Effect of nutritionally modified infant formula on academic performance: linkage of seven dormant randomised controlled trials to national education data.

OBJECTIVE: To compare differences in academic performance between adolescents who were randomised in infancy to modified or standard infant formula. DESIGN: Linkage of seven dormant randomised controlled trials to national education data. SETTING: Five hospitals in England, 11 August 1993 to 29 October 2001, and schools in England, September 2002 to August 2016. PARTICIPANTS: 1763 adolescents (425 born preterm, 299 born at term and small for gestational age, 1039 born at term) who took part in one of seven randomised controlled trials of infant formula in infancy. INTERVENTIONS: Nutrient enriched versus standard term formula (two trials), long chain polyunsaturated fatty acid (LCPUFA) supplemented versus unsupplemented formula (two trials), high versus low iron follow-on formula (one trial), high versus low sn-2 palmitate formula (one trial), and nucleotide supplemented versus unsupplemented formula (one trial). MAIN OUTCOME MEASURES: The primary outcome, determined by linkage of trial data to school data, was the mean difference in standard deviation scores for mandated examinations in mathematics at age 16 years. Secondary outcomes included differences in standard deviation scores in English (16 and 11 years) and mathematics (11 years). Analysis was by intention to treat with multiple imputation for participants missing the primary outcome. RESULTS: 1607 (91.2%) participants were linked to school records. No benefit was found for performance in mathematics examinations at age 16 years for any modified formula: nutrient enriched in preterm infants after discharge from hospital, standard deviation score 0.02 (95% confidence interval -0.22 to 0.27), and nutrient enriched in small for gestational age term infants -0.11 (-0.33 to 0.12); LCPUFA supplemented in preterm infants -0.19 (-0.46 to 0.08) and in term infants -0.14 (-0.36 to 0.08); iron follow-on formula in term infants -0.12 (-0.31 to 0.07); and sn-2 palmitate supplemented formula in term infants -0.09 (-0.37 to 0.19). Participants from the nucleotide trial were too young to have sat their General Certificate of Secondary Education (GCSE) examinations at the time of linkage to school data. Secondary outcomes did not differ for nutrient enriched, high iron, sn-2 palmitate, or nucleotide supplemented formulas, but at 11 years, preterm and term participants randomised to LCPUFA supplemented formula scored lower in English and mathematics. CONCLUSIONS: Evidence from these randomised controlled trials indicated that the infant formula modifications did not promote long term cognitive benefit compared with standard infant formulas.

An economic analysis of human milk supplementation for very low birth weight babies in the USA.

BACKGROUND: An exclusive human milk diet (EHMD) using human milk based products (pre-term formula and fortifiers) has been shown to lead to significant clinical benefits for very low birth weight (VLBW) babies (below 1250 g). This is expensive relative to diets that include cow's milk based products, but preliminary economic analyses have shown that the costs are more than offset by a reduction in the cost of neonatal care. However, these economic analyses have not completely assessed the economic implications of EHMD feeding, as they have not considered the range of outcomes affected by it. METHODS: We conducted an economic analysis of EHMD compared to usual practice of care amongst VLBW babies in the US, which is to include cow's milk based products when required. Costs were evaluated from the perspective of the health care payer, with societal costs considered in sensitivity analyses. RESULTS: An EHMD substantially reduces mortality and improves other health outcomes, as well as generating substantial cost savings of $16,309 per infant by reducing adverse clinical events. Cost savings increase to $117,239 per infant when wider societal costs are included. CONCLUSIONS: An EHMD is dominant in cost-effectiveness terms, that is it is both cost-saving and clinically beneficial, for VLBW babies in a US-based setting.

Percepção dos moradores do distrito de Eleutério, município de Itapira-SP, acerca da utilização de plantas medicinais / Perception of the residents of the district of Eleutério municipality of Itapira-SP on the use of medicinal plants / Percepción de los habitantes del distrito de Eleuterio municipio de Itapira-SP acerca de la utilización de plantas medicinales

