A Role for Data Science in Precision Nutrition and Early Brain Development.

Multimodal brain magnetic resonance imaging (MRI) can provide biomarkers of early influences on neurodevelopment such as nutrition, environmental and genetic factors. As the exposure to early influences can be separated from neurodevelopmental outcomes by many months or years, MRI markers can serve as an important intermediate outcome in multivariate analyses of neurodevelopmental determinants. Key to the success of such work are recent advances in data science as well as the growth of relevant data resources. Multimodal MRI assessment of neurodevelopment can be supplemented with other biomarkers of neurodevelopment such as electroencephalograms, magnetoencephalogram, and non-imaging biomarkers. This review focuses on how maternal nutrition impacts infant brain development, with three purposes: (1) to summarize the current knowledge about how nutrition in stages of pregnancy and breastfeeding impact infant brain development; (2) to discuss multimodal MRI and other measures of early neurodevelopment; and (3) to discuss potential opportunities for data science and artificial intelligence to advance precision nutrition. We hope this review can facilitate the collaborative march toward precision nutrition during pregnancy and the first year of life.

Growth and Gastrointestinal Tolerance in Healthy Term Infants Fed Milk-Based Infant Formula Supplemented with Five Human Milk Oligosaccharides (HMOs): A Randomized Multicenter Trial.

Background: Five of the most abundant human milk oligosaccharides (HMOs) in human milk are 2'-fucosyllactose (2'-FL), 3-fucosyllactose (3-FL), lacto-N-tetraose (LNT), 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL). Methods: A randomized, double-blind, controlled parallel feeding trial evaluated growth in healthy term infants fed a control milk-based formula (CF; n = 129), experimental milk-based formula (EF; n = 130) containing five HMOs (5.75 g/L; 2'-FL, 3-FL, LNT, 3'-SL and 6'-SL) or human milk (HM; n = 104). Results: No significant differences (all p ≥ 0.337, protocol evaluable cohort) were observed among the three groups for weight gain per day from 14 to 119 days (D) of age, irrespective of COVID-19 or combined non-COVID-19 and COVID-19 periods. There were no differences (p ≥ 0.05) among the three groups for gains in weight and length from D14 to D119. Compared to the CF group, the EF group had more stools that were soft, frequent and yellow and were similar to the HM group. Serious and non-serious adverse events were not different among groups, but more CF-fed infants were seen by health care professionals for illness from study entry to D56 (p = 0.044) and D84 (p = 0.028) compared to EF-fed infants. Conclusions: The study demonstrated that the EF containing five HMOs supported normal growth, gastrointestinal (GI) tolerance and safe use in healthy term infants.

Increased Breastfeeding Proportion Is Associated with Improved Gross Motor Skills at 3-5 Years of Age: A Pilot Study.

Breastmilk provides key nutrients and bio-active factors that contribute to infant neurodevelopment. Optimizing maternal nutrition could provide further benefit to psychomotor outcomes. Our observational cohort pilot study aims to determine if breastfeeding extent and breastmilk nutrients correlate with psychomotor outcomes at school age. The breastfeeding proportion at 3 months of age and neurodevelopmental outcomes at 3-5 years of age were recorded for 33 typically developing newborns born after uncomplicated pregnancies. The association between categorical breastfeeding proportion and neurodevelopmental outcome scores was determined for the cohort using a Spearman correlation with and without the inclusion of parental factors. Vitamin E and carotenoid levels were determined in breastmilk samples from 14 of the mothers. After the inclusion of parental education and income as covariates, motor skill scores positively correlated with breastmilk contents of α-tocopherol (Spearman coefficient 0.88, p-value = 0.02), translutein (0.98, p-value = 0.0007), total lutein (0.92, p-value = 0.01), and zeaxanthin (0.93, p-value = 0.0068). Problem solving skills negatively correlated with the levels of the RSR enantiomer of α-tocopherol (-0.86, p-value = 0.03). Overall, higher exposure to breastfeeding was associated with improved gross motor and problem-solving skills at 3-5 years of age. The potential of α-tocopherol, lutein, and zeaxanthin intake to provide neurodevelopmental benefit is worthy of further investigation.

Assessment of Maternal Macular Pigment Optical Density (MPOD) as a Potential Marker for Dietary Carotenoid Intake during Lactation in Humans.

