Placental transfer of SSRI and SNRI antidepressants and effects on the neonate.

INTRODUCTION: We investigated placental transfer and neurobehavioural effects in neonates exposed to citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline (SSRI's), or to venlafaxine (an SNRI). METHODS: Women receiving antidepressants during pregnancy and their neonates were studied. Cord and maternal drug concentrations were measured at birth and in the neonates plasma on day 3. Neonates were also assessed using a range of neurobehavioral tests and compared to controls. RESULTS: Median cord/maternal distribution ratio was 0.7-0.86 (range) for SSRIs, 0.72 for the SNRI venlafaxine and 1.08 for the O-desmethyl metabolite. Neonatal abstinence scores were significantly higher (p<0.05) in exposed infants than controls on day 1. Brazelton scores for habituation, social-interactive, motor and autonomic clusters, and serotonin scores were significantly greater (p<0.05) in exposed infants. DISCUSSION: Transfer of SSRIs and SNRIs across the placenta was substantial. Neonates developed mild behavioral symptoms in the early perinatal period but these were self-limiting and similar for both SSRIs and the SNRI venlafaxine.

Long-chain polyunsaturated fatty acid supplementation in preterm infants.

BACKGROUND: 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. OBJECTIVES: The aim of this review is to assess whether supplementation of formula with LCPUFA is safe and of benefit to preterm infants. SEARCH STRATEGY: Trials were identified by MEDLINE (February 2007), Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007) and by checking reference lists of relevant articles and conference proceedings. SELECTION CRITERIA: All randomised trials of formula supplemented with LCPUFA and with clinical endpoints were reviewed. DATA COLLECTION AND ANALYSIS: Fifteen randomised trials assessing the clinical effects of feeding formula supplemented with LCPUFA were included in the review. MAIN RESULTS: Of the fifteen randomised trials included in the review, four of these were not classified as of high quality, due to low follow-up, uncertainty regarding concealment of patient allocation and randomisation, and problems with assessment methodology. VISUAL ACUITY: Visual acuity over the first year was measured by Teller or Lea acuity cards in eight studies, by VEP in six studies and by ERG in two studies. Most studies found no significant differences in any visual assessment between supplemented and control infants. DEVELOPMENT: Most of the trials have used Bayley Scales of Infant Development (BSID) at 12 to 24 months post-term with three out of seven studies reporting some benefit of LCPUFA in different populations of supplemented infants at different postnatal ages. Meta-analysis of BSID of four studies at 12 months (N = 364) and three studies at 18 months (N = 494) post-term showed no significant effect of supplementation on neurodevelopment. Carlson 1992 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: Four out of thirteen studies reported benefits of LCPUFA on growth of supplemented infants at different postnatal ages. Two trials (Carlson 1992; Carlson 1996) suggested that LCPUFA supplemented infants grow less well than controls, possibly due to a reduction in AA levels that occurs when n-3 supplements are used without n-6 supplements. Recent trials with addition of AA to the supplement have reported no significant negative effect on growth. Fewtrell 2002 reported mild reductions in length and weight z scores at 18 months. Contrary to these results, meta-analysis of five studies (Uauy 1990; Carlson 1996; Hansen 1997; Vanderhoof 1999; Innis 2002) showed increased weight and length at two months post-term in supplemented infants. Meta-analysis of four studies at 12 months (N = 271) and two studies at 18 months (N = 396) post-term showed no significant effect of supplementation on weight, length or head circumference. SIDE EFFECTS: Uauy 1992 reported no significant effect of LCPUFA supplementation on bleeding time and red cell membrane fragility. AUTHORS' CONCLUSIONS: Infants enrolled in the trials were relatively mature and healthy preterm infants. Assessment schedule and methodology, dose and source of supplementation and fatty acid composition of the control formula varied between trials. When the results of the RCT's are pooled, no clear long-term benefits were demonstrated for infants receiving formula supplemented with LCPUFA. There was no evidence that supplementation of formula with n-3 and n-6 LCPUFA impaired the growth of preterm infants.

Long-chain polyunsaturated fatty acid supplementation in infants born at term.