A fitoterapia e o uso de plantas medicinais fazem parte da prática da medicina popular, que complementa o tratamento usualmente empregado para a população de menor renda. Essa utilização tem merecido crescente interesse, assim, a presente pesquisa investigou a percepção dos moradores de Eleutério, um Distrito Municipal de Itapira-SP, estritamente rural acerca da utilização de plantas medicinais. Participaram desta pesquisa 40 moradores de ambos os sexos, escolhidos de forma aleatória, com idade acima de 18 anos, residentes neste Distrito. Para tanto, a pesquisa foi realizada por meio de uma entrevista estruturada empregando um questionário, sendo os dados anotados em planilha para análise e comparação. Em relação ao uso de plantas medicinais, foram verificados que 80% da amostra fazem uso de alguma planta medicinal e 28% não seguem nenhum protocolo de preparo. Quanto aos possíveis efeitos tóxicos, 50% relatam que por serem natural não apresentam efeitos colaterais indesejáveis. Este estudo demonstra que a população deste distrito realiza a utilização de plantas medicinais com certa frequência, havendo a necessidade de uma maior divulgação quanto a essa prática, uma vez que, as pessoas em geral tem demonstrado interesse na fitoterapia como alternativa para o tratamento de diversas afecções(AU)

Phytotherapy and the use of medicinal plants are part of the practice of folk medicine, which complements the treatment usually employed for the lower income population. This use has been of growing interest, so the present research investigated the perception of the residents of Eleutério, a Municipal District of Itapira-SP, strictly rural about the use of medicinal plants. A total of 40 randomly selected male and female residents of this age group aged 18 years and older participated in this study. For this, the research was performed through a structured interview using a questionnaire, the data being annotated in a spreadsheet for analysis and comparison. Regarding the use of medicinal plants, it was verified that 80% of the sample makes use of some medicinal plant and 28% do not follow any protocol of preparation. Regarding possible toxic effects, 50% report that because they are natural they do not present undesirable side effects. This study demonstrates that the population of this district uses medicinal plants with some frequency, and there is a need for greater dissemination regarding this practice, since the general population has shown an interest in phytotherapy as an alternative for the treatment of several diseases(AU)

La fitoterapia y el uso de plantas medicinales forman parte de la práctica de la medicina popular, que complementa el tratamiento usualmente empleado para la población de menores ingresos. Esta utilización ha merecido creciente interés, así, la presente investigación investigó la percepción de los habitantes de Eleuterio, un Distrito Municipal de Itapira-SP, estrictamente rural acerca de la utilización de plantas medicinales. Participaron en esta investigación 40 residentes de ambos sexos, elegidos de forma aleatoria, con edad superior a 18 años, residentes en este Distrito. Para ello, la investigación fue realizada por medio de una entrevista estructurada empleando un cuestionario, siendo los datos anotados en planilla para análisis y comparación. En cuanto al uso de plantas medicinales, se verificó que el 80% de la muestra hace uso de alguna planta medicinal y el 28% no sigue ningún protocolo de preparación. En cuanto a posibles efectos tóxicos, el 50% informa que por ser natural no presentan efectos colaterales indeseables. Este estudio demuestra que la población de este distrito realiza la utilización de plantas medicinales con cierta frecuencia, habiendo la necesidad de una mayor divulgación en cuanto a esa práctica, una vez que la población en general ha demostrado interés en la fitoterapia como alternativa para el tratamiento de diversas condiciones(AU)

Docosahexaenoic acid supplementation, vascular function and risk factors for cardiovascular disease: a randomized controlled trial in young adults.

BACKGROUND: A high consumption of omega-3 long-chain polyunsaturated fatty acids, and particularly docosahexaenoic acid (DHA), has been suggested to reduce the risk of cardiovascular disease (CVD). However, while DHA supplementation may have benefits for secondary prevention, few studies have investigated the role of DHA in the primary prevention of CVD. Here, we tested the hypothesis that DHA supplementation improves endothelial function and risk factors for CVD. METHODS AND RESULTS: Healthy volunteers (n=328), aged 18 to 37 years, were randomly assigned to 1.6 g DHA/day (from a microalgae source) together with 2.4 g/day carrier oil (index group) or to 4.0 g/day olive oil (control) (both given in eight 500-mg capsules/day for 16 weeks). Flow-mediated endothelium-dependent vasodilation (FMD) of the brachial artery (primary outcome) was measured before and after the intervention (n=268) using high-resolution vascular ultrasound. FMD was the same in both groups at randomization (mean, SD; 0.27, 0.1 mm), but postintervention was higher in the control group (0.29, 0.1 mm) compared with the DHA-supplemented group (0.26, 0.1 mm; mean difference -0.03 mm; 95% CI -0.005 to -0.06 mm; P=0.02). Of other outcomes, only triglyceride (mean difference -28%, 95% CI -40% to -15%; P<0.0001) and very low-density lipoprotein concentrations were significant lower in DHA-supplemented individuals compared with controls. CONCLUSIONS: DHA supplementation did not improve endothelial function in healthy, young adults. Nevertheless, lower triglyceride concentrations with DHA supplementation was consistent with previous reports and could have benefits for the prevention of CVD.