Pregnancy and lactation can change the maternal nutrient reserve. Non-invasive, quantitative markers of maternal nutrient intake could enable personalized dietary recommendations that improve health outcomes in mothers and infants. Macular pigment optical density (MPOD) is a candidate marker, as MPOD values generally reflect carotenoid intake. We evaluated the association of MPOD with dietary and breastmilk carotenoids in postpartum women. MPOD measurements and dietary intake of five carotenoids were obtained from 80 mothers in the first three months postpartum. Breastmilk samples from a subset of mothers were analyzed to determine their nutrient composition. The association between MPOD and dietary or breastmilk carotenoids was quantitatively assessed to better understand the availability and mobilization of carotenoids. Our results showed that dietary α-carotene was positively correlated with MPOD. Of the breastmilk carotenoids, 13-cis-lutein and trans-lutein were correlated with MPOD when controlled for the total lutein in breastmilk. Other carotenoids in breastmilk were not associated with MPOD. Maternal MPOD is positively correlated with dietary intake of α-carotene in the early postpartum period, as well as with the breastmilk content of lutein. MPOD may serve as a potential marker for the intake of carotenoids, especially α-carotene, in mothers in the early postpartum period.

Efficacy of Soy-Based Formulas in Alleviating Gastrointestinal Symptoms in Infants With Milk-Based Formula Intolerance: A Randomized Clinical Trial.

A randomized, blinded pilot clinical study was conducted to assess gastrointestinal (GI) tolerance in healthy, full-term infants (2-9 weeks old), whose pediatricians recommended a formula change due to perceived cow's milk formula intolerance. Infants were randomized and exclusively fed either a commercial control soy formula (SF; n = 22), an experimental partially hydrolyzed SF (10% hydrolyzed, n = 23), or a 5% hydrolyzed SF (n = 26) for 2 weeks. Age-matched reference cohorts (n = 72) with no GI intolerance on milk-based formula were assessed in parallel. Results indicated that all SF-fed groups contributed to reduction (P < .05) in common GI tolerance symptoms to levels not different from the non-symptomatic reference cohort at study end. The control SF group had more reduced fussiness, gas, and crying and higher formed stools versus hydrolyzed SF groups. In conclusion, the study suggests that SFs reduced GI intolerance symptoms in otherwise healthy infants with poor tolerance on milk-based formulas.

Physiological Impact of Palm Olein or Palm Oil in Infant Formulas: A Review of Clinical Evidence.

Palm oil/olein (PO/POL) is used in infant formulas to imitate the fatty acid profile of human milk (HM) and achieve similar levels of palmitic acid (PA). However, the positions of fatty acids on the triacylglyceride differ between PO/POL and HM, which affect fat absorption and produce unintended physiological consequences. Recent papers have reviewed evidence for physiological benefits of PO/POL and beta-palmitate (sn-2-palmitate) in infant formulas. The aim of the present review is to supplement the assessment of available clinical evidence on the physiological effects of PO/POL formulas in healthy infants. We intend to focus on PO/POL and not on sn-2-palmitate, since the latter was recently extensively reviewed. Clinical evidence supports that PO/POL in infant formulas leads to a lower fat, DHA, palmitate and calcium absorption, and bone mineralization; soft stools; and growth (weight accretion) compared to formulas without PO/POL. Consequently, it seems prudent to be considerate and cautious when adding PO/POL to infant formulas. While HM is the gold standard for infant nutrition, the development of infant formula should be based on achieving positive physiological outcomes, rather than just replicating HM nutrient composition.

Maternal Dietary Intake of Omega-3 Fatty Acids Correlates Positively with Regional Brain Volumes in 1-Month-Old Term Infants.

Maternal nutrition is an important factor for infant neurodevelopment. However, prior magnetic resonance imaging (MRI) studies on maternal nutrients and infant brain have focused mostly on preterm infants or on few specific nutrients and few specific brain regions. We present a first study in term-born infants, comprehensively correlating 73 maternal nutrients with infant brain morphometry at the regional (61 regions) and voxel (over 300 000 voxel) levels. Both maternal nutrition intake diaries and infant MRI were collected at 1 month of life (0.9 ± 0.5 months) for 92 term-born infants (among them, 54 infants were purely breastfed and 19 were breastfed most of the time). Intake of nutrients was assessed via standardized food frequency questionnaire. No nutrient was significantly correlated with any of the volumes of the 61 autosegmented brain regions. However, increased volumes within subregions of the frontal cortex and corpus callosum at the voxel level were positively correlated with maternal intake of omega-3 fatty acids, retinol (vitamin A) and vitamin B12, both with and without correction for postmenstrual age and sex (P < 0.05, q < 0.05 after false discovery rate correction). Omega-3 fatty acids remained significantly correlated with infant brain volumes after subsetting to the 54 infants who were exclusively breastfed, but retinol and vitamin B12 did not. This provides an impetus for future larger studies to better characterize the effect size of dietary variation and correlation with neurodevelopmental outcomes, which can lead to improved nutritional guidance during pregnancy and lactation.

