Higher early pregnancy plasma myo-inositol associates with increased postprandial glycaemia later in pregnancy: Secondary analyses of the NiPPeR randomized controlled trial.

AIM: Myo-inositol supplementation from ~13 weeks' gestation reportedly improves glycaemia regulation in metabolically at-risk women, with speculation that earlier supplementation might bring further improvement. However, the NiPPeR trial of a myo-inositol-containing supplement starting preconception did not lower gestational glycaemia in generally healthy women. We postulated that the earlier timing of supplementation influences the maternal metabolic adaptation for gestational glycaemia regulation. METHODS: In total, 585 women were recruited from Singapore, UK and New Zealand for the NiPPeR study. We examined associations of plasma myo-inositol concentrations at 7 and 28 weeks' gestation with 28 weeks plasma glucose (PG; fasting, and 1 h and 2 h in 75 g oral glucose tolerance test) and insulin indices using linear regression adjusting for covariates. RESULTS: Higher 7-week myo-inositol, but not 28-week myo-inositol, associated with higher 1 h PG [ßadj (95% confidence intervals) 0.05 (0.01, 0.09) loge mmol/L per loge µmol/L, p = .022] and 2 h PG [0.08 (0.03, 0.12), p = .001]; equivalent to 0.39 mmol/L increase in 2 h PG for an average 7-week myo-inositol increase of 23.4 µmol/L with myo-inositol supplementation. Higher 7-week myo-inositol associated with a lower 28-week Stumvoll index (first phase), an approximation of insulin secretion [-0.08 (-0.15, -0.01), p = .020] but not with 28-week Matsuda insulin sensitivity index. However, the clinical significance of a 7-week myo-inositol-related increase in glycaemia was limited as there was no association with gestational diabetes risk, birthweight and cord C-peptide levels. In-silico modelling found higher 28-week myo-inositol was associated with lower gestational glycaemia in White, but not Asian, women after controlling for 7-week myo-inositol effects. CONCLUSION: To our knowledge, our study provides the first evidence that increasing first trimester plasma myo-inositol may slightly exacerbate later pregnancy post-challenge glycaemia, indicating that the optimal timing for starting prenatal myo-inositol supplementation needs further investigation.

Human milk fatty acid composition and its association with maternal blood and adipose tissue fatty acid content in a cohort of women from Europe.

PURPOSE: Human milk (HM) composition is influenced by factors, like maternal diet and body stores, among other factors. For evaluating the influence of maternal fatty acid (FA) status on milk FA composition, the correlation between FA content in HM and in maternal plasma, erythrocytes, and adipose tissue was investigated. METHODS: 223 European women who delivered at term, provided HM samples over first four months of lactation. Venous blood and adipose tissue (only from mothers who consented and underwent a C-section delivery) were sampled at delivery. FAs were assessed in plasma, erythrocytes, adipose tissue, and HM. Evolution of HM FAs over lactation and correlations between FA content in milk and tissues and between mother's blood and cord blood were established. RESULTS: During lactation, arachidonic acid (ARA) and docosahexaenoic acid (DHA) significantly decreased, while linoleic acid (LA), alpha-linolenic acid (ALA), and eicosapentaenoic acid (EPA) remained stable. Positive correlations were observed between HM and adipose tissue for palmitic, stearic, oleic, and polyunsaturated fatty acids (PUFAs). Correlations were found between milk and plasma for oleic, LA, ARA, ALA, DHA, monounsaturated fatty acids (MUFAs), and PUFAs. No correlation was observed between erythrocytes and HM FAs. LA and ALA were more concentrated in maternal blood than in infant blood, contrary to ARA and DHA, supporting that biomagnification of LCPUFAs may have occurred during pregnancy. CONCLUSIONS: These data show that maternal adipose tissue rather than erythrocytes may serve as reservoir of PUFAs and LCPUFAs for human milk. Plasma also supplies PUFAs and LCPUFAs to maternal milk. If both, adipose tissue and plasma PUFAs, are reflection of dietary intake, it is necessary to provide PUFAs and LCPUFAs during pregnancy or even before conception and lactation to ensure availability for mothers and enough supply for the infant via HM.

Infant feeding practice and gastrointestinal tolerance: a real-world, multi-country, cross-sectional observational study.