Timing of the introduction of complementary foods in infancy: a randomized controlled trial.

OBJECTIVE: To increase knowledge on iron status and growth during the first 6 months of life. We hypothesized that iron status would be better in infants who received complementary foods in addition to breast milk compared with those exclusively breastfed. METHODS: One hundred nineteen healthy term (≥37 weeks) singleton infants were randomly assigned to receive either complementary foods in addition to breast milk from age 4 months (CF) or to exclusive breastfeeding for 6 months (EBF). Dietary data were collected by 3-day weighed food records, and data on iron status and growth were also collected. RESULTS: One hundred infants (84%) completed the trial. Infants in the CF group had higher mean serum ferritin levels at 6 months (P = .02), which remained significant when adjusted for baseline characteristics. No difference was seen between groups in iron deficiency anemia, iron deficiency, or iron depletion. The average daily energy intake from complementary foods of 5-month-olds in the CF group was 36.8 kJ per kg body weight. Infants in both groups grew at the same rate between 4 and 6 months of age. CONCLUSIONS: In a high-income country, adding a small amount of complementary food in addition to breast milk to infants' diets from 4 months of age does not affect growth rate between 4 and 6 months, but has a small and positive effect on iron status at 6 months. The biological importance of this finding remains to be determined.

10-year cognition in preterms after random assignment to fatty acid supplementation in infancy.

OBJECTIVE: To test the hypothesis that long-chain polyunsaturated fatty acid (LCPUFA) supplementation in infancy would improve cognition into later childhood (after 9 years) at both general and specific levels. METHODS: A comprehensive cognitive battery was completed by 107 formerly preterm infants (mean age: 128 months). As infants, they had been assigned randomly to receive LCPUFA-supplemented (N = 50) or control (N = 57) formula, between birth and 9 months; the docosahexaenoic acid level (DHA) in the supplemented formulas was 0.5%. In addition to randomized comparisons, we planned supplementary analyses to examine the effects of both gender and feeding group (those receiving some maternal breast milk versus those receiving none). RESULTS: There were no significant differences between randomized diet groups on any cognitive measure. There was significant interaction between gender and supplementation; girls only showed beneficial effects of LCPUFAs on literacy. Significant interaction also occurred between feeding group and supplementation; increases of 0.7 SD in verbal IQ, full-scale IQ, and memory scores were found for the LCPUFA group, but only for infants who received only formula and no maternal breast milk. CONCLUSIONS: The results of this post-9-year cognitive follow-up study in a randomized trial of LCPUFA-supplemented formula for preterm infants suggest no overall group effects but indicate that gender-specific and diet-specific effects may exist. The data provide some evidence that LCPUFAs are a key factor in the cognitive benefits of breast milk. Caution is advised in data interpretation because of the small groups used.

Short-term exposure to exogenous lipids in premature infants and long-term changes in aortic and cardiac function.

OBJECTIVE: Intravenous lipid use is associated with an acute hyperlipidemia, but long-term consequences have not been studied. We investigated whether elevated lipids in humans during the critical period of preterm neonatal life have a long-term impact on aortic and myocardial function relevant to adult disease. METHODS AND RESULTS: We followed up 102 subjects born prematurely and now aged 23 to 28 years. Eighteen received intravenous lipids as neonates and were matched to controls with equivalent perinatal characteristics. Global and regional aortic stiffness and left ventricular function were assessed by cardiovascular magnetic resonance. Those who received intravenous lipids had greater aortic stiffness in early adulthood (P=0.0002), with greater stiffness in the abdominal aorta (P=0.012). The relationship was graded according to the elevation in neonatal cholesterol induced by intravenous lipids (P<0.0001) but not other metabolic parameters altered by the infusion. Peak systolic circumferential strain was also reduced in the lipid group (P=0.006), which, again, was proportional to neonatal cholesterol level (P<0.01). CONCLUSIONS: Aortic and myocardial function in young adulthood is associated with intralipid exposure during neonatal life for preterm infants, in a graded manner related to the rise in cholesterol. Circulating cholesterol during critical developmental periods may have long-term impacts on the human cardiovascular system.