BACKGROUND: The n-3 and n-6 fatty acids linolenic acid and linoleic acid are precursors of the n-3 and n-6 long chain fatty acids (LCPUFA). Infant formula has historically only contained the precursor fatty acids. Controversy exists over whether LCPUFA are also essential nutrients in infancy. Over the last few years, some manufacturers have added LCPUFA to formulae and marketed them as providing an advantage for the development of term infants. OBJECTIVES: To assess whether supplementation of formula with LCPUFA is safe and of benefit to term infants. SEARCH STRATEGY: Eligible studies were identified by searching MEDLINE (March 2007), EMBASE 1980 - 2007, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007) and CINAHL (December 1982 - March 2007). Abstracts of the Society for Pediatric Research were hand searched from 1980 to 2006 inclusive. Reference lists of published narrative and systematic reviews were also reviewed. No language restrictions were applied. SELECTION CRITERIA: All randomised and quasi randomised trials comparing LCPUFA supplemented formula milk vs. non-supplemented formula milk and with clinical endpoints were reviewed. DATA COLLECTION AND ANALYSIS: Methodological quality of eligible studies was assessed according to allocation concealment, blinding of intervention, blinding of outcome assessment and completeness of follow up. Data were sought regarding effects on visual acuity, neurodevelopmental outcomes and physical growth. When appropriate, meta-analysis was conducted to provide a pooled estimate of effect. Continuous data were analysed using weighted mean difference (WMD). There were no categorical outcomes in this review. MAIN RESULTS: Twenty randomised studies were identified. Fourteen were included (n = 1719) and six excluded. Eleven included studies were of good quality. The main outcomes assessed were visual acuity, neurodevelopmental and physical growth. Visual acuity was measured at various stages throughout the first three years of life by nine studies. Visual evoked potential was used to assess visual acuity in five studies. The remaining four used Teller visual acuity cards. The results were inconsistent. Three studies reported beneficial effect of LCPUFA supplementation on visual acuity while the remaining six did not. Neurodevelopmental outcome was measured at different ages throughout the first two years by eleven studies. Bayley scales of infant development (BSID) was used in eight studies. Only one showed beneficial effect of LCPUFA supplementation on BSID scales. Pooled meta-analysis of the data also did not show any statistically significant benefit of LCPUFA supplementation on either mental or psychomotor developmental index of BSID. One study reported better novelty preference measured by Fagan Infant test at nine months in supplemented infants compared with controls. Another study reported better problem solving at 10 months with supplementation. One study used Brunet and Lezine developmental test to assess the developmental quotient and did not find beneficial effects of LCPUFA supplementation. Physical growth was measured at various ages throughout first three years of life by twelve studies. Some studies reported the actual measurements while some reported the rate of growth over a time period. Some studies z scores. Irrespective of the type of LCPUFA supplementation, duration of supplementation and method of assessment, none of the individual studies found beneficial or harmful effects of LCPUFA supplementation. Meta-analysis of relevant studies also did not show any effect of LCPUFA supplementation on growth of term infants. AUTHORS' CONCLUSIONS: The results of most of the well conducted RCTS have not shown beneficial effects of LCPUFA supplementation of formula milk on the physical, visual and neurodevelopmental outcomes of infants born at term. Only one group of researchers have shown some beneficial effects on VEP acuity. Two groups of researchers have shown some beneficial effect on mental development. Routine supplementation of milk formula with LCPUFA to improve the physical, neurodevelopmental or visual outcomes of infants born at term can not be recommended based on the current evidence. Further research is needed to see if the beneficial effects demonstrated by Dallas 2005 trial of Birch et al can be replicated in different settings.

Best practice guidelines for the operation of a donor human milk bank in an Australian NICU.

Until the establishment of the PREM Bank (Perron Rotary Express Milk Bank) donor human milk banking had not occurred in Australia for the past 20 years. In re-establishing donor human milk banking in Australia, the focus of the PREM Bank has been to develop a formal and consistent approach to safety and quality in processing during the operation of the human milk bank. There is currently no existing legislation in Australia that specifically regulates the operation of donor human milk banks. For this reason the PREM Bank has utilised existing and internationally recognised management practices for managing hazards during food production. These tools (specifically HACCP) have been used to guide the development of Standard Operating Procedures and Good Manufacturing Practice for the screening of donors and processing of donor human milk. Donor screening procedures are consistent with those recommended by other human milk banks operating internationally, and also consistent with the requirements for blood and tissue donation in Australia. Controlled documentation and record keep requirements have also been developed that allow complete traceability from individual donation to individual feed dispensed to recipient and maintain a record of all processing and storage conditions. These operational requirements have been developed to reduce any risk associated with feeding pasteurised donor human milk to hospitalised preterm or ill infants to acceptable levels.

Novel feeding system to promote establishment of breastfeeds after preterm birth: a randomized controlled trial.