Impact of palm olein in infant formulas on stool consistency and frequency: a meta-analysis of randomized clinical trials.

Background: Meta-analysis studies have documented that palm olein (PALM) predominant formulas reduce calcium and fat absorption, and bone mineralization in infants, but none have been documented for stool consistency and frequency. Objective: The study objective was to conduct a meta-analysis of published randomized clinical trials (RCTs) on the effect of PALM-based formulas on stool consistency and frequency in infants. Design: A literature search was conducted in BIOSIS Previews®, Embase®, Embase® Alert, MEDLINE® and Cochrane databases. PALM-based RCTs with available stool outcomes were selected and meta-analyzed. Mean rank stool consistency (MRSC, primary outcome) and stool frequency (secondary outcome) were compared between infants fed PALM-based and PALM-free formulas (NoPALM), using random effects model. Results: Nine out of identified16 studies were meta-analyzed. The mean MRSC (scale of 1 = watery to 5 = hard) in the NoPALM-fed infants was lower (softer stools) compared to the PALM-fed infants (mean difference ‒0.355, 95% Confidence Interval [CI] of ‒0.472 to ‒0.239, p < 0.001). Difference for stool frequency was not significant (p = 0.613). Conclusion: Meta-analysis of RCTs indicated that NoPALM-fed infants have significantly softer stools but similar stool frequencies versus PALM-fed infants, despite differences in study types and design. Future meta-analysis could benefit from including comparison with human milk-fed infants.

Milk protein-based formulas containing different oils affect fatty acids balance in term infants: A randomized blinded crossover clinical trial.

BACKGROUND: Palm olein is used in infant formula fat blends in order to match the fatty acid profile of human milk. While the effects on fatty acid balance have been evaluated, the use of palm olein in combination with palm kernel oil and supplementation with docosahexaenoic acid (DHA) and arachidonic acid (ARA) has not been similarly assessed in infants. This study evaluated the effects of infant formulas containing different fat compositions on the balance of fat, fatty acids, and calcium. METHODS: In this randomized, crossover, double-blinded study, 33 healthy term infants (68-159 ± 3 days of age at enrollment) were fed two formulas for 14 days in a tolerance period, followed by a 4-day metabolic balance period in 17 of the male subjects. The study compared two commercially available milk-based powdered formulas in Brazil; the PALM formula contained palm olein (44%), kernel palm oil (21.7%), and canola oil (18.5%) as the predominant fats, whereas the NoPALM formula contained other fat sources. RESULTS: Fat absorption (%) was greater for NoPALM versus PALM-fed infants (96.55 and 95.50%, respectively; p = 0.023). The absorption percentage of palmitic acid (C16:0) did not differ significantly between formulas (p > 0.05), but this acid was excreted at significantly higher concentrations in the PALM (29.42 mg/kg/day) than in the NoPALM (12.28 mg/kg/day) formula groups. DHA and ARA absorption percentages were also higher in NoPALM-fed infants. Calcium absorption was higher in NoPALM-fed infants (58.00%) compared to those fed PALM (40.90%), but the difference was not significant (p = 0.104) when calcium intake was used as a covariate. However, calcium retention was higher in NoPALM-fed infants compared to that in PALM-fed infants with or without calcium intake as a covariate. Adverse events did not differ between groups (p > 0.05). CONCLUSIONS: The absorption of essential fatty acids was similar for both formulas; however, long-chain polyunsaturated fatty acids (DHA and ARA) were better absorbed from the NoPALM formula. Fat absorption and calcium retention were lower in term infants fed the PALM-based formula. CLINICAL TRIAL REGISTRATION: Clinicaltrial.gov # NCT00941564 .

Soy protein-based infant formulas with supplemental fructooligosaccharides: gastrointestinal tolerance and hydration status in newborn infants.

