarised in the Table, Characteristics of Included Studies. The composition and dose of LCPUFA supplement varied. Some studies supplemented with only n-3 fatty acids and some with n-3 and n-6 fatty acids. If infants were randomised to more than one supplement, the supplement that contained both n-3 and n-6 LCPUFA was selected for the comparison over one containing only n-3. If the two supplements were n-3 and n-6 as fish/fungal oil or egg-TG/fish oil, we chose the fish/fungal group as microbial oils are more similar to human milk fat than egg-TG. For this review, if more than one control group was included, the control group receiving a formula with a LA:ALA ratio most like breast milk was selected.
The quality of the trials was assessed predominantly based on method of
randomisation, blinding of intervention and blinding of outcome assessment,
giving attention to the possibility of selection bias, performance bias,
exclusion bias and detection bias.
The Uauy 1990; Carlson
1992; Clandinin 1997; Hansen 1997; Vanderhoof
1999; O'Connor 2001; Fewtrell 2002; Innis
2002 and van Wezel 2002 trials were
assessed to be of good quality. The Carlson 1996
and Fadella 1996 trials were not classified
as of high quality despite blinded assessment and complete follow-up due
to problems with assessment methodology. The developmental assessment tool
changed in the middle of the Carlson 1996
trial whereas Fadella 1996 used methodologies
for VEP & ERG assessments that deviate from generally accepted international
standards.
Visual development-assessment methods
Visual acuity is a measure of the smallest element that can be resolved and may be assessed in infants by using gratings which consist of black and white stripes or checkerboard patterns. Grating acuity can be measured by using behavioural (Teller acuity cards) or visual evoked potential (VEP) methods. Each pairing of a black and white stripe is referred to as a cycle and the spatial frequency of a grating is defined by the number of cycles per degree of viewing angle. As grating spatial frequency increases, the stripes become finer and are more difficult to discriminate, eventually appearing as an even grey to the observer. Grating acuity is the highest spatial frequency where the stripes can be resolved.
The VEP is the electrical activity of the brain that is generated in response to a reversing contrast checkerboard or grating. The VEP is recorded from an electrode placed over the occipital pole. The amplitude of the VEP increases linearly with spatial frequency near the visual acuity threshold. Linear regression is used to fit a straight line through the linear portion of the VEP amplitude versus spatial frequency curve and visual acuity is determined from the intercept of the regression line with the spatial frequency axis. Studies in this review have used different methods for assessing VEP (transient, steady state and sweep VEP). Transient VEP reflects a slow pattern reversal rate and records individual responses where the brain has time to recover after each reversal. A steady state VEP reflects a quick pattern reversal rate in which the next evoked response is actually evoked before the previous one has finished. The evoked responses hence run into each other so the output looks almost like a sine wave. The faster the reversal rate the more condensed the wave. The sweep/swept VEP is also a steady state technique but uses a different stimulus-usually stripes (instead of checks) that sweep through from the largest to the smallest in about 10 seconds.
Behavioural methods for assessing visual acuity rely on the strong preference shown by infants for patterned stimuli over non-patterned stimuli. Both the acuity card procedure (ACP) and the forced preferential looking (FPL) procedure have been used in conjunction with the Teller acuity cards for measuring the development of visual acuity in infants. The FPL procedure tests binocular grating acuity; the tester views the infant through a peephole, without knowledge of the spatial-frequency gratings on the cards, and makes a forced-choice judgement about which card the infant prefers. Individual acuities are converted to log cycles/degree and SD are in octaves which are determined by dividing one log SD by 0.3.
Electroretinogram (ERG) is an assessment of retinal function. The more mature the retinal function, the lower the threshold required to elicit a response, and the higher the maximum amplitude recorded (threshold and Vmax are reported in log units).
For this review, most of the visual data is analysed as mean+/- SD in
log values. This form of data presentation and the varying assessment methods
preclude the use of meta-analysis.
Visual development - results
Visual acuity using Teller cards was measured in the Carlson 1992 and Carlson 1996 studies. In the 1993 study, the supplement was fed until 12 months and visual acuity was better in the supplemented group at 2 and 4 months post-term but not at 6, 9, and 12 months (the data are published in Figures only and therefore cannot be included in the Tables for this review). In the 1996 study, LCPUFA supplementation was fed until 2 months post-term and visual acuity assessed over 12 months post-term. At 2 months, the supplemented infants without bronchopulmonary dysplasia (BPD) had better visual acuity compared with control but supplemented infants with BPD had poorer visual acuity compared with controls. No differences between supplemented and control groups (with or without BPD) were detected at 4, 6, 9 and 12 months.
In the Hansen 1997 study, visual acuity was also assessed with Teller acuity cards and no difference was documented between supplemented and control infants at 2 and 4 months post-term.
Fadella 1996 assessed vision using the flash VEP; waveforms of the supplemented group were of different morphology and some of shorter latency than those of the control group - the latencies of N4 and P4 were shorter in the supplemented group but the latencies of N2, P2, N3 and P3 were not significantly different between the groups. There are concerns with the methodology of assessment in this study in that it deviates from international standards (International Society for Clinical Electrophysiologists in Vision). Therefore, the data reported are difficult to interpret and sensitivity may have been decreased so much that changes due to the intervention may not have been detected.
Uauy 1990 measured visual acuity at two months post-term using visual evoked potentials (VEP) and Teller acuity cards and report that the LCPUFA supplemented infants had better visual acuity (data were not available for this review).
Uauy 1990 also assessed retinal function and demonstrated that Vmax for rod function measured by the ERG was higher in supplemented infants when compared with control infants at 36 weeks postconceptional age (PCA) but there were no significant differences at 4 months post-term. The function of the cones, which are more mature at birth, was not affected (data not included in this review). Fadella 1996 measured ERG at 52 weeks PCA or 3 months post-term. There were no significant differences between the groups in ERG (a and b latencies, and a-b amplitude), however, subjects were not dark-adapted, their pupils were not dilated and electrodes were placed on the forehead instead of using contact lens or gold foil electrodes.