The 10-year follow-up of a randomised trial of long-chain polyunsaturated fatty acid supplementation in preterm infants: effects on growth and blood pressure.

OBJECTIVE: To test the hypothesis that consumption of infant formulas containing long-chain polyunsaturated fatty acids (LCPUFAs) by preterm infants would favourably influence growth, body composition and blood pressure (BP) at age 10 years. METHODS: This was a follow-up study of a preterm cohort (<35 weeks and birth weight <2000 g) randomly assigned to unsupplemented or LCPUFA-supplemented formulas to 9 months post term. The setting was a research clinic at Yorkhill Hospital for Sick Children, Glasgow, UK. A total of 107 children aged 9-11 years who participated in the original randomised controlled trial (45% follow-up) took part. Main outcome measures were: (1) anthropometry, (2) body composition and (3) BP. RESULTS: There were no differences in growth or BP between randomised groups for the whole cohort. However, girls who had received LCPUFA-supplemented formula were heavier (42.20 (SD 9.61) vs 36.94 (9.46) kg, p=0.05), had greater skin fold thicknesses (biceps 10.7 (3.3) vs 8.5 (3.6) mm, p=0.03; suprailiac 16.7 (8.2) vs 12.0 (7.5) mm, p=0.03) and higher BP (mean 82.2 (8.4) vs 78.1 (6.2) mm Hg, p=0.04: systolic 111.4 (10.1) vs 105.9 (9.0) mm Hg, p=0.04: diastolic 64.8 (8.4) vs 61.1 (5.4) mm Hg, p=0.05). Differences in weight SD score (0.85 (95% CI 0.13 to 1.58), p=0.02), Ln sum of skin fold thicknesses (0.27 (0.02 to 0.52), p=0.04) and BP (mean 4.6 mm Hg (0.43 to 8.84), p=0.03; systolic 6.1 (0.45 to 11.7), p=0.04) remained after adjustment for prerandomisation confounders. Differences in BP were not significant following adjustment for current weight. CONCLUSIONS: Girls born preterm and randomised to LCPUFA-supplemented formula showed increased weight, adiposity and BP at 9-11 years, which might have adverse consequences for later health. No effects were seen in boys. Long-term follow-up of other LCPUFA supplementation trials is required to further investigate this finding.

Infant formula supplementation with long-chain polyunsaturated fatty acids has no effect on Bayley developmental scores at 18 months of age--IPD meta-analysis of 4 large clinical trials.

OBJECTIVES: To find out whether supplementation of formula milk by long-chain polyunsaturated fatty acids (LCPUFA) affects neurodevelopment at 18 months of age in term or preterm infants by an individual patient data (IPD) meta-analysis. MATERIALS AND METHODS: Data of 870 children from 4 large randomised clinical trials for formula milk with and without LCPUFAs allowed for assessing the effect of LCPUFA with adjustment for potential confounders and extensive subgroup analysis on prematurity, LCPUFA source, and dosage. Any additional clinical trials examining the effect of LCPUFA supplementation on Bayley Scales of Infant Development at 18 months were regarded as relevant. Two relevant studies were identified by MEDLINE, but were not available to us. An IPD meta-analysis was performed with subgroup analyses by preterm delivery, very low birth weight (<1500 g), trials with higher amounts of docosahexaenoic acid (DHA) and arachidonic acid (AA), and specific sources of LCPUFA. The sample size of 870 children was sufficient to detect clinically relevant differences in Bayley Scales even in subgroups. RESULTS: There were no significant differences in mental or psychomotor developmental indexes between LCPUFA-supplemented and control groups for all children or in subgroups. This was confirmed with adjustment for the possible confounders: sex, gestational age, birth weight, maternal age, and maternal smoking. The adjusted mean differences in mental developmental index and psychomotor developmental index for all of the children were -0.8 (95% confidence interval -2.8 to 1.2) and -1.0 (-2.7 to 0.7), respectively. CONCLUSIONS: These data based on considerable sample size provide substantial evidence that LCPUFA supplementation of infant formula does not have a clinically meaningful effect on the neurodevelopment as assessed by Bayley scores at 18 months. Inclusion of all relevant data should not have led to differing conclusions except, possibly, for very-low-birth-weight infants.