OBJECTIVE: We aimed to determine if a novel feeding system where milk only flowed when the preterm infant created a vacuum would influence time to full oral feeds, the length of stay (LOS) in hospital and breastfeeding at discharge. STUDY DESIGN: This was a randomized controlled trial in the tertiary neonatal intensive care unit at King Edward Memorial Hospital, Perth, Australia. Eligibility criteria were: preterm infants of gestational age 25 to 34 weeks receiving >75% human milk by gastric tube. Infants were randomly assigned to being fed with a novel teat (NT) or conventional teat (CT). Intention to treat analysis was performed. RESULT: Time to full suck feeds was not different between groups. LOS was shorter (mean: 2.5 days; P=0.026) and less formula was fed at discharge in the NT group (P=0.036). CONCLUSION: Use of a NT that releases milk when the infant applies vacuum while establishing breastfeeding reduces duration of hospitalization of preterm infants.

Is surgical ligation of patent ductus arteriosus necessary? The Western Australian experience of conservative management.

BACKGROUND: Surgical ligation of patent ductus arteriosus (PDA) is widely practised in preterm infants despite no clear evidence that this improves outcomes. Geographical isolation meant that ductal ligation was not an option in King Edward Memorial Hospital until recently. OBJECTIVE: A retrospective data analysis to test the hypothesis that outcomes of infants with persistent PDA were no worse than those of infants with no significant duct or a duct that closed after medical treatment. PATIENTS AND METHODS: A total of 252 infants (gestation < or =28 weeks) born between 1 January 2000 and 30 June 2002 were divided into three groups: group 1, no significant PDA (n = 154); group 2, significant PDA which closed after medical treatment (n = 65); group 3, significant PDA remaining patent after medical treatment (n = 33). A significant PDA was defined by a left atrium to aortic root ratio of >1.4 or a ductal diameter >1.5 mm with a left to right shunt. RESULTS: Twenty four (10%) infants died at median (interquartile range) 15.5 (9-35) days. After adjustment for gestational age, relative to group 1, the infants from group 3 were at a 4.02 times increased risk of death (95% confidence interval 1.12 to 14.51). There was no significant difference between groups in the incidence of chronic lung disease, chronic lung disease or death, necrotising enterocolitis, intraventricular haemorrhage, duration of oxygen, or hospital stay. CONCLUSION: Mortality was higher in infants with a persistent PDA, but other morbidities were not significantly different. A randomised trial is needed to determine whether surgical ligation will reduce mortality in such infants.

Early introduction of lipids to parenterally-fed preterm infants.

BACKGROUND: Lipids are essential components of parenteral nutrition for preterm infants. Parenteral lipids can be administered through a peripheral vein, and their early introduction offers the potential advantages of increasing energy intake and providing essential fatty acids and fat soluble vitamins. Concerns have been raised about potential adverse effects including chronic lung disease (CLD), increase in pulmonary vascular resistance, impaired pulmonary gas diffusion, bilirubin toxicity, sepsis and free radical stress. OBJECTIVES: To determine the safety and efficacy of 'early' (/= stage 2 necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), patent ductus arteriosus (PDA), sepsis, intraventricular haemorrhage (IVH), clinically significant thrombocytopenia and significant jaundice. Methodological quality of eligible studies was assessed according to allocation concealment, blinding of intervention, blinding of outcome assessment and completeness of follow up. When appropriate, meta-analysis was conducted to provide a pooled estimate of effect. For categorical data the Typical relative risk (RR), Typical risk difference (RD) and number needed to treat (NNT) with 95% confidence intervals (CI) were calculated. Continuous data were analysed using weighted mean difference (WMD). MAIN RESULTS: Five studies (n = 397) were included in the review. All studies compared the effectiveness and safety of 'early' introduction versus 'no early' introduction of lipids in preterm infants. The timing of introduction of 'early lipids' ranged from < 12 hours after birth to day five of life. The timing of introduction of lipids in the 'no early' lipid group ranged from day six after birth to day 14 after birth. The initial dose ranged from 0.5 - 1 g/kg/day with gradual daily increments up to a maximum of 2.5 - 3.5 g/kg/day. For the primary outcomes (growth, death and CLD), there was no statistically significant difference between the 'early' lipid and 'no early' lipid groups. Days to regain birth weight: [WMD 0.59 (95% CI -2.41, 3.58); two trials; N = 71]. Rate of weight gain (g/day) during period of hospital stay: [MD -2.40 (95% CI -5.30, 0.50); one trial; N = 129]Death (irrespective of time): [Typical RR 1.04 (95% CI 0.69, 1.56); Typical RD 0.01 (95% CI -0.07, 0.08); five trials; N = 397]Neonatal deaths: [Typical RR 1.35 (95% CI 0.78, 2.34); Typical RD 0.05 (95% CI -0.04, 0.13); four trials; N = 268].CLD: [Typical RR 1.10 (95% CI 0.81, 1.49); Typical RD 0.04 (95% CI -0.09, 0.17); two trials; N = 193]. For the secondary outcomes of other respiratory morbidities including duration of respiratory support, duration of supplemental oxygen, PTX, pulmonary haemorrhage, PIE, NEC, ROP, PDA, sepsis, IVH and significant jaundice, there were no statistically significant differences between 'early' and 'no early' lipid groups. AUTHORS' CONCLUSIONS: No statistically significant effects of 'early introduction' of lipids on short term nutritional or other clinical outcomes, either benefits or adverse effects, were demonstrated in the studies reviewed. Based on the currently available evidence, 'early' initiation of lipids (