BACKGROUND: Signs of feeding intolerance, such as gastrointestinal (GI) symptoms, are frequently observed in otherwise healthy formula-fed infants in the first months of life. The primary objective of this observational study was to examine GI tolerance in formula-fed infants (FFI) vs. breastfed infants (BFI) in a real-world setting with a secondary objective being the comparison of infants fed formula with pre- and/or probiotics (FFI_PP) and those fed formula without any pre- and/or probiotics (FFI_noPP) as well as BFI. METHODS: A six-country, cross-sectional study in full-term exclusively/predominantly FFI (n = 2036) and BFI (n = 760) aged 6-16 weeks was conducted using the validated Infant Gastrointestinal Symptom Questionnaire (IGSQ) and a Feeding Practice and Gut Comfort Questionnaire. RESULTS: The IGSQ composite score in FFI was non-inferior compared to BFI (mean difference [95%CI]: 0.17 [-0.34, 0.67]; non-inferiority p-value < 0.0001) and scores for BFI and FFI were below the threshold of 23, indicating no GI discomfort. Adjusted mean IGSQ scores ± SE were similar in FFI_PP (22.1 ± 0.2) and BFI (22.3 ± 0.3) while FFI_noPP (23.4 ± 0.3) was significantly higher and above 23 indicating some GI discomfort (mean differences [95%CI] FFI_noPP minus FFI_PP and FFI_noPP minus BFI were 1.28 [0.57, 1.98] and 1.09 [0.38, 1.80], respectively; both p < 0.01). Hard stools and difficulty in passing stool were more common in FFI compared to BFI (p < 0.01) but were less common in FFI_PP compared to FFI_noPP (p < 0.01). FFI_PP showed significantly less crying than FFI_noPP and was similar to BFI. Significantly fewer physician-confirmed colic episodes (Rome IV criteria) were reported in FFI_PP compared with FFI_noPP or BFI. CONCLUSIONS: In this real-world observational study, FFI had non-inferior overall GI tolerance compared to BFI. Within FFI, infants receiving formulas with pre- and/or probiotics had a better GI tolerance, improved stooling and less infantile colic compared to those receiving formula without any pre- and/or probiotics and were more similar to BFI. TRIAL REGISTRATION: NCT03703583, 12/10/2018 ( https://clinicaltrials.gov/ct2/show/NCT03703583 ).

Human milk oligosaccharides, infant growth, and adiposity over the first 4 months of lactation.

BACKGROUND: The relationship between human milk oligosaccharides (HMOs) and infant growth and adiposity is not fully understood and comprehensive studies are missing from the current literature. METHODS: We screened and recruited 370 healthy, pregnant women and their infants from seven European countries. Breastmilk samples were collected using standardized procedures at six time points over 4 months, as were infant parameters. Correlations and associations between HMO area under the curve, anthropometric data, and fat mass at 4 months were tested. RESULTS: Lacto-N-neotetraose had a negative correlation with the change in length (rs = -0.18, P = 0.02). Sialyllacto-N-tetraose c (LSTc) had a positive correlation with weight for length (rs = 0.19, P = 0.015). Infants at the 25th upper percentile were fed milk higher in 3'-sialyllactose and LSTc (P = 0.017 and P = 0.006, respectively) compared to the lower 25th percentile of the weight-for-length z-score gain over 4 months of lactation. No significant associations between growth and body composition and Lewis or secretor-dependent HMOs like 2'-fucosyllactose were identified. CONCLUSIONS: Changes in the HMO composition of breastmilk during the first 4 months appear to have little influence on infant growth and body composition in this cohort of healthy mothers and infants. IMPACT: Modest associations exist between individual HMO and infant growth outcomes at least in healthy growing populations. Our study provides a comprehensive investigation of associations between all major HMO and infant growth and adiposity including several time points. Certain groups of HMOs, like the sialylated, may be associated with adiposity during the first months of lactation. HMO may modulate the risk of future metabolic disease. Future population studies need to address the role of specific groups of HMOs in the context of health and disease to understand the long-term impact.

Gastrointestinal Tolerance of Formula-Fed Infants During the Immediate Postnatal Period in Saudi Arabia: An Observational Study.

Objective. Feeding intolerance during the early postnatal period can be distressing for families. To assess this, infants (n = 150) of mothers who had previously decided to exclusively or partially formula feed were enrolled ≤24 hours after birth. Methods. Infants were fed with a single ready-to-feed, 100% partially hydrolyzed whey protein-based formula until discharge, in accordance with standard hospital practice. Parents recorded daily the presence/severity of gastrointestinal (GI) symptoms/behaviors, rated from 0 (never) to 5 (always). A validated questionnaire was completed at discharge to evaluate symptoms of GI discomfort; scores can range from 0 to ~140 (lower scores indicate fewer symptoms). Results. Mean ± SD daily scores ranged from 0.12 ± 0.40 (fussiness/irritability) to 1.26 ± 0.90 (spitting up), indicating that GI symptoms/behaviors occurred, on average, "never" or "almost never." Mean GI discomfort scores were also very low (9.9 ± 7.4). Conclusion. These results indicate that the ready-to-feed formula was very well accepted and well tolerated during this period among healthy newborns in Saudi Arabia.