Fadella 1996 also measured auditory evoked responses at 52 weeks post-conceptional age and found no differences between the groups (nine latencies measured, these results are not listed in this review but are available in the publication).
Innis 2002 measured visual acuity (Teller acuity cards) at 2 and 4 months post-term and found no difference between supplemented and control groups.
O'Connor 2001 measured visual acuity by Teller acuity cards at 2, 4 and 6 months post-term and found no difference between supplemented and control groups. However, swept-parameter VEP was better in the supplemented groups compared with control group in a subgroup of infants at 6 months post-term. van Wezel 2002 also reported no significant differences in visual acuity between the supplemented and control groups at 3 and 12 months post-term by flash VEP and at 3, 6, 12 and 14 months post-term by Teller acuity cards. However, the sample size in this study was small and calculated on cerebral myelination assessed by magnetic resonance imaging. They found no significant difference in cerebral myelination between groups.
Development
Carlson 1992 and Carlson 1996 report the results of the Fagan
Infantest of development at 12 months. Data are also published at six and
nine months for the 1993 study but not included in this review. The Fagan
Infantest measures novelty preference based on the observation that after
habituation to a familiar stimulus has occurred, a preference will be shown
for a different (novel) stimulus if both the familiar and novel stimuli are
presented together. A novelty preference score is derived for the average
percent of total time spent viewing the novel stimuli on ten discrete paired
comparison tests. Infants with average scores of > 57% are said to have
a significant novelty preference i.e. the time spent looking at the novel
stimuli compared that spent looking at the familiar stimuli is greater than
by chance alone. Novelty preference has been interpreted as an early measure
of information processing capacity (Fagan 1970).
Only a subset of the Carlson 1996 cohort was
assessed by the same version of the Fagan test as the Carlson 1992 cohort and so the Meta-analysis
was limited to the subset of 1996 cohort. Contrary to their hypothesis, novelty
preference was lower in the supplemented group. However, the number of looks
was higher and the duration of each look was shorter in the supplemented
group, which the investigators thought may indicate better cognition.
Carlson 1992 study reported Bayley developmental
scores at 12 months. Mean psychomotor developmental index (PDI) was lower
in the supplemented group. Fewtrell 2002
reported Bayley Scales of Infant Development (BSID) and Knoblock, Passamanik
& Sherrard's Developmental Screening Inventory at 9 and 12 months and
found no difference between groups. O'Connor
2001 measured BSID at 12 months and vanWezel at 12 and 24 months post-term
and no significant differences were reported between groups. Meta-analysis
of BSID of three studies at 12m with >320 infants shows no significant
effect of supplementation on development.
Growth and side effects
Growth has been measured in ten studies. In Carlson 1993, data were taken from the published figures of z-scores, as only mean absolute values were published. Z-scores are normalised growth parameters and express growth in standard deviations from the mean.
Data from the Carlson 1992 and Carlson 1996 studies suggest that normalised
weight (but not length and head circumference) is lower in preterm infants
who receive supplemented formula when compared with controls. In the Uauy 1990; Fadella 1996;
Clandinin 1997 and Vanderhoof 1999 studies, growth (weight, length
and head circumference) was not affected by the supplement. In the Hansen 1997 trial, weight was higher at 2 months
post-term in the supplemented group compared with controls, but not significantly
different at 4 months post-term. O'Connor
2001 measured anthropometrics at term, 2, 4, 6, 9 and 12 months post-term
and reported change in weight, length and head circumference over time.
They reported no significant difference in growth parameters between supplemented
and control groups ( when comparing 'intent to treat' groups and subgroups
who received > 80% enteral feed as trial formula). Of interest, length
gain was greater amongst <1250g infants in the control vs supplemented
group (5.74 vs 5.67 mm/wk, p=0.0078). Authors have been contacted for data
on absolute weights for meta-analysis.
Innis 2002 measured growth at term, 2 and
4 months and found supplementation enhances weight and length gains (data
for head circumference not given). Vanderhoof
1999 measured growth at term, 2 and 12 months and found no difference
between the groups. Fewtrell 2002 found no
difference in z scores but a reduction in absolute weight and length in the
supplemented group at 18 months post-term.
Combining results indicated that supplementation infants had increased length at term ( Clandinin 1997; Vanderhoof 1999; Innis 2002, n=272 ) and at two months ( Uauy 1990; Carlson 1996; Vanderhoof 1999; Innis 2002, n=297 ), and increased weight at 2 months ( Uauy 1990; Carlson 1996; Vanderhoof 1999; Innis 2002, Hansen 1997, n=485). reduction in weight z scores was only reported in Carlson 1992 and Carlson 1996 at 12 months ( n=116).
Uauy 1990 found no significant difference in bleeding time between groups at 34 weeks postconceptional age (2.15+/-0.69, n=22 vs 1.68+/-0.66, n=20 ). There were no differences in bleeding time at four months post-term. They also measured lipid peroxidation status by malonyl dialdehyde production (thiobarbituric acid-reactive substances) and by fragility determination of peroxide-stressed RBC and found no difference between LCPUFA supplemented and control groups (5.33+/-1.00, n=30 vs 7.24+/-0.97, n=28 (TBARS -azide/+azide x 100%). Similarly, there was no difference between the groups in membrane fluidity assessed by diphenylhexatriene fluorescence polarisation.
Data from randomised clinical trials do not demonstrate a long-term benefit to preterm infants of supplementing formula with LCPUFA.
Visual acuity was measured by Teller acuity cards in six studies, by VEP in four studies and ERG was assessed in two studies. Results cannot be added in this review because log units are used. Most studies found no differences in any visual assessment between supplemented and control infants (exceptions are Uauy 1992 and O'Connor 2001 studies where VEP acuity was more mature at 2 months post-term, and at 6 months post-term in a subgroup of supplemented infants respectively).