Changes in the polyunsaturated fatty acids of breast milk from mothers of full-term infants over 30 wk of lactation.

The fatty acid composition of breast milk from 23 breast-feeding women was serially assessed by capillary gas chromatography from the 6th to the 30th wk of lactation. The proportions of total n-3 and n-6 fatty acids were unchanged with time, although some significant differences were noted for individual polyunsaturated fatty acids (PUFAs). Of the n-3 PUFAs, only docosahexaenoic acid (DHA, 22:6n-3) concentrations changed, decreasing between 6 and 16 wk from 0.26 +/- 0.13% to 0.21 +/- 0.13% of total fatty acids but remaining at this proportion until 30 wk. Of the n-6 PUFAs, 18:3, 20:3, 20:4, and 22:5 all showed reductions with time. Compared with concentrations observed in a 1981 study, linoleic acid was higher (14% compared with 11% of total fatty acids), whereas the concentration of DHA was lower (0.21% compared with 0.32% of total fatty acids), possibly reflecting a general change in the diets of Australian women.

Are iron-folate supplements harmful?

Zinc absorption during pregnancy was measured before and 24 h after 2 wk of daily, oral, iron-folate supplements. Absorption was reduced 24 h after iron-folate, which suggests a mucosal rather than a luminal effect. Also, zinc absorption in 10 healthy volunteers was reduced by folate supplements alone. Therefore, routine iron and folate supplementation may both have deleterious effects on zinc metabolism, especially during pregnancy when iron-folate supplements are often prescribed despite adequate dietary intakes of iron and folate but not of zinc.

Nutritional rehabilitation in Bangladesh--the importance of zinc.

Our aim was to investigate whether zinc deficiency becomes apparent during nutritional rehabilitation and limits the rate of weight gain. Twenty-five severely malnourished children, who were admitted to the Children's Nutrition Unit in Bangladesh, were alternately allocated to two groups. Their mean dietary Zn intake was 3.7 mg/d and mean caloric intake greater than 150 kcal.kg-1.d-1; one group received a daily Zn supplement of 50 mg for 2 wk. During the first week, weight gain was similar in the two groups, but during the second week, weight gain was 73% more in the Zn-supplemented group (8.83 +/- 1.56 vs 5.09 +/- 1.62 g.kg-1.d-1). The 95% confidence limits were 0.88 less to 8.36 g.kg-1.d-1 more gain in children receiving Zn supplements. The results strongly suggest that Zn supplements are beneficial to severely malnourished children during nutritional rehabilitation. Polymorphonuclear (PMN) cell Zn increased in the group receiving Zn supplements (p less than 0.001), confirming that the Zn content of PMN cells reflects available Zn.

Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants.

Breast-fed infants score better on visual and developmental tests than do formula-fed infants and this has been related to higher concentrations of erythrocyte docosahexaenoic acid (DHA, 22:6 omega 3). This prompted an investigation into the relationship between brain, retina, and erythrocyte fatty acids and diet in infancy. Total lipids of erythrocytes, retina, and brain cortex from 35 term infants were analyzed by capillary gas chromatography. Breast-fed infants had a greater proportion of DHA in their erythrocytes and brain cortex relative to those fed formula (P < 0.005) but differences were not observed in retina. Cortex DHA increased in breast-fed (but not formula-fed) infants with age (r2 = 0.72, P < 0.01, n = 15), largely an effect of length of feeding (r2 = 0.62, P < 0.01, n = 35). There was an association between age at death and erythrocyte DHA with cortex DHA (r2 = 0.50, P < 0.01). In contrast, accretion of cortex arachidonic acid was dependent on age but not diet. The higher concentration of DHA in brains of breast-fed infants may explain the improved neurodevelopment reported in breast-fed compared with formula-fed infants.