Limosilactobacillus reuteri DSM 17938-Containing Infant Formulas and the Associations with Gastrointestinal Tolerance: A Cross-Sectional Observational Study.

Limosilactobacillus (L.; previously Lactobacillus) reuteri has been shown to influence gastrointestinal (GI) tolerance. This study was a secondary analysis of GI tolerance data from a multi-country, cross-sectional, observational study in healthy infants using the validated Infant Gastrointestinal Symptom Questionnaire (IGSQ) and a gut comfort questionnaire. Breastfed infants (BFI; n = 760) were compared to formula-fed infants receiving either L. reuteri-containing formula (FFI + LR; n = 470) or standard formula without any probiotic or prebiotic (FFI-Std; n = 501). The IGSQ composite scores (adjusted mean ± SE) in FFI + LR (22.17 ± 0.39) was significantly lower than in FFI-Std (23.41 ± 0.37) and similar to BFI (22.34 ± 0.30;), indicating better GI tolerance in FFI + LR than in FFI-Std. Compared with FFI-Std, FFI + LR had lower reports of difficulty in passing stools (11% vs. 22%; adjusted-odds ratio (OR) (95%CI) = 0.46 (0.31-0.68)), fewer hard stools (mean difference = -0.12 (-0.21, -0.02)) and less physician-confirmed colic (OR = 0.61 (0.45-0.82)), and similar to BFI. Parent-reported crying time (mean difference = -0.15 (-0.28, -0.01)), frequency of spitting-up/vomiting (mean difference = -0.18 (-0.34, -0.03)), volume of spit-up (mean difference = -0.20 (-0.32, -0.08)) and fussiness due to spitting-up/vomiting (mean difference = -0.17 (-0.29, -0.05)) were lower in FFI + LR versus FFI-Std and similar to BFI. In this study, L. reuteri-containing formula was associated with improved digestive tolerance and behavioral patterns.

Bifidobacterium longum subsp. longum Reduces Perceived Psychological Stress in Healthy Adults: An Exploratory Clinical Trial.

Emerging science shows that probiotic intake may impact stress and mental health. We investigated the effect of a 6-week intervention with Bifidobacterium longum (BL) NCC3001 (1 × 1010 CFU/daily) on stress-related psychological and physiological parameters in 45 healthy adults with mild-to-moderate stress using a randomized, placebo-controlled, two-arm, parallel, double-blind design. The main results showed that supplementation with the probiotic significantly reduced the perceived stress and improved the subjective sleep quality score compared to placebo. Comparing the two groups, momentary subjective assessments concomitant to the Maastricht Acute Stress Test revealed a lower amount of pain experience in the probiotic group and a higher amount of relief at the end of the procedure in the placebo group, reflected by higher scores in the positive affect state. The awakening of the salivary cortisol response was not affected by the intervention, yet the reduction observed in the salivary cortisol stress response post-intervention was higher in the placebo group than the probiotic group. Multivariate analysis further indicated that a reduction in perceived stress correlated with a reduction in anxiety, in depression, and in the cortisol awakening response after the 6-week intervention. This exploratory trial provides promising insights into BL NCC3001 to reduce perceived stress in a healthy population and supports the potential of nutritional solutions including probiotics to improve mental health.

A Probiotic Intervention With Bifidobacterium longum NCC3001 on Perinatal Mood Outcomes (PROMOTE Study): Protocol for a Decentralized Randomized Controlled Trial.