The Fagan Infantest measures novelty preference which, under controlled conditions, has moderate predictive validity for performance in standardised intelligence tests in childhood (Fagan 1983). Normal infants should have a novelty preference with the mean novelty preference for term infants being 62%. Carlson 1992 and Carlson 1996 demonstrated lower novelty preferences in the supplemented compared with the control group. Despite this, the investigators concluded that supplemented preterm infants may have more rapid visual information processing given that they had more looks and each look was of shorter duration. Most other studies have used the BSID and have shown no effect of supplementation at 12-24 months post-term.
LCPUFA supplementation appears safe in preterm infants when growth is used as the safety parameter. Most studies find no significant effect on growth. However, Carlson 1992, Carlson 1996 suggest that preterm infants fed n-3 LCPUFA supplements grow less well than controls and they give some evidence that poor growth in their studies may be due to a reduction in AA levels which occurs when n-3 supplements alone are used. Recent studies add AA to the supplement and usually find no significant effect on growth. The only exception is Fewtrell 2002 where mild reductions in length and weight z scores were reported at 18 months. Contrary to these results, the meta-analysis of the five studies (Uauy 1990; Carlson 1996; Hansen 1997; Vanderhoof 1999; Innis 2002) showed increased weight and length at 2 months post-term in supplemented infants.
No positive long-term effects on visual or intellectual development have been demonstrated. The justification for adding LCPUFA to formula is based on the rationale of mimicking the composition of human milk and not on evidence of important clinical benefits. A supplement containing a balance of n-3 and n-6 LCPUFA is unlikely to impair the growth of preterm infants. Overall, methodology varies considerably between studies making a summary of the combined data difficult. Some of the disparity between findings may be due to different combinations of LCPUFA in the supplement and different concentrations of essential fatty acids in the control formula. Higher ALA and lower LA:ALA will favour DHA synthesis. Another variable is the medical complications and treatments associated with preterm birth with most studies only enrolling relatively healthy infants.
The data available do not support the suggestion that supplementation of formula benefits the development of preterm infants. Providing an optimal ratio of linoleic to alpha linolenic acid (the precursors of LCPUFA), and sufficient alpha linolenic acid for infants to synthesise their own docosahexaenoic acid (DHA), may be adequate. No harm has been demonstrated with respect to growth when formula is supplemented with LCPUFA (DHA and AA).
The methodology as well as the composition of the LCPUFA supplemented and the control formulas have shown little consistency in the trials conducted so far. These data may be useful in deciding the best dose and source of LCPUFA supplement to use in future studies, preferably including more immature preterm infants who are at risk of developmental delay.
Nil
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Carlson 1992 | Randomisation, intervention and outcome assessment were blinded and follow-up of subjects was complete. | Entry criteria included no need for mechanical ventilation and no significant intraventricular haemorrhage or retinopathy of prematurity. 10 subjects who could not tolerate enteral feeds were replaced. Seventy-nine infants were enrolled, 67 completed study (33 supplemented, 34 control). Subjects were predominantly from lower socio-economic groups and black. Supplemented group GA 29+/-2w, BW 1074+/-193g. Control group GA 29+/-2w, BW 1133+/-163g. | Preterm formula (PT) until discharge (approximately 1800g) then term formula (T). Supplemented formula 18.7% & 32.6% (PT & T) 18:2n-6, 3.1% & 4.9% (PT & T)18:3n-3, 0.3% 20:5n-3, 0.2% 22:6n-3. Control formula 19.1% & 33.1% (PT & T) 18:2n-6, 3.0% & 4.8% (PT & T) 18:3n-3. | Visual acuity (Teller acuity cards) and growth at term (0m),
and 2,4,6.5,9&12m post-term. Fagan infant test at 6.5, 9 and 12m post-term. Red blood cell and plasma fatty acids. |
Visual acuity and growth parameters given in Figures; investigators
contacted for actual values but no response. |
C |
| Carlson 1996 | Randomisation, intervention and outcome assessment were blinded. Follow up was complete. Infants were randomised by sealed envelopes, stratified by gender. | Ninety-four infants were recruited and 59 completed study
through to 4m. Selection criteria included birthweight between 747 and 1275g.
More controls dropped out than supplemented infants and replacements were
added to balance the groups. Forty percent of subjects had bronchopulmonary
dysplasia (defined as an oxygen requirement for > 28 days) which is
associated with impaired vision and development. Therefore, data are given
for subgroups of infants with or without bronchopulmonary dysplasia. Supplemented group for visual acuity GA 28.5+/-1.2w, BW 1069+/-153g no BPD & GA 27.0+/-1.1w, BW 947+/-130g with BPD vs in control group GA 28.6+/-1.3w, BW 1112+/-106g no BPD & GA 27.5+/-1.6w, 975+/-151g. For the Fagan test of infant development , supplemented group GA27.9+/-1.5, BW 1027+/-153g, n=15 vs control GA 28.2+/- 1.5w, BW 1050+/-149g, n=12. |
Supplemented formula fed from 3-5 days of age to 48w PCA. Supplemented formula 21.2% 18:2n-6, 2.4% 18:3n-3, 0.06% 20:5n-3, 0.20% 22:6n-3 vs control formula 21.2% 18:2n-6, 2.4% 18:3n-3. All fed standard formula from 2m PCA to 12m PCA (34.3% 18:2n-6, 4.8% 18:3n-3). | Visual acuity (Teller acuity cards), plasma fatty acids and growth (including normalised data). Fagan test of infant development were reported for a subset at 12m. | Change of test format for infant development resulted in a smaller sample size than planned (sample size required n=60, sample size assessed n=27) - the authors comment on type 2 error resulting from the unplanned loss of power. Only the results from infants tested with the same version of the Fagan test used in their 1993 study were published and therefore available for the review. | A |