A critical appraisal of the role of dietary long-chain polyunsaturated fatty acids on neural indices of term infants: a randomized, controlled trial.

OBJECTIVE: To determine whether dietary long-chain polyunsaturated fatty acids (LCPUFA), such as docosahexaenoic acid (DHA) and arachidonic acid, affect visual evoked potential (VEP) acuity of formula-fed infants, relative to breastfed infants. A secondary objective was to assess the effect of LCPUFA on Bayley's mental developmental index (MDI) and psychomotor developmental index (PDI). METHODS: Formula-fed infants were randomly allocated, in a double-blind manner, to either a placebo (no LCPUFA; n = 21), DHA supplemented (n = 23), or DHA+arachidonic acid supplemented formula (n = 24). Infants were fed their assigned formula from the first week of life until 1 year of age. A parallel reference group of breastfed infants was recruited and followed (n = 46). Infant VEP acuity was assessed at 16 and 34 weeks, and Bayley's MDI and PDI were assessed at 1 and 2 years of age. RESULTS: There were no differences among the randomized formula groups for VEP acuity at either 16 or 34 weeks of age. Breastfed infants had better VEP acuity at 34 weeks of age, but not at 16 weeks, compared with all formula-fed infants. Bayley's MDI and PDI were similar in the 3 formula-fed groups at 1 and 2 years. Breastfed infants had higher MDI scores than formula-fed infants at 2 years of age even after adjusting for environmental variables. CONCLUSIONS: LCPUFA supplementation did not influence VEP acuity development in these well-nourished, formula-fed infants.

Dietary long-chain polyunsaturated fatty acids do not influence growth of term infants: A randomized clinical trial.

OBJECTIVE: To determine if dietary long-chain polyunsaturated fatty acids (LCPUFA) affect the growth of formula-fed infants relative to breastfed infants. METHODS: A randomized, double-blind trial of three formula-fed groups and a parallel reference group of breastfed infants was conducted. The three treatments were a placebo (no LCPUFA), docosahexaenoic acid (DHA) supplemented, and DHA plus arachidonic acid supplemented formulas fed for 12 months. Infant weight, length, head circumference, and fatty acid status were assessed at 6, 16, 34 weeks, and 1 year of age. Anthropometrics were repeated at 2 years of age. RESULTS: There were no differences between the randomized formula groups for weight, length, or head circumference even after adjustment for gender, gestational age, and the actual age at assessment. Post hoc regressions demonstrated a small negative association between DHA status at 16 weeks of age and weight at 1 and 2 years. CONCLUSIONS: Dietary LCPUFA do not influence growth of healthy term infants to a clinically significant degree.

A double-blind trial of zinc supplementation in pregnancy.

A double-blind randomised trial of oral zinc supplementation was carried out during the last two trimesters of pregnancy. Fifty-six women at risk of delivering a small-for-gestational-age baby received either zinc supplement (22.5 mg daily) or placebo. Twenty-nine of the women were compliant. Zinc significantly reduced the incidence of intrauterine growth retardation, and most measured indices of labour and fetal health were better in the supplemented group. Larger studies are now needed to confirm a role for selective zinc supplementation in at-risk pregnancies.

Randomised clinical trial of parenteral selenium supplementation in preterm infants.