Early diet and peak bone mass: 20 year follow-up of a randomized trial of early diet in infants born preterm.

BACKGROUND: Preterm infants are at risk of metabolic bone disease due to inadequate mineral intake with unknown consequences for later bone health. OBJECTIVE: To test the hypotheses that (1) early diet programs peak bone mass and bone turnover; (2) human milk has a beneficial effect on these outcomes; (3) preterm subjects have reduced peak bone mass compared to population reference data. DESIGN: 20 year follow-up of 202 subjects (43% male; 24% of survivors) who were born preterm and randomized to: (i) preterm formula versus banked breast milk or (ii) preterm versus term formula; as sole diet or supplement to maternal milk. Outcome measures were (i) anthropometry; (ii) hip, lumbar spine (LS) and whole body (WB) bone mineral content (BMC) and bone area (BA) measured using DXA; (iii) bone turnover markers. RESULTS: Infant dietary randomization group did not influence peak bone mass or turnover. The proportion of human milk in the diet was significantly positively associated with WBBA and BMC. Subjects receiving >90% human milk had significantly higher WBBA (by 3.5%, p=0.01) and BMC (by 4.8%, p=0.03) than those receiving <10%. Compared to population data, subjects had significantly lower height SDS (-0.41 (SD 1.05)), higher BMI SDS (0.31 (1.33)) and lower LSBMD SDS (-0.29 (1.16)); height and bone mass deficits were greatest in those born SGA with birthweight <1250 g (height SDS -0.81 (0.95), LSBMD SDS -0.61 (1.3)). CONCLUSION: Infant dietary randomization group did not affect peak bone mass or turnover suggesting the observed reduced final height and LS bone mass, most marked in growth restricted subjects with the lowest birthweight, may not be related to sub-optimal early nutrition. The higher WB bone mass associated with human milk intake, despite its low nutrient content, may reflect non-nutritive factors in breast milk. These findings may have implications for later osteoporosis risk and require further investigation.

IPD meta-analysis shows no effect of LC-PUFA supplementation on infant growth at 18 months.

AIM: Clinical trials on the effects of long-chain polyunsaturated fatty acids (LC-PUFA) supplementation of formula milk on growth of term and preterm children have shown conflicting results. We examined the effects of LC-PUFAs-- especially docosahexaenoic acid (DHA) and arachidonic acid (AA)--on growth at 18 months. METHODS: We performed a meta-analysis based on individual patient data (IPD) of 901 children from four large, randomised clinical trials of formula milk with and without LC-PUFAs. Anthropometrics were assessed by z-scores based on weight for age, length for age, head circumference for age and body mass index (BMI) for age at 18 months. The studies differed in LC-PUFA composition and infant characteristics (two studies on preterm children, two on term children). RESULTS: Multivariate regression analyses including the possible confounders, sex, gestational age, birth weight, smoking in the last trimester and maternal age, as well as interaction terms showed no significant effects of LC-PUFA supplementation on any z-score. Subgroup analyses on trials with high amounts of DHA and on studies with duration of supplementation of at least 6 months yielded the same result. These findings cannot be explained by the lack of power. CONCLUSION: Our IPD meta-analysis shows no evidence that LC-PUFA supplementation affects children's growth at 18 months of age.

Dietary nucleotides and fecal microbiota in formula-fed infants: a randomized controlled trial.