| Clandinin 1997 | Intervention and outcome assessments were blinded and all subjects were followed. | Medically stable preterm infants (n=84), with birthweights appropriate for gestational age (AGA), who were receiving full enteral feeds by day 14 were randomised to control or one of three supplemented formulae. Infants were excluded or withdrawn (n=18) if they received parenteral nutrition after 14 days of age, or they received steroids, red cell or plasma transfusions, or intravenous lipid after 8 days of age. Eighteen infants received the medium level LC PUFA supplement vs 18 the control formula (gestational age (GA) 31.9+/- 1.8w, birthweight (BW) 1.73+/-0.44kg vs GA 31.6+/- 2.3w, BW 1.74+/- 0.30kg). | The control formula contained 12.8% LA and 1.4% ALA. There were three supplemented formulae: low (0.32% AA & 0.24% DHA), medium (0.49% AA & 0.35% DHA) and high (1.1% AA & 0.76% DHA). The AA and DHA were obtained from single cell oils. | Fatty acids in erythrocyte membrane phospholipids, lymphocyte membrane phospholipids and plasma phospholipids were measured at 2 and 6 weeks. Anthropometric measurements were recorded at birth, and at 2 and 6 weeks of age. (6 week measurement/ 38 weeks PMA entered as term data) | The formula-fed group receiving the medium level of LCPUFA supplementation had erythrocyte fatty acids similar to the breastmilk-fed group and therefore are included as the comparison with controls for this review. | A |
| Fadella 1996 | Infants were randomised on day 10 to supplemented or control formula. Randomisation and intervention were not blinded. It is not stated whether assessment of outcome was blinded. Follow-up of subjects is complete. | Preterm AGA infants were included if >50% nutrition was enteral on day 10. Supplemented group; GA 31.1+-1.2 weeks, BW 1583+-310g, n=21. Control group; GA 31.3+-1.2 weeks, 1463+-273g, n=25. | Supplemented formula LA 10.8-12.2%, ALA 0.40-0.73%, DHA 0.23%,
AA 0.23%. Control formula LA18.6-19.4%, ALA 0.25-0.9%, DHA 0.01%, AA 0.02%. |
At 52 weeks post-conceptional age, flash visual evoked potentials
(VEP), electroretinograms (ERG) and auditory responses were measured. Red blood cell (RBC) total fatty acids were also measured. |
Sixty-six infants were enrolled, 17 of whom formed a breastmilk-fed
reference group. The formula groups received up 25% milk as breastmilk. Methodology of assessment for VEP and ERG deviate from international standards and therefore interpretation is difficult. |
C |
| Fewtrell 2002 | Infants were randomised, double-blind, stratified by birthweight (< & > 1200g), centre-wise in permuted blocks by independent personnel to receive supplemented or control formula. Assessment was blinded and follow up was complete. | Preterm infants (n=195) from three centres were included if BW <1750g and fully formula fed by 10 days, and no congenital malformations. Supplemented group BW 1336+/-284g, GA 30.4+/-2.3w. Control group BW 1353+/-274g, GA 30.3+/-2.4w. | Control preterm formula contained 10.6 % fa LA and 0.7% fa ALA. Supplemented preterm formula contained 0.17% fa DHA, 0.31% fa AA and 0.04% fa EPA. Trial formula was fed for a mean+/-SD of 33+/-17 days. | Primary outcome was neurodevelopment at 18m post-term. Bayley Scales of Infant Development (MDI, PDI) at 18 months post-term. Knoblock, Passamanik & Sherrard's Developmental Screening Inventory at 9 m post-term. Neurological impairment at 9 and 18 m post-term. Growth in hospital and at 9 and 18 m post-term. | Funded by Numico Research BV (Wageningen, The Netherlands). | A |
| Hansen 1997 | Infants were randomised to receive control formula or one of two supplemented formulae. It is unclear whether assessment was blinded or whether follow up was complete. | Preterm infants (n=194) with BW 0.86 - 1.56kg. | The supplemented formulae contained either 0.15% algal DHA or 0.14% algal DHA and 0.27% fungal AA. The LA:ALA ratio of the control formula is not available. | Anthropometric measurements and visual acuity (Teller acuity cards) were recorded at 2 and 4 months postconceptional age. | Abstract only is available. The formula supplemented with DHA and AA was compared with control formula for this review. There was a breastmilk-fed reference group (n=80). 194 infants were randomised. An assumption was made for this review that there were 64 per group. | B |
| Innis 2002 | Double-blind prospective randomised trial (blinding of assessment unclear). Infants randomised to one of three formula by computer-generated randomisation schedules. Two different codes were used for each of the formulas to ensure blinding. Follow up was complete. | 194 healthy preterm infants BW 846-1560g. Exclusion - SGA, >24 days of age when full enteral feeds tolerated, nec or other GI disease, impaired vision, disease/congenital malformation that may impair growth. Supplemented GA 29.7+/-1.7g, BW 1.28+/-0.18w, n=66. Control GA 29.5+/-1.7w, BW 1.23+/-0.18g, n=62. | There were three preterm formulas: control (21-22% LA, 3- 3.1%ALA); two supplemented (0.34% DHA from DHA enriched oil, or 0.33% DHA and 0.60% AA from algal/fungal oils, neither had EPA). For this meta-analysis and review, we chose the supplement with DHA and AA. Formulas were fed from when 50kcal/kg/d was tolerated, for at least 28 days until discharge. Term formula without DHA and AA was fed after discharge. | RBC fatty acids at discharge and 48w PMA. Anthropometrics at 40, 48 and 57w PMA. Visual acuity (Teller acuity cards) at 48 and 57w PMA. | Sponsored by Mead Johnson Nutritionals, Indiana. | B |