AIM: To determine whether selenium supplementation of parenteral nutrition with 3 micrograms/kg/day of selenious acid is safe and effective in improving the selenium status of preterm infants. METHODS: Thirty eight preterm infants with mean (SEM) birthweight of 1171 (38) g and gestational age 29 (0.3) weeks were randomly allocated to a non-supplemented (PN-selenium, n = 19) or supplemented (PN+selenium, n = 19) group. The study began at 2.8 (0.2) (range 1-5) days of age. Term breastfed (n = 23) and formula fed (n = 8) infants were used as a reference group. RESULTS: Initially there was no difference between the preterm groups in plasma or erythrocyte selenium or glutathione peroxidase activity. Plasma selenium declined by a mean (SEM) of -13.3 (3.2) micrograms/l from 28 (4) to 16 (3) micrograms/l over the first three weeks in the PN-selenium group, but there was no fall in the supplemented infants and no net change in either group over six weeks. Over six weeks, there was a net decline in erythrocyte selenium of -106 (27) ng/g haemoglobin in the PN-selenium group, but no change in the PN+selenium group, such that at week 6 erythrocyte selenium was lower in the PN-selenium group (401 (17) ng/g haemoglobin) than the PN+selenium group (493 (25) ng/g haemoglobin). Urinary selenium was substantially higher in the PN+selenium group at each week. Initially term and preterm plasma selenium concentrations were similar, but they increased in term breastfed infants (+17 (2) micrograms/l), with both groups of preterm infants having lower plasma selenium concentrations at week 6 compared with term breastfed infants (PN-selenium 22 (3) micrograms/l; PN+selenium 23 (4) micrograms/l and term breastfed 49 (2) micrograms/l). CONCLUSIONS: Selenium supplementation of PN at 3 g/kg/day prevented depletion in newborns, but was inadequate to achieve selenium concentrations equivalent to those of breastfed term infants. Whether higher doses are more effective remains to be determined, particularly in light of the high urinary selenium secretion in supplemented infants. Selenium supplementation of both parenteral nutrition and formulas is recommended, but the optimal form and dose remain unclear.

Long-chain polyunsaturated fatty acid supplementation in infants born at term.

BACKGROUND: The n-3 and n-6 fatty acids linolenic acid and linoleic acid are precursors of the n-3 and n-6 longchain fatty acids (LCPUFA). Infant formula has historically only contained the precursor fatty acids. Controversy exists over whether LCPUFA are also essential nutrients in infancy. Over the last few years some manufacturers have added LCPUFA to formulae and marketed them as providing an advantage for the development of term infants. OBJECTIVES: The aim of this review is to assess whether supplementation of formula with LCPUFA is safe and of benefit to term infants. SEARCH STRATEGY: Trials were identified by MEDLINE, checking reference lists of articles and conference proceedings, and by personal communication. SELECTION CRITERIA: All randomised trials of formula supplemented with LCPUFA and with clinical endpoints were reviewed. DATA COLLECTION AND ANALYSIS: Ten randomised studies were identified. One of these studies was excluded due to supplementation commencing after three weeks of age. Eight of the nine included trials were assessed to be of good quality. There was insufficient information available to assess the quality of the other included trial. MAIN RESULTS: Visual acuity was assessed by visual evoked potentials (VEP) at 4 and 7-8 months in the studies of Makrides et al (1995 & 1996). The supplemented infants had an improved rate of visual maturation at both time points in the first study, but no difference was found between the groups at the same time points in the second study. VEP acuity was also assessed in the study of Austed et al (1997) and no effect of supplementation was found at any time point over the first year. This contrasts with the study of Birch et al (1998) where VEP acuity was better in the supplemented group compared with the control group at 6 weeks, 4 and 12 months but not at 6 months. Visual acuity was assessed by Teller acuity cards in the study of Carlson et al (1996), Clausen et al (1996), Austed et al (1997) and Birch et al (1998). Supplementation had no effect on visual acuity over the first year of life except at one of five time points in the study of Carlson et al (1996). Intellectual development was measured in seven studies. The two largest studies showed no effect of supplementation on development, either at 18 months (Lucas et al 1999) or at one and three years (Janowsky et al 1995, Scott et al 1997). The next largest study reported better developmental scores at 18 months in the supplemented group (Birch et al 2000) but when combined with data of Lucas et al, no significant benefit is shown. Makrides et al (1995 & 1996) also showed no benefit to development with supplementation over the first two years of life. Agostini et al 1995 reported a benefit in development at 4 months of age with supplementation but when the infants were followed up with the same test at 1 and 2 years, no difference between groups was found (Agostini et al 1997). The Portland study showed no effect of supplementation on language development at one and three years (Janowsky et al 1995, Scott et al 1997). Clausen et al (1996) reported better novelty preference measured by Fagan Infant test at nine months in supplemented infants compared with controls. Willatts et al (1998) reported better problem solving at 10 months with supplementation. Growth was measured in the studies of Makrides et al (1995 & 1996), Austed et al (1997), Willatts et al 1998, Lucas et al 1999 and Birch et al 2000. LCPUFA supplementation did not influence growth in any of these studies. REVIEWER'S CONCLUSIONS: At present there is little evidence from randomised trials of LCPUFA supplementation to support the hypothesis that LCPUFA supplementation confers a benefit for visual or general development of term infants. Minor effects on VEP acuity have been suggested but appear unlikely when all studies are reviewed. A beneficial effect on information processing is possible but larger studies over longer periods are required to conclude that LCPUFA supplementation provides a benefit when compared with standard formula. Data from randomised trials do not suggest that LCPUFA supplements influence the growth of term infants.