BACKGROUND: Dietary nucleotides are nonprotein nitrogenous compounds that are thought to be important for growth, repair, and differentiation of the gastrointestinal tract. A higher nucleotide intake may also have favorable effects on the fecal microbial composition and incidence of diarrhea in infancy. However, few studies have tested this hypothesis with an experimental study design. OBJECTIVE: We tested the hypothesis that nucleotide supplementation of infant formula has beneficial effects on fecal bacteriology. DESIGN: Oligonucleotide probes were used to measure bacterial genus-specific 16S ribosomal RNA in stools of a subset of infants (mean age: 20.4 wk) who were randomly assigned to nucleotide-supplemented (31 mg/L; n = 35) or control formula (n = 37) from birth until age 20 wk or were breastfed (reference group; n = 44). The microbial pattern was assessed as the ratio of Bacteroides-Porphyromonas-Prevotella group (BPP) to Bifidobacterium species. RESULTS: The ratio of BPP to Bifidobacterium spp. rRNA in infants randomly assigned to the nucleotide-supplemented formula was lower than in infants receiving the control formula (mean difference: -118%; 95% CI: -203%, -34%; P = 0.007), but it did not differ in infants who were breastfed. The difference between randomized formula-fed groups was independent of potential confounding factors (P = 0.003). CONCLUSIONS: Our data support the hypothesis that nucleotide supplementation improves the composition of the gut microbiota in formula-fed infants. Because this effect could contribute to previously described benefits of nucleotide supplementation for gastrointestinal tract and immune function, these findings have important implications for optimizing the diet of formula-fed infants.

Optimal duration of exclusive breastfeeding: what is the evidence to support current recommendations?

Before 2001, the World Health Organization (WHO) recommended that infants be exclusively breastfed for 4-6 mo with the introduction of complementary foods (any fluid or food other than breast milk) thereafter. In 2001, after a systematic review and expert consultation, this advice was changed, and exclusive breastfeeding is now recommended for the first 6 mo of life. The systematic review commissioned by the WHO compared infant and maternal outcomes for exclusive breastfeeding for 3-4 mo versus 6 mo. That review concluded that infants exclusively breastfed for 6 mo experienced less morbidity from gastrointestinal infection and showed no deficits in growth but that large randomized trials are required to rule out small adverse effects on growth and the development of iron deficiency in susceptible infants. Others have raised concerns that the evidence is insufficient to confidently recommend exclusive breastfeeding for 6 mo for infants in developed countries, that breast milk may not meet the full energy requirements of the average infant at 6 mo of age, and that estimates of the proportion of exclusively breastfed infants at risk of specific nutritional deficiencies are not available. Additionally, virtually no data are available to form evidence-based recommendations for the introduction of solids in formula-fed infants. Given increasing evidence that early nutrition and growth have effects on both short- and longer-term health, it is vital that this issue be investigated in high-quality randomized studies. Meanwhile, the consequences of the WHO recommendation should be monitored in different settings to assess compliance and record and act on adverse events. The policy should then be reviewed in the context of new data to formulate evidence-based recommendations.

Infant nutrition and stereoacuity at age 4-6 y.

BACKGROUND: Breastfeeding has been reported to benefit visual development in children. A higher concentration of docosahexaneoic acid (DHA) in breast milk than in formula has been proposed as one explanation for this association and as a rationale for adding DHA to infant formula, but few long-term data support this possibility. OBJECTIVE: The objectives of the study were, first, to test the hypothesis that breastfeeding benefits stereoscopic visual maturation and, second, if that benefit is shown, to ascertain whether it is mediated by the dietary intake of DHA. DESIGN: Stereoacuity was measured by using the random dot E test (primary outcome), and visual acuity was measured by using the Sonksen-Silver acuity system (secondary outcome) in previously breastfed (n = 78) or formula-fed (n = 184) children aged 4-6 y who had been followed prospectively from birth. In the formula-fed group, children were randomly assigned to receive formula with either DHA or arachidonic acid (n = 94) or a control formula (n = 90) for the first 6 mo. RESULTS: Breastfed children had a significantly (P = 0.001) greater likelihood of foveal stereoacuity (high-grade or < 100 s/arc) than did formula-fed children (odds ratio: 2.5; 95% CI: 1.4, 4.5) independent of potential confounding (P = 0.005). Stereoacuity did not differ significantly between children randomly assigned to DHA-supplemented or control formula. None of the groups differed in Sonksen-Silver visual acuity. CONCLUSIONS: These findings support the hypothesis that breastfeeding benefits long-term stereoscopic development. An effect of DHA cannot be excluded, but the lack of difference in stereoacuity between infants randomly assigned to DHA-containing and those assigned to control formula raises the hypothesis that factors in breast milk other than DHA account for the observed benefits.

Randomized, double-blind trial of long-chain polyunsaturated fatty acid supplementation with fish oil and borage oil in preterm infants.