Unlike milk-based infant formulas, soy-based infant formulas containing supplemental fructooligosaccharides (FOS) have not been clinically evaluated. A randomized, double-blind, 28 day parallel feeding trial compared gastrointestinal (GI) tolerance and hydration in healthy term newborn infants fed either a commercialized soy formula (with history of safe use) containing sucrose as 20% of total carbohydrate, no supplemental short-chain FOS (scFOS) and no mixed carotenoids (lutein, lycopene, beta-carotene) as a control (CF, n = 62 infants) or one of two experimental soy-based formulas, EF1 (n = 64) and EF2 (n = 62) containing scFOS (2.5 g/L) and mixed carotenoids. EF1 differed from EF2 by containing sucrose. Results indicated no significant study group differences (p > 0.05) in study completion rates (CF = 81, EF1 = 86, & EF2 = 87%), growth, mean rank stool consistency, stool frequency, formula intake, spit-up/vomit, and safety measures (urine specific gravity, USG; hydration status and adverse events). Mean USGs for study groups were normal (<1.03). The EF1 > CF group in percent yellow stools (p < 0.01 at age 14 days). In conclusion, the study suggested that term infants fed soy-based formulas supplemented with scFOS and mixed carotenoids, with or without sucrose in the 1st 35 days of infancy demonstrated good tolerance and hydration comparable to the control soy-based formula with history of safe use.

Milk protein-based infant formula containing rice starch and low lactose reduces common regurgitation in healthy term infants: a randomized, blinded, and prospective trial.

OBJECTIVE: Spit-up (regurgitation) reduction with prethickened milk protein-based infant formulas containing rice starch has been clinically demonstrated in infants with heavy spit-ups but not in otherwise healthy normal infants with common spit-ups. The objective of this study was to evaluate growth, gastrointestinal tolerance, and efficacy to reduce common spit-up in normal, healthy term infants fed an investigational rice starch prethickened lactose-free milk protein-based infant formula. METHODS: This double-blind, randomized, parallel study evaluated the investigational rice starch prethickened lactose-free (low lactose < 100 mg/L) milk protein-based infant formula compared to a standard, commercially available, iso-nutrient, lactose-containing (100% of carbohydrate) milk-based infant formula (control) for growth and gastrointestinal tolerance in healthy term infants (n = 132/group) fed from 14 ± 3 days to 112 days of age. Data were classified and analyzed as evaluable (EV; subjects completing study per protocol) or intent-to-treat data (ITT; all subjects with available data). RESULTS: Growth as indicated by weight gain (primary variable) and formula intake were not significantly different (p > 0.05) between feeding groups (EV or ITT). Though both formulas were well tolerated, spit-up frequency was significantly lower (p < 0.05) in the rice versus control group by 53% at 28 days of age, 54% at 56 days, 48% at 84 days, and 32% at 112 days (EV). Importantly, infants in the rice group were 1.6 to 1.8 times more likely to report zero spit-up than infants in the control group. The rice group also had higher percentages of soft and yellow stools. CONCLUSIONS: The rice starch prethickened lactose-free milk protein-based formula (rice) supported normal growth and safe use as the sole source of feeding for normal infants over the first 4 months of life. The rice formula was efficacious in providing a clinically relevant reduction of spit-up frequency in otherwise healthy term infants.

Calcium and fat metabolic balance, and gastrointestinal tolerance in term infants fed milk-based formulas with and without palm olein and palm kernel oils: a randomized blinded crossover study.

BACKGROUND: Effects of palm olein (POL) on calcium and fat metabolic balance and gastrointestinal (GI) tolerance have been clinically evaluated but its use in combination with palm kernel oil (PKO), and canola oil has not been similarly assessed in infants. METHODS: Calcium and fat balance and GI tolerance were evaluated in 33 healthy term infants (age = 68-159 d) in a randomized, double-blinded, 14 d crossover trial at a day care center in Salvador, Brazil; followed by a 4d hospital ward metabolic balance study in 17 of the male subjects. The study compared two commercially available milk-based powdered formulas in Brazil; one containing POL (44% of total fat), PKO (21.7%) and canola oil (18.5%) as predominant fats (PALM), and the other containing none (NoPALM). Occasional human milk (HM) supplementation was allowed at home. RESULTS: Formula and HM intakes, and growth were not different (p > 0.05). Calcium absorption (%) for infants fed NoPALM (58.8 ± 16.7%; means ± SD) was higher (p = 0.023) than those fed PALM (42.1 ± 19.2%), but was not significant (p = 0.104) when calcium intake was used as a covariate. Calcium intake was higher (p < 0.001) in NoPALM versus PALM fed infants. However, calcium retention (%) was higher in infants fed NoPALM compared to PALM with (p = 0.024) or without (p = 0.015) calcium intake as a covariate. Fat absorption (%) for NoPALM was greater than PALM fed infants (NoPALM = 96.9 ± 1.2 > PALM = 95.1 ± 1.5; p = 0.020 in Study Period I). Mean rank stool consistency was softer in infants fed NoPALM versus PALM (p < 0.001; metabolic period). Adverse events, spit-up/vomit, fussiness and gassiness were not different (p > 0.05). Formula acceptability was high and comparable for both formula feedings, regardless of HM supplementation. CONCLUSIONS: Term infants fed PALM based formula (containing palm olein, palm kernel and canola oils) demonstrated lower calcium retention and fat absorption, and less softer stool consistency versus infants fed NoPALM based formula. Study suggested formula fat differences may affect GI function in infants.