Long-chain polyunsaturated fatty acid supplementation in preterm infants.

BACKGROUND: This section is under preparation and will be included in the next issue. OBJECTIVES: The n-3 and n-6 essential fatty acids alpha linolenic acid and linoleic acid 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 infant formula with LCPUFA is safe and of benefit to preterm infants. SEARCH STRATEGY: Trials were identified by MEDLINE and by checking reference lists of relevant articles and conference proceedings. SELECTION CRITERIA: All randomised trials of formula supplemented with LCPUFA and with clinical endpoints were reviewed. DATA COLLECTION AND ANALYSIS: Eight randomised trials were identified. Five were assessed as being of high quality and one is awaiting assessment. Problems with the remaining two included a change in assessment methodology mid-study (Memphis 1996) and assessment methodology that deviated from generally accepted international standards (Bologna 1996). MAIN RESULTS: Studies from Dallas (Uauy et al 1990, Birch et al 1992, Hoffman & Uauy 1992, Uauy et al 1994) and Memphis (Carlson et al 1991, Carlson et al 1992, Carlson et al 1993, Werkman & Carlson 1996) suggest that early visual development is better in formula-fed infants who receive a LCPUFA supplement compared with those fed standard formula. However, the effects were not long-term, with no differences detected between groups after 4 months of age. The Bologna group (Fadelli et al 1996) reported some differences in the visual evoked potential at 3 months post-term but their methodology was questionable making interpretation of the data difficult. In the largest study (the Mead Johnson study, Hansen et al 1997), no difference in visual acuity was demonstrated between LCPUFA supplemented and control infants at 2 and 4 months post-term. The Memphis studies used the Fagan Infantest (Fagan 1970) to measure infant development and demonstrated lower novelty preferences (possibly predictive of lower intelligence) in preterm infants supplemented with LCPUFA. However, the supplemented infants had more looks at the novel stimulus and each look was of shorter duration which may represent more rapid visual information processing. Normalised weight (expressed as SD from the mean for age) was lower in preterm infants who were fed supplemented formula in the Memphis studies. No difference in growth between supplemented and control infants was documented in the Dallas, Bologna, Alberta (Clandinin et al 1997) and Wyeth (Vanderhoof et al 1997) studies while the Mead Johnson study documented higher weights in supplemented infants compared with controls at two months post-term. The Dallas study documented little effect of LCPUFA supplements on bleeding time and membrane fragility. REVIEWER'S CONCLUSIONS: No long-term benefit has been demonstrated for preterm infants receiving formula supplemented with LCPUFA. There is some evidence that n-3 LCPUFA supplementation of formula increases the early rate of visual maturation in preterm infants. Supplementation of formula with n-3 and n-6 LCPUFA does not impair the growth of preterm infants.

Long-chain polyunsaturated fatty acid supplementation in infants born at term.

