Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) I-Cognitive Function and Metabolic Risk.

Neonatal nutritional supplements are widely used to improve growth and development but may increase risk of later metabolic disease, and effects may differ by sex. We assessed effects of supplements on later development and metabolism. We searched databases and clinical trials registers up to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter cognitive impairment in toddlers (13 trials, n = 1410; adjusted relative risk (aRR) 0.88 [95% CI 0.68, 1.13]; p = 0.31) or older ages, nor alter metabolic risk beyond 3 years (5 trials, n = 438; aRR 0.94 [0.76, 1.17]; p = 0.59). However, supplementation reduced motor impairment in toddlers (13 trials, n = 1406; aRR 0.76 [0.60, 0.97]; p = 0.03), and improved motor scores overall (13 trials, n = 1406; adjusted mean difference 1.57 [0.14, 2.99]; p = 0.03) and in girls not boys (p = 0.03 for interaction). Supplementation lowered triglyceride concentrations but did not affect other metabolic outcomes (high-density and low-density lipoproteins, cholesterol, fasting glucose, blood pressure, body mass index). Macronutrient supplementation for infants born small may not alter later cognitive function or metabolic risk, but may improve early motor function, especially for girls.

Efficacy of maternal B12 supplementation in vegetarian women for improving infant neurodevelopment: protocol for the MATCOBIND multicentre, double-blind, randomised controlled trial.

INTRODUCTION: Vitamin B12 deficiency is widely prevalent across many low- and middle-income countries, especially where the diet is low in animal sources. While many observational studies show associations between B12 deficiency in pregnancy and infant cognitive function (including memory, language and motor skills), evidence from clinical trials is sparse and inconclusive. METHODS AND ANALYSIS: This double-blind, multicentre, randomised controlled trial will enrol 720 vegetarian pregnant women in their first trimester from antenatal clinics at two hospitals (one in India and one in Nepal). Eligible mothers who give written consent will be randomised to receive either 250 mcg methylcobalamin or 50 mcg (quasi control), from enrolment to 6 months post-partum, given as an oral daily capsule. All mothers and their infants will continue to receive standard clinical care. The primary trial outcome is the offspring's neurodevelopment status at 9 months of age, assessed using the Development Assessment Scale of Indian Infants. Secondary outcomes include the infant's biochemical B12 status at age 9 months and maternal biochemical B12 status in the first and third trimesters. Maternal biochemical B12 status will also be assessed in the first trimester. Modification of association by a priori identified factors will also be explored. ETHICAL CONSIDERATIONS AND DISSEMINATION: The study protocol has been approved by ethical committees at each study site (India and Nepal) and at University College London, UK. The study results will be disseminated to healthcare professionals and academics globally via conferences, presentations and publications. Researchers at each study site will share results with participants during their follow-up visits.Trial registration numberCTRI/2018/07/015048 (Clinical Trial Registry of India); NCT04083560 (ClinicalTrials.gov).

Should We Promote Catch-Up Growth or Growth Acceleration in Low-Birthweight Infants?

The idea that catch-up growth or growth acceleration has adverse effects on long-term health has generated much debate. This pattern of growth is most commonly seen after birth in infants of low birthweight; a global problem affecting over 20 million newborns a year. Faster postnatal growth may have short-term benefits but increases the long-term risk of aging, obesity and metabolic disease. Consequently, the optimal pattern of postnatal growth is unclear and is likely to differ in different populations. In infants born prematurely, faster postnatal growth improves long-term cognitive function but is associated with later risk factors for cardiovascular disease. So, on balance, the current policy is to promote faster growth by increasing nutrient intake (e.g. using higher-nutrient preterm formulas). Whether the same policy should apply to larger preterm infants is not known. Similarly, in infants from impoverished environments, the short-term benefits of faster postnatal growth may outweigh long-term disadvantages. However, whether similar considerations apply to infants from countries in transition is uncertain. For term infants from developed countries, promoting catch-up growth by nutritional supplementation has few advantages for short- or long-term health. Overall therefore, a 'one size fits all' solution for the optimal pattern of postnatal growth is unlikely.

Suboptimal Micronutrient Intake among Children in Europe.

Adequate dietary intake of micronutrients is not necessarily achieved even in resource-rich areas of the world wherein overeating is a public health concern. In Europe, population-based data suggests substantial variability in micronutrient intake among children. Two independent surveys of micronutrient consumption among European children were evaluated. Stratified by age, the data regarding micronutrient intake were evaluated in the context of daily requirements, which are typically estimated in the absence of reliable absolute values derived from prospective studies. The proportion of children living in Europe whose intake of at least some vitamins and trace elements are at or below the estimated average requirements is substantial. The most common deficiencies across age groups included vitamin D, vitamin E, and iodine. Specific deficiencies were not uniform across countries or by age or gender.  Micronutrient intake appears to be more strongly influenced by factors other than access to food. Substantial portions of European children may be at risk of reversible health risks from inadequate intake of micronutrients. Despite the growing health threat posed by excess intake of calories, adequate exposure to vitamins, trace elements, and other micronutrients may deserve attention in public health initiatives to optimize growth and development in the European pediatric population.

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.

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.

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.

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.