| O'Connor 2001 | Infants were randomised to 3 groups based on centre, gender, stratified 750-1250g/1251-1800 BW. Infants were enrolled from eight centres in UK and North America. It is assumed that the study was double -blind but this is not clearly stated. Assessment was blinded and follow up was complete. | 470 infants <33w gestation and between 750-1805g birthweight and < d 28 age (control n=144, fungal/fish n=140, egg-TG/fish N=143, human milk exclusively n=43. Exclusions include serious congenital malformations, major surgery, asphyxia, PVL and IVH>grade 2 and serious systemic infection. Supplemented group BW 1305+/-293, GA | Infants fed preterm formula until term corrected age then post-discharge (nutrient-enriched) formula until 12 m post-term. There were two supplemented groups (fish/fungal oil or egg-TG/fish oil) and, for this meta-analysis and review, we chose the fish/fungal group as microbial oils are more similar to human milk fat than egg-TG, and there were minimal differences between fish/fungal and egg-TG/fish groups. Supplemented formula contained 0.42% AA and 0.26% DHA until term, and then 0.42% AA and 0.16% DHA until 12 m. Control formula contained 16-19% LA and 2.5% ALA. Infants in all groups also received human milk, for example at term, 35% control and 28% supplemented infants consumed human milk at least once per day. | Primary outcome was Bayley Scales of Infant development at 12m. Visual acuity was assessed by Teller acuity cards at 2, 4 and 6 m corrected age, and by VEP in 2/8 centres at 4 and 6 m corrected age. Fagan test of Infant Intelligence was administered at 6 and 9 m corrected age. MacArthur Communicative Development Inventories was administered at 9 and 14 months corrected age. Growth was measured at term and 2,4,6,9 and 12 months. | Sponsored by Ross Products Division, Abbott Laboratories, Ohio. Authors contacted to provide data for growth and visual acuity, as these appear only in Figures in the publication. |
A |
| Uauy 1990 | Outcome assessment was blinded but it is not stated whether randomisation and intervention were blinded. Follow-up of subjects was complete. | Supplemented group GA 30.7+/-1.2w, BW 1281+/-101g. Control groups a) GA 30.9++/-1.6w, BW 1340+/-106g, b) GA 29.6+/-1.6w, BW 1224+/-92g. | Infants were fed study formulae, on average, from day 10 to day 45. Infants were randomised to the supplemented group who received soy/marine oil (18:2n-6 20.4%, 18:3n-3 1.4%,n-6>C18 0.1%, n-3>C18 1.0%) or control group a) corn oil (18:2n-6 24.2%, 18:3n-3 0.5%) or control group b) soy oil (18:2n-6 20.8%, 18:3n-3 2.7%). | ERG at 36 w and 57 w post-conceptional age (PCA). VEP acuity at 36 & 57 weeks PCA. FPL acuity at 57 weeks PCA. Lipid peroxidation products (TBARS) or thiobarbituric acid reactive substances expressed as -azide/+azide x 100%which normalises for individual variation, high % suggests a high capacity for lipid peroxidaton). Infant bleeding times 57w PCA. RBC membrane fluidity at 25 and 37 degrees. Growth at 40w, 48w and 57w PCA. | For the purpose of this analysis, control group b) was used as the LA:ALA ratio is most similar to other studies and current commercial formula. | B |
| van Wezel 2002 | Double blind study with complete follow up. Infants were randomised using computer-generated random list and applied by an independent research officer. Assessment was blinded and follow up was complete. | Preterm infants (<34 weeks GA and <1750g). Supplemented group BW 1.282+/-0.316kg, GA 30.4+/-1.5wk, n=22. Control group BW 1.30+/-0.257g, GA 30.4+/-1.6wk , n=20. Inclusion criteria - normal neurological examination and cerebral ultrasounds. Exclusion criteria - significant cerebral damage, retinopathy, chronic disease or feeding problems. | Supplemented preterm and term formula contained 0.34% DHA and 0.68% AA from microalgae . LA and ALA levels are not given. Preterm formula was fed until a weight of 3kg. Infants then received a term formula with or without supplement as per randomisation until 6 m corrected age. | Cerebral myelination assessed by magnetic resonance imaging (MRI). Bayley Scales of Infant Development (MDI, PDI), Visual acuity by flash VEP and Teller cards, RBC and plasma fatty acids. | Sponsored by Nutricia, Numico Research | A |
| Vanderhoof 1999 | Randomisation computerised and stratified by BW (750-1000, 1001-1500, 1501-2000). Blinding by coded labels and verified by "trained sensory panel". It is unclear whether assessment was blinded. Follow up was complete. | Supplemented group BW 1522+/-370g, GA 31.0+/-2.5wks, n=77. Control group BW 1484+/-365, GA 30.8+/-2.7, n=78. Inclusion criteria - preterm bw 750-2000g, 0-28 da of age, medically stable, received enteral feeds for < 24 hrs, AGA. Exclusion criteria - significant acute/chronic illness, systemic infections, major congenital malformations, IVH>grade 2, PVL, seizures. Withdrawal criteria - if bw>1000g and full enteral feeds not attained by d 28; if bw 750-1000 and full enteral feeds not attained by d 42; for all infants, if unable to tolerate full enteral feeds., or need for mechanical ventilation after full enteral feeds attained; or oxygen dependency at 36w PCA, and/or >5d course steroids. Infants enrolled from 16 sites. | Supplemented preterm formula LA 12.1% fa, ALA 1.5% fa, AA 0.50% fa and DHA 0.35% (LCPUFA from single cell oil source). Control preterm formula LA 12.8% fa, ALA 1.4% fa, AA and DHA 0%. Infants were fed one of two preterm formulas, with or without LCPUFA, until 48 weeks PCA . All infants were then fed a standard term formula (unsupplemented) until 92 weeks PCA. | Anthropometrics, adverse events and plasma fatty acids were measured to 92 weeks PCA. | Sponsored by Wyeth Nutritionals International, Philadelphia, Pennsylvania, USA | A |
Carlson SE, Cooke RJ, Rhodes PG, Peeples JM, Werkman SH, Tolley EA. Longterm feeding of formulas high in LA and marine oil to VLBW infants: phospholipid fatty acids. Pediatr Res 1991;30:404-412.
* Carlson SE, Cooke RJ, Werkman SH, Tolley EA. First year growth of infants fed standard formula compared with marine oil supplemented formula. Lipids 1992;27:901-907.
Carlson SE, Werkman SH, Peeples JM, Cooke RJ, Tolley EA. Arachidonic acid correlates with first year growth in preterm infants. Proc Natl Acad Sci 1993;90:1073-1077.