BACKGROUND: This section is under preparation and will be included in the next issue. OBJECTIVES: The n-3 and n-6 essential fatty acids alpha linolenic acid and linoleic acid are the precursors of the n-3 and n-6 longchain polyunsaturated fatty acids (LCPUFA). Controversy exists over whether LCPUFA are essential nutrients during infancy. The aim of this review is to assess whether supplementation of formula with LCPUFA is safe and of benefit to term infants. SEARCH STRATEGY: Trials were identified by MEDLINE, checking reference lists of articles and conference proceedings, and by personal communication. SELECTION CRITERIA: All randomised trials of formula supplemented with LCPUFA and with clinical endpoints were reviewed. DATA COLLECTION AND ANALYSIS: Eight randomised studies were identified. One of these studies was excluded due to supplementation commencing after three weeks of age, and one is awaiting assessment. The remaining six trials were assessed to be of good quality. MAIN RESULTS: Visual acuity was assessed by visual evoked potentials at 4 and 7-8 months in the studies of Makrides et al (1995 & 1996). The supplemented infants had an improved rate of visual maturation at both time points in the first study, but no difference was found between the groups at 4 months in the second study. Visual acuity was assessed by Teller acuity cards in the study of Carlson et al (1996), Clausen et al (1996) and Austed et al (1997). Supplementation had no consistent effect on visual acuity over the first year of life. General development was measured in five studies, all with small numbers. Two suggested a benefit of supplementation. One reported a benefit with supplementation at 4 months ( developmental quotient, DQ measured with the Brunet Lezine test, Agostini et al 1995), but when the groups were reassessed with the same test at 1 and 2 years, no differences were found in DQ (Agostini et al 1997). The other study reported a benefit with supplementation at 9 months (novelty preference measured by Fagan Infantest, Clausen et al 1996). The Adelaide studies showed no effect of supplementation on DQ at one year (Bayley Scales of Infant Development (BSID), Makrides et al 1995 &1996). The Portland study showed no effect of supplementation on development at one year (BSID) or at three years (Stanford Binet IQ test). The Portland study showed no effect of supplementation on language development at one year (McArthur Communicative Development Inventory, Janowsky et al 1995) or at three years (Peabody Picture Vocabulary Test, Scott et al 1997). Growth was measured in a small number of infants in the studies of Makrides et al (1995 & 1996) and Austed et al (1997). There was no suggestion that LCPUFA supplementation reduced the growth of term infants. REVIEWER'S CONCLUSIONS: At present there is little evidence from randomised trials of LCPUFA supplementation to support the hypothesis that LCPUFA supplementation confers any benefit on visual or cognitive development. There are no data from the randomised trials presently available to indicate that LCPUFA supplements influence the growth of term infants.

Longchain polyunsaturated fatty acid supplementation in preterm infants.

BACKGROUND: 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. OBJECTIVES: The aim of this review is to assess whether supplementation of formula with LCPUFA is safe and of benefit to preterm infants. SEARCH STRATEGY: 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) and by checking reference lists of relevant articles and conference proceedings. SELECTION CRITERIA: All randomised trials of formula supplemented with LCPUFA and with clinical endpoints were reviewed. DATA COLLECTION AND ANALYSIS: Eleven randomised trials assessing the clinical effects of feeding formula supplemented with LCPUFA were included in the review. MAIN RESULTS: Of the eleven randomised trials included in the review, two of these were not classified as of high quality despite blinded assessment and complete follow-up, due to problems with assessment methodology. VISUAL ACUITY: Visual acuity over the first year was measured by Teller acuity cards in six studies, by VEP in four studies and by ERG in two studies. Most studies found no significant differences in any visual assessment between supplemented and control 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. REVIEWER'S CONCLUSIONS: Infants enrolled in the trials were relatively mature and healthy preterm infants. Assessment schedule and methodology, dose and source of supplementation and fatty acid composition of the control formula varied between trials. No long-term benefits were demonstrated for infants receiving formula supplemented with LCPUFA. There was no evidence that supplementation of formula with n-3 and n-6 LCPUFA impaired the growth of preterm infants.

Utilization of docosahexaenoic acid from intravenous egg yolk phospholipid.

Docosahexaenoic acid (DHA, 22:6n-3) is provided directly to human premature infants during parenteral nutrition from the egg yolk fraction of an intravenous fat emulsion. This study aimed to determine whether the high egg yolk phospholipid content of Intralipid 10% (IL 10%, Pharmacia, Uppsala, Sweden) relative to the standard emulsion Intralipid 20% (IL 20%, Pharmacia) could be a strategy to increase the delivery of DHA to the developing brain. Male, Large White piglets were randomly selected from sows 3 d after birth. Piglets were assigned to receive a 9-d continuous intravenous infusion commencing 5 d after birth of either Intralipid (IL) 10%, IL 20%, or Lipofundin S 20% (LFS; B. Braun, Melsungen, Germany). There were four piglets in each treatment group. IL 10% provides twice as much DHA as IL 20%, while LFS provides no DHA. Protein and other nutrients were provided enterally using a low-fat milk formula. After 9 d, animals were killed, and the fatty acid compositions of blood, liver, and cerebral cortex were analyzed. IL 10% infusion approximately doubled the amount of plasma phospholipid DHA (microg/mL of plasma) in comparison to IL 20%. However, red blood cells, liver, and cerebral cortex phospholipid DHA levels were indistinguishable between these two groups. LFS was associated with reduced levels of DHA in plasma, red blood cell and liver phospholipids in comparison to IL 20%. We conclude that infusion of additional phospholipid is an ineffective strategy for increasing DHA delivery to piglet tissues. This may be due to the formation of inert phospholipid particles in plasma. The data do not support the concept of using IL 10% as a means of providing additional DHA to premature human infants.