BACKGROUND: Perinatal mood disorders such as depression and anxiety are common, with subclinical symptomology manifesting as perinatal mood disturbances being even more prevalent. These could potentially affect breastfeeding practices and infant development. Pregnant and lactating women usually limit their exposure to medications, including those for psychological symptoms. Interestingly, the naturally occurring probiotic Bifidobacterium longum (BL) NCC3001 has been shown to reduce anxious behavior in preclinical models and feelings of low mood in nonpregnant human adults. During the COVID-19 pandemic, mental health issues increased, and conventionally conducted clinical trials were restricted by social distancing regulations. OBJECTIVE: This study, Probiotics on Mothers' Mood and Stress (PROMOTE), aimed to use a decentralized clinical trial design to test whether BL NCC3001 can reduce symptoms of depression, anxiety, and stress over the perinatal period. METHODS: This double-blind, placebo-controlled, randomized, and 3-parallel-arm study aimed to recruit 180 women to evaluate the efficacy of the probiotic taken either during pregnancy and post partum (from 28-32 weeks' gestation until 12 weeks after delivery; n=60, 33.3%) or post partum only (from birth until 12 weeks after delivery; n=60, 33.3%) in comparison with a placebo control group (n=60, 33.3%). Participants consumed the probiotic or matched placebo in a drink once daily. Mood outcomes were measured using the State-Trait Anxiety Inventory and Edinburgh Postnatal Depression Scale questionnaires, captured electronically at baseline (28-32 weeks' gestation) and during e-study sessions over 5 further time points (36 weeks' gestation; 9 days post partum; and 4, 8, and 12 weeks post partum). Saliva and stool samples were collected longitudinally at home to provide mechanistic insights. RESULTS: In total, 520 women registered their interest on our website, of whom 184 (35.4%) were eligible and randomized. Of these 184 participants, 5 (2.7%) withdrew after randomization, leaving 179 (97.3%) who completed the study. Recruitment occurred between November 7, 2020, and August 20, 2021. Advertising on social media brought in 46.9% (244/520) of the prospective participants, followed by parenting-specific websites (116/520, 22.3%). Nationwide recruitment was achieved. Data processing is ongoing, and there are no outcomes to report yet. CONCLUSIONS: Multiple converging factors contributed to speedy recruitment and retention of participants despite COVID-19-related restrictions. This decentralized trial design sets a precedent for similar studies, in addition to potentially providing novel evidence on the impact of BL NCC3001 on symptoms of perinatal mood disturbances. This study was ideal for remote conduct: because of the high digital literacy and public trust in digital security in Singapore, the intervention could be self-administered without regular clinical monitoring, and the eligibility criteria and outcomes were measured using electronic questionnaires and self-collected biological samples. This design was particularly suited for a group considered vulnerable-pregnant women-during the challenging times of COVID-19-related social restrictions. TRIAL REGISTRATION: ClinicalTrials.gov NCT04685252; https://clinicaltrials.gov/ct2/show/NCT04685252. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41751.

Real-world evidence study on tolerance and growth in infants fed an infant formula with two human milk oligosaccharides vs mixed fed and exclusively breastfed infants.

INTRODUCTION: Human milk oligosaccharides (HMOs) are important components of human milk having diverse functions in the development of infants. Randomized controlled trials (RCTs) have demonstrated that infant formulas with the HMOs 2'-fucosyllactose (2'FL) and lacto-N-neotetraose (LNnT) are safe, well-tolerated, and support normal growth. This study aimed to generate real-world evidence (RWE) on growth and gastrointestinal (GI) tolerance in infants consuming a formula with 1 g/L 2'FL and 0.5 g/L LNnT, including a mixed feeding group not studied before in RCTs. PARTICIPANTS AND METHODS: This 8-week open-label prospective multicenter study was conducted in Germany and Austria, and included groups of healthy, exclusively breastfed infants (BF), exclusively formula-fed infants (FF) who received the HMO-formula, and infants mixed fed with both HMO formula and human milk (MF). Co-primary outcomes were anthropometry and gastrointestinal tolerance via validated Infant Gastrointestinal Symptom Questionnaire (IGSQ). Secondary outcomes included formula satisfaction and adverse events (AEs). RESULTS: One-hundred six infants completed the study (46 FF, 22 MF, and 38 BF). Mean anthropometric z-scores were comparable between groups and generally within ± 0.5 of WHO medians at week 8. IGSQ composite scores demonstrated good GI tolerance in all groups with no significant group differences at week 4 or 8. IGSQ composite scores in FF improved during the course of the study and parents provided high satisfaction ratings for the HMO-formula. Four potentially product-related AEs were reported in FF (no in MF). CONCLUSIONS: In this RWE study examining an infant formula with HMOs, growth and GI tolerance outcomes were confirming the good tolerance and safety of this early feeding option previously reported in RCTs.

Mode of Neonatal Delivery Influences the Nutrient Composition of Human Milk: Results From a Multicenter European Cohort of Lactating Women.

Background: The effect of the mode of neonatal delivery (cesarean or vaginal) on the nutrient composition of human milk (HM) has rarely been studied. Given the increasing prevalence of cesarean section (C-section) globally, understanding the impact of C-section vs. vaginal delivery on the nutrient composition of HM is fundamental when HM is the preferred source of infant food during the first 4 postnatal months. Objective: This study aimed to evaluate the