Carlson SE, Werkman SH, Rhodes PG, Tolley EA. Visual acuity development in healthy preterm infants: effect of marine oil supplementation. Am J Clin Nutr 1993;58:35-42.
Carlson SE. Lipid requirements of VLBW infants for optimal growth and development. In: Lipids, Learning and the Brain: Fats in infant formula. Report of the 103rd Ross Conference on Pediatric Research. Columbus, Ohio: Ross Labs, 1993.
Werkman SH, Carlson SE. A randomised trial of visual attention of preterm infants fed DHA until 9 months. Lipids 1996;31:91-97.
Carlson 1996 {published data only}
* Carlson SE, Werkman SH, Tolley EA. Effect of long chain n-3 fatty acid supplementation on visual acuity and growth of preterm infants with and without bronchopulmonary dysplasia. Am J Clin Nutr 1996;63:687-697.
Carlson SE, Werkman SH. A randomised trial of visual attention of preterm infants fed DHA until 2 months. Lipids 1996;31:85-90.
Clandinin 1997 {published data only}
Clandinin MT, Van Aerde JE, Parrott A, Field CJ, Euler AR, Lien EL. Assessment of the efficaceous dose of arachidonic and docosahexaenoic acids in preterm infant formulas: fatty acid composition of erythrocyte membrane lipids. Pediatr Res 1997;42:819-825.
Fadella 1996 {published data only}
Fadella G, Giovani M, Alessandroni R et al. Visual evoked potentials and dietary LCPUFA in preterm infants. Arch Dis Child 1996;75:F108-112.
Fewtrell 2002 {published data only}
Fewtrell MS, Morley R, Abbott RA, Singhal A, Isaacs EB, Stephenson T, MacFayden U, Lucas A. Double-blind, randomised trial of long-chain polyunsaturated fatty acids in formula fed to preterm infants.. Pediatrics 2002;110:73-82.
Hansen 1997 {published data only}
Hansen J, Schape D et al. Docosahexaenoic acid plus arachidonic acid enhance preterm infant growth. In: Essential Fatty Acids & Eicosanoids. Edinburgh, 1997:T16.
Innis 2002 {published data only}
Innis SM, Adamkin DH, Hall RT, Kalhan SC, Lair C, Lim M et al. Docosahexanoic acid and arachidonic acid enhance growth with no adverse effects in preterm infants fed formula.. J Pediatr 2002;140:547-554.
O'Connor 2001 {published data only}
O'Connor DL, Hall R, Adamkin D, Austead N, Castillo M, Connor WE et al. Growth and development in preterm infants fed longchain polyunsaturated fatty acids: A prospective randomised trial.. Pediatrics Aug 2001;108:359-371.
Uauy 1990 {published data only}
Birch DG, Birch EE, Hoffman DR, Uauy RD. Retinal development of very low birthweight infants fed diets differing in n-3 fatty acids. Invest Ophthalmol Vis Sci 1992;33:2365-2376.
Hoffman DR, Uauy R. Essentiality of dietary n-3 fatty acids for premature infants; plasma and red blood cell fatty acid composition. Lipids 1992;27:886-895.
Uauy R, Hoffman DR, Birch EE, Birch DG, Jameson DM, Tyson J. Safety and efficacy of n-3 fatty acids in the nutrition of very low birthweight infants: soy oil and marine oil supplementation of formula. J Pediatr 1994;124:612-620.
* Uauy RD, Birch DG, Birch EE, Tyson JE, Hoffman DR. Effect of dietary omega 3 fatty acids on retinal function of very low birthweight neonates. Pediatr Res 1990;28:485-492.
van Wezel 2002 {published data only}
van Wezel-Meijler G, van der Knaap MS, Huisman J, Jonkman EJ, Valk J, Lafeber HN. Dietary supplementation of long-chain polyunsaturated fatty acids in preterm infants: effects on cerebral maturation.. Acta Paediatr. 2002;91(9):942-50.
Vanderhoof 1999 {published data only}
* Vanderhoof J, Gross S, Hegyi T, Clandinin T, Porcelli P, DeCristofaro J, Rhodes T, Tsang R, Shattuck K, Cowett R, Adamkin D, McCarton C, Heird W, Hook-Morris B, Pereira G, Chan G, Van Aerde J, Boyle F, Pramuk K, Euler A, Lien EL. 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;29:318-326.
Vanderhoof J, Gross S, Hegyi T. A multicenter long-term safety and efficacy trial of preterm formula supplemented with long-chain polyunsaturated fatty acids. J Pediatr Gastroenterol Nutr 2000;31:121-127.
Donzelli GP, Cafaggi L, Rapisardi G, Moroni M, Pratesi S. Longchain polyunsaturated fatty acids and early neural and visual development in preterm infants. Pediatr Res 1996;40:527.
Lim 2002 {published data only}
Lim M, Antonson D, Clandinin M, vanAerde J, Green D, Stevens K et al. Formulas with DHA and ARA for LBW infants are safe. Pediatr Res 2002;51:319A.
* indicates the primary reference for the study
Bjerve KS, Bredde OL, Bonaa K, Johnson H, Vatten L, Vik T. Clinical and epidemiological studies with alpha linolenic acid and longchain n-3 fatty acids. In: Sinclair AJ, Gibson RA, editor(s). Third International Conference on Essential Fatty Acids and Eicosanoids. Illinois: AOCS, March 1992.
Clandinin MT, Chappell JE, Leong S, Heim T, Swyer PR, Chance GW. Intrauterine fatty acid secretion rates in human brain: implications for fatty acid requirements. Early Hum Dev 1980;4:121-9.
Clark KJ, Makrides M, Neumann MA, Gibson RA. Determination of the optimal ratio of linoleic acid to alpha linolenic acid in infant formulas. J Pediatr 1992;120:S151-8.
Fagan JF. Memory in the infant. J Exp Child Psych 1970;9:217-226.