OBJECTIVE: To test the efficacy and safety of long-chain polyunsaturated fatty acid (LCPUFA) supplementation with gamma-linolenic acid, a precursor of arachidonic acid, and docosahexaenoic acid in preterm infants. STUDY DESIGN: Preterm (<35 weeks, < or =2000 g birth weight) infants (n=238) randomly assigned to unsupplemented or LCPUFA-supplemented formula to 9 months after term. The main outcome measure was the Bayley Mental and Psychomotor Indexes (MDI, PDI) at 18 months after term. Safety outcome measures were anthropometry (9 and 18 months), feed tolerance, infection, and clinical complications. RESULTS: There were no significant differences in neurodevelopment between groups overall. In preplanned subgroup analyses, LCPUFA-supplemented boys had significantly higher Bayley MDI than did control boys (difference, 5.7 points; 95% CI, 0.3 to 11.1; P=.04). LCPUFA-supplemented infants showed significantly greater weight gain (difference, 310 g; 95% CI, 30 to 590 g; P=.03) and length gain (difference, 1.0 cm; 95% CI, 0.02 to 1.9; P=.05) between birth and 9 months, with greater effect in boys (weight difference at 9 months, 510 g; 95% CI, 80 to 930 g; P=.02; length difference at 18 months, 1.8 cm; 95% CI, 0.1 to 1.8; P=.03). CONCLUSIONS: This trial, using the strategy of providing gamma-linolenic acid as a source of arachidonic acid, showed efficacy for growth and for neurodevelopment in boys, with no adverse effects. These data have important implications for LCPUFA-supplementation strategy in preterm infants.

Neurodevelopment in children born small for gestational age: a randomized trial of nutrient-enriched versus standard formula and comparison with a reference breastfed group.

OBJECTIVE: Many studies have shown that children born small for gestational age (SGA) are at a neurodevelopmental disadvantage. We have shown that nutrient enrichment of formula fed to term SGA infants improves their growth and hypothesized that it also would improve their neurodevelopmental outcome. DESIGN: A randomized, controlled trial of standard term-infant (n = 147) or nutrient-enriched (n = 152) formula for the first 9 months. A reference group of 175 breastfed SGA infants was also recruited. SETTING: Subjects were recruited in 5 maternity hospitals in Cambridge, Nottingham, and Leicester, all in the United Kingdom. PARTICIPANTS: Healthy, term infants (gestation: > or =37 weeks) with birth weight <10th centile. OUTCOME MEASURES: Bayley mental and psychomotor scores at 18 months (primary) and developmental scores from Knobloch, Pasamanick, and Sherrard's developmental screening inventory at 9 months (secondary). RESULTS: There was no significant intergroup difference in Bayley Mental Development Index (MDI) or Psychomotor Development Index (PDI) scores at 18 months. However, at 9 months, children fed the enriched formula had a significantly lower developmental quotient (99.5 vs 102.0; 95% confidence interval [CI] for difference: -4.6, -0.4). A significant disadvantage was seen in girls (-5.1; 95% CI: -7.8, -2.4) but not in boys (0.9; 95% CI: -2.4, 4.2). Breastfed infants had significantly higher MDI and PDI scores at 18 months than formula-fed infants. Confounding factors accounted for approximately 34% of the observed association between breastfeeding and MDI score and none of the association between breastfeeding and PDI score. CONCLUSIONS: The previously reported enhanced linear growth in SGA children fed enriched formula was not matched by a neurodevelopmental advantage. At 9 months, girls fed the enriched formula had a significant developmental disadvantage, although this was not seen at 18 months. Later follow-up will determine any long-term effects on health or development. Meanwhile, use of enriched formula for term SGA children should not be promoted. It seems that breastfeeding may be especially beneficial for neurodevelopment in children born SGA.

Growth and development of premature infants fed predominantly human milk, predominantly premature infant formula, or a combination of human milk and premature formula.