Lactose-free milk protein-based infant formula: impact on growth and gastrointestinal tolerance in infants.

Lactose, the major carbohydrate in human milk and standard milk-based formulas, provides energy for growth in infants. The use of lactose-free milk protein-based infant formulas has increased in the United States. However, clinical studies of their impact on growth, safety, and gastrointestinal tolerance in infants are limited. Thus, a prospective, blinded, randomized clinical trial was conducted in healthy, normal-term infants fed an experimental lactose-free milk protein-based formula (NoLAC; n = 63) versus a standard commercial lactose-containing milk-based formula (LAC; n = 65) for 112 days. Growth (weight, length, and head circumference) was similar and normal in both groups (weight gain: NoLAC = 31.1 ± 0.9 g/day, LAC = 29.4 ± 0.9 g/day, mean ± SEM; P = .895). Serum biochemistries for both groups were within infants' normal reference ranges. Both groups had comparable tolerance but the NoLAC group had softer stools and lower spit-ups. Thus, the study suggests that absence of lactose in milk-based formula does not adversely affect normal growth in term infants.

Growth, tolerance and biochemical measures in healthy infants fed a partially hydrolyzed rice protein-based formula: a randomized, blinded, prospective trial.

OBJECTIVE: To evaluate growth, tolerance and plasma biochemistries in infants fed an experimental rice protein-based infant formula. DESIGN: Randomized, blinded, 16 week parallel feeding trial of 65 healthy infants fed either an experimental partially hydrolyzed rice protein-based infant formula fortified with lysine and threonine (RPF, n = 32), or a standard intact cow's milk protein-based formula (CMF, n = 33) as a control. Assessments occurred at enrollment (average 2 days), 2, 4, 8, and 16 weeks of age. RESULTS: Growth as indicated by weight, length, and head circumference was not different between the 2 formula groups. All plasma biochemistries for both groups were within reference normal range. However, RPF group had lower phosphorus and urea nitrogen, lower essential amino acids except threonine, which was higher, and lower ratio of essential (including semi-essential) to non-essential amino acids. Differences in the concentrations and ratios of amino acids became less as feeding progressed with age. Plasma total protein, albumin, prealbumin, calcium, magnesium, and alkaline phosphatase were not different between groups. CONCLUSION: Healthy infants fed an experimental partially hydrolyzed rice protein-based formula had normal growth, tolerance, and plasma biochemistry comparable to those of infants fed a standard intact milk protein-based formula, despite some differences in amino acid profiles.

Reduced bone mineralization in infants fed palm olein-containing formula: a randomized, double-blinded, prospective trial.

OBJECTIVE: Palm and palm olein (PO) oils are used in some infant formula fat blends to match the fatty acid profile of human milk, but their presence has been shown to lower calcium and fat absorption. We aimed to determine if the reported differences in calcium absorption could affect skeletal development by comparing bone mineral accretion in healthy term infants fed a milk-based formula with (PMF) or without PO. METHODS: Whole body bone mineralization was evaluated in healthy term infants fed 1 of 2 coded, commercially available, ready-to-feed infant formulas in a randomized, double-blind, parallel study. Subjects were fed either 1). PMF formula (Enfamil with iron; Mead Johnson Division of Bristol Myers, Evansville, IN; N = 63) containing PO/coconut/soy/high-oleic sunflower oils (45/20/20/15% oil); or 2). milk-based formula without PO (Similac with iron; Ross Products Division Abbott Laboratories, Columbus, OH; N = 65), containing high-oleic safflower/coconut/soy oils (40/30/30% oil) from enrollment by 2 weeks after birth until 6 months. Anthropometrics and formula intake were determined monthly; total body bone mineral content (BMC) and bone mineral density (BMD) were measured at baseline, 3, and 6 months of age using dual energy x-ray absorptiometry. RESULTS: Intent-to-treat analyses indicated no significant differences between feeding groups in weight, length, head circumference, or formula intake throughout the study. BMC and BMD were not different at baseline but repeated measures analyses show that infants fed PMF had significantly lower BMC and BMD at 3 and 6 months. CONCLUSIONS: Healthy term infants fed a formula containing PO as the predominant oil in the fat blend had significantly lower BMC and BMD than those fed a formula without PO. The inclusion of PO in infant formula at levels needed to provide a fatty acid profile similar to that of human milk leads to lower bone mineralization.