Fagan JF, Singer LT. Infant recognition memory as a measure of intelligence. In: Lipsitt LP, editor(s). Advances in Infant Research. Vol. 2. Ablex, Norwood, 1983:31-72.
Gibson RA, Kneebone GM. Fatty acid composition of human colostrum and mature breastmilk. Am J Clin Nutr 1981;34:46-53.
Lucas A, Morley R, Cole TJ, Lister G, Leeson-Payne C. Breastmilk and subsequent intelligence quotient in children born preterm. Lancet 1992;339:261-4.
Makrides M, Simmer K, Goggin M, Gibson RA. Erythrocyte docosahexaenoic acid correlates with the visual response of the healthy, term infant. Pediatr Res 1993;33:3242-53.
Makrides M, Neumann M, Simmer K, Pater J, Gibson R. Are longchain polyunsaturated fatty acids essential nutrients in infancy? Lancet 1995;345:1463-8.
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Neuringer M, Connor WE, Lin DS, Barstad L, Luck S. Biochemical and functional effects of prenatal and postnatal n-3 fatty acids on retina and brain in rhesus monkeys. Proc Natl Acad Sci USA 1986;83:4021-5.
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Simmer K. Longchain polyunsaturated fatty acid supplementation in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 2, 2000. Oxford: Update Software.
01.01 Visual acuity (log cycles/degree) at term
01.02 Visual acuity (log cycles/degree) at 2m post-term
01.03 Visual acuity (log cycles/ degree) at 4m post-term
01.04 Visual acuity (log cycles /degree) at 6m post-term
01.05 Visual acuity (log cycles/degree) at 9m post-term
01.06 Visual acuity (log cycles/degree) at 12m post-term
01.07 Rod ERG at 36w PCA
01.08 ERG at 3m post-term, amplitude(uV)
01.09 Rod ERG at 4m post-term
01.10 VEP at 3m post-term
01.11 Fagan infant test at 12m post-term
01.12 Fagan infant test at 9m post-term (% total time)
01.13 Bayley MDI at 12m post-term
01.14 Bayley PDI at 12m post-term
01.15 Weight at 6w post-term (kg)
01.16 Length at 6w post-term (cm)
01.17 Head circumference at 6w post-term (cm)
01.18 Weight at term (kg)
01.19 Length at term (cm)
01.20 Head circ at term (cm)
01.21 Weight at 2m post-term (kg)
01.22 Length at 2m post-term (cm)
01.23 Head circumference at 2m post-term (cm)
01.24 Growth rate until 3m post-term
01.25 Weight at 4m post-term (kg)
01.26 Length at 4m post-term (cm)
01.27 Head circumference at 4m post-term (cm)
01.28 Weight at 12m post-term (kg)
01.29 Length at 12m post-term (cm)
01.30 Head circumference at 12m post-term (cm)
01.31 Normalised weight at 12m post-term
01.32 Normalised length at 12m post-term
01.33 Normalised head circumference at 12m post-term
01.34 Lipid peroxidation (TBARS -azide/+azide x 100%), 4m post-term
01.35 RBC fragility (hemolysis with 8-10% H2O2) , 4m post-term
01.36 Infant bleeding time 4m post-term (ped device, min)
01.37 Bayley MDI at 18m post-term
01.38 Bayley PDI at 18 m post-term
01.39 KPS Developmental Screening Inventory at 9 m post-term (overall quotient)
01.40 Weight at 9 m post-term
01.41 Length at 9 m post-term
01.42 Head circumference at 9 m post-term
01.43 Normailsed weight at 9 m post-term
01.44 Normalised length at 9 m post-term
01.45 Normalised head circumference at 9 m post-term
01.46 Weight at 18 m post-term
01.47 Length at 18 m post-term
01.48 Head circumference at 18 m post-term
01.49 Normalised weight at 18 m post-term
01.50 Normalised length at 18 m post-term
01.51 Normalised head circumference at 18 m post-term
01.52 Fagan Infant test at 6m post-term, novelty time (%total time)
01.53 MacArthur Communicative Inventories at 14 months post-term
01.54 Bayley MDI at 24 months post-term
01.55 Bayley PDI at 24 months post-term
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Supplement vs control | ||||
| 01 Visual acuity (log cycles/degree) at term | WMD (fixed), 95% CI | No total | ||
| 02 Visual acuity (log cycles/degree) at 2m post-term | WMD (fixed), 95% CI | No total | ||
| 03 Visual acuity (log cycles/ degree) at 4m post-term | WMD (fixed), 95% CI | No total | ||
| 04 Visual acuity (log cycles /degree) at 6m post-term | WMD (fixed), 95% CI | No total | ||
| 05 Visual acuity (log cycles/degree) at 9m post-term | WMD (fixed), 95% CI | No total | ||
| 06 Visual acuity (log cycles/degree) at 12m post-term | WMD (fixed), 95% CI | No total | ||
| 07 Rod ERG at 36w PCA | WMD (fixed), 95% CI | No total | ||
| 08 ERG at 3m post-term, amplitude(uV) | WMD (fixed), 95% CI | No total | ||
| 09 Rod ERG at 4m post-term | WMD (fixed), 95% CI | No total | ||
| 10 VEP at 3m post-term | WMD (fixed), 95% CI | No total | ||
| 11 Fagan infant test at 12m post-term | WMD (fixed), 95% CI | Subtotals only | ||