BACKGROUND: In a recent meta-analysis, human milk feeding of low birth-weight (LBW) infants was associated with a 5.2 point improvement in IQ tests. However, in the studies in this meta-analysis, feeding regimens were used (unfortified human milk, term formula) that no longer represent recommended practice. OBJECTIVE: To compare the growth, in-hospital feeding tolerance, morbidity, and development (cognitive, motor, visual, and language) of LBW infants fed different amounts of human milk until term chronologic age (CA) with those of LBW infants fed nutrient-enriched formulas from first enteral feeding. METHODS: The data in this study were collected in a previous randomized controlled trial assessing the benefit of supplementing nutrient-enriched formulas for LBW infants with arachidonic acid and docosahexaenoic acid. Infants (n = 463, birth weight, 750-1,800 g) were enrolled from nurseries located in Chile, the United Kingdom, and the United States. If human milk was fed before hospital discharge, it was fortified (3,050-3,300 kJ/L, 22-24 kcal/oz). As infants were weaned from human milk, they were fed nutrient-enriched formula with or without arachidonic and docosahexaenoic acids (3,300 kJ/L before term, 3,050 kJ/L thereafter) until 12 months CA. Formula fed infants were given nutrient-enriched formula with or without added arachidonic and docosahexaenoic acids (3,300 kJ/L to term, 3,050 kJ/L thereafter) until 12 months CA. For the purposes of this evaluation, infants were categorized into four mutually exclusive feeding groups: 1) predominantly human milk fed until term CA (PHM-T, n = 43); 2) >/= 50% energy from human milk before hospital discharge (>/= 50% HM, n = 98); 3) < 50% of energy from human milk before hospital discharge (< 50% HM, n = 203); or 4) predominantly formula fed until term CA (PFF-T, n = 119). RESULTS: PFF-T infants weighed approximately 500 g more at term CA than did PHM-T infants. This absolute difference persisted until 6 months CA. PFF-T infants were also longer (1.0-1.5 cm) and had larger head circumferences (0.3-1.1 cm) than both PHM-T and >/= 50% HM infants at term CA. There was a positive association between duration of human milk feeding and the Bayley Mental Index at 12 months CA (P = 0.032 full and P = 0.073 reduced, statistical models) after controlling for the confounding variables of home environment and maternal intelligence. Infants with chronic lung disease fed >/= 50% HM until term CA (n = 22) had a mean Bayley Motor Index about 11 points higher at 12 months CA compared with infants PFF-T (n = 24, P = 0.033 full model). CONCLUSION: Our data suggest that, despite a slower early growth rate, human milk fed LBW infants have development at least comparable to that of infants fed nutrient-enriched formula. Exploratory analysis suggests that some subgroups of human milk fed LBW infants may have enhanced development, although this needs to be confirmed in future studies.

Double-blind, randomized trial of long-chain polyunsaturated fatty acid supplementation in formula fed to preterm infants.

OBJECTIVE: We tested the hypothesis that balanced addition of long-chain polyunsaturated fatty acid (LCPUFA) to preterm formula during the first weeks of life would confer long-term neurodevelopmental advantage in a double-blind, randomized, controlled trial of preterm formula with and without preformed LCPUFA. METHODS: The participants were 195 formula-fed preterm infants (birth weight <1750 g, gestation <37 weeks) from 2 UK neonatal units and 88 breast milk-fed infants. Main outcome measures were Bayley Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) at 18 months and Knobloch, Passamanick and Sherrard's Developmental Screening Inventory at 9 months' corrected age. Safety outcome measures were anthropometry at 9 and 18 months, tolerance, infection, necrotizing enterocolitis, and death. RESULTS: There were no significant differences in developmental scores between randomized groups, although infants who were fed LCPUFA-supplemented formula showed a nonsignificant 2.6-point (0.25 standard deviation) advantage in MDI and PDI at 18 months, with a greater (nonsignificant) advantage (MDI: 4.5 points; PDI: 5.8 points) in infants below 30 weeks' gestation. LCPUFA-supplemented infants were shorter than control infants at 18 months (difference in length standard deviation score: 0.44; 95% confidence interval: 0.08-0.8). No other significant short- or long-term differences in safety outcomes were observed. Breastfed infants had significantly higher developmental scores at 9 and 18 months than both formula groups and were significantly heavier and longer at 18 months than LCPUFA-supplemented but not control infants. CONCLUSIONS: With the dose, duration, and preparation of LCPUFA used, efficacy was not demonstrated, although an advantage in later neurodevelopment cannot be excluded by global tests of development up to 18 months, particularly in infants below 30 weeks' gestation. The surprising effect of LCPUFA-supplemented formula on growth 18 months beyond the intervention period needs to be confirmed in other studies using similar supplementation strategies. Additional follow-up of this cohort is critical at an age when more specific tests of cognitive function are possible.