| 12 Fagan infant test at 9m post-term (% total time) | WMD (fixed), 95% CI | Subtotals only | ||
| 13 Bayley MDI at 12m post-term | 3 | 339 | WMD (fixed), 95% CI | -0.45 [-3.05, 2.15] |
| 14 Bayley PDI at 12m post-term | 3 | 328 | WMD (fixed), 95% CI | -1.69 [-4.94, 1.55] |
| 15 Weight at 6w post-term (kg) | WMD (fixed), 95% CI | Subtotals only | ||
| 16 Length at 6w post-term (cm) | WMD (fixed), 95% CI | Subtotals only | ||
| 17 Head circumference at 6w post-term (cm) | WMD (fixed), 95% CI | Subtotals only | ||
| 18 Weight at term (kg) | 3 | 273 | WMD (fixed), 95% CI | 0.09 [-0.03, 0.20] |
| 19 Length at term (cm) | 3 | 272 | WMD (fixed), 95% CI | 0.70 [0.02, 1.38] |
| 20 Head circ at term (cm) | 2 | 162 | WMD (fixed), 95% CI | 0.29 [-0.17, 0.75] |
| 21 Weight at 2m post-term (kg) | 5 | 485 | WMD (fixed), 95% CI | 0.21 [0.08, 0.33] |
| 22 Length at 2m post-term (cm) | 4 | 297 | WMD (fixed), 95% CI | 0.47 [0.00, 0.94] |
| 23 Head circumference at 2m post-term (cm) | 3 | 187 | WMD (fixed), 95% CI | 0.03 [-0.33, 0.38] |
| 24 Growth rate until 3m post-term | 3 | 138 | WMD (fixed), 95% CI | 0.00 [-0.04, 0.04] |
| 25 Weight at 4m post-term (kg) | 4 | 356 | WMD (fixed), 95% CI | 0.16 [-0.02, 0.34] |
| 26 Length at 4m post-term (cm) | 3 | 167 | WMD (fixed), 95% CI | 0.25 [-0.40, 0.89] |
| 27 Head circumference at 4m post-term (cm) | 2 | 66 | WMD (fixed), 95% CI | -0.66 [-1.34, 0.02] |
| 28 Weight at 12m post-term (kg) | 2 | 153 | WMD (fixed), 95% CI | -0.21 [-0.46, 0.04] |
| 29 Length at 12m post-term (cm) | 2 | 153 | WMD (fixed), 95% CI | -0.28 [-0.95, 0.40] |
| 30 Head circumference at 12m post-term (cm) | 2 | 153 | WMD (fixed), 95% CI | -0.24 [-0.66, 0.19] |
| 31 Normalised weight at 12m post-term | 2 | 116 | WMD (fixed), 95% CI | -0.33 [-0.56, -0.09] |
| 32 Normalised length at 12m post-term | 2 | 116 | WMD (fixed), 95% CI | 0.03 [-0.16, 0.22] |
| 33 Normalised head circumference at 12m post-term | 2 | 116 | WMD (fixed), 95% CI | -0.14 [-0.38, 0.10] |
| 34 Lipid peroxidation (TBARS -azide/+azide x 100%), 4m post-term | WMD (fixed), 95% CI | No total | ||
| 35 RBC fragility (hemolysis with 8-10% H2O2) , 4m post-term | WMD (fixed), 95% CI | No total | ||
| 36 Infant bleeding time 4m post-term (ped device, min) | WMD (fixed), 95% CI | No total | ||
| 37 Bayley MDI at 18m post-term | 1 | 158 | WMD (fixed), 95% CI | 2.60 [-2.02, 7.22] |
| 38 Bayley PDI at 18 m post-term | 1 | 158 | WMD (fixed), 95% CI | 2.00 [-2.51, 6.51] |
| 39 KPS Developmental Screening Inventory at 9 m post-term (overall quotient) | 1 | 158 | WMD (fixed), 95% CI | 1.50 [-1.70, 4.70] |
| 40 Weight at 9 m post-term | 1 | 158 | WMD (fixed), 95% CI | -0.31 [-0.62, 0.00] |
| 41 Length at 9 m post-term | 1 | 158 | WMD (fixed), 95% CI | -0.90 [-1.80, 0.00] |
| 42 Head circumference at 9 m post-term | 1 | 158 | WMD (fixed), 95% CI | -0.30 [-0.78, 0.18] |
| 43 Normailsed weight at 9 m post-term | 1 | 158 | WMD (fixed), 95% CI | -0.35 [-0.72, 0.02] |
| 44 Normalised length at 9 m post-term | 1 | 158 | WMD (fixed), 95% CI | -0.30 [-0.69, 0.09] |
| 45 Normalised head circumference at 9 m post-term | 1 | 158 | WMD (fixed), 95% CI | -0.10 [-0.51, 0.31] |
| 46 Weight at 18 m post-term | 1 | 158 | WMD (fixed), 95% CI | -0.37 [-0.73, -0.01] |
| 47 Length at 18 m post-term | 1 | 158 | WMD (fixed), 95% CI | -1.50 [-2.47, -0.53] |
| 48 Head circumference at 18 m post-term | 1 | 158 | WMD (fixed), 95% CI | -0.30 [-0.86, 0.26] |
| 49 Normalised weight at 18 m post-term | 1 | 158 | WMD (fixed), 95% CI | -0.33 [-0.68, 0.02] |
| 50 Normalised length at 18 m post-term | 1 | 158 | WMD (fixed), 95% CI | -0.44 [-0.80, -0.08] |
| 51 Normalised head circumference at 18 m post-term | 1 | 158 | WMD (fixed), 95% CI | -0.10 [-0.52, 0.32] |
| 52 Fagan Infant test at 6m post-term, novelty time (%total time) | 1 | 187 | WMD (fixed), 95% CI | -0.50 [-2.64, 1.64] |
| 53 MacArthur Communicative Inventories at 14 months post-term | 2 | 399 | WMD (fixed), 95% CI | 0.34 [-3.05, 3.72] |
| 54 Bayley MDI at 24 months post-term | 1 | 42 | WMD (fixed), 95% CI | 4.20 [-7.96, 16.36] |
| 55 Bayley PDI at 24 months post-term | 1 | 42 | WMD (fixed), 95% CI | -3.60 [-12.11, 4.91] |
| This review is published as a Cochrane review
in The Cochrane Library 2004, Issue 1, 2004 (see www.CochraneLibrary.net
for information). Cochrane reviews are regularly updated as new evidence
emerges and in response to comments and criticisms, and The Cochrane
Library should be consulted for the most recent version of the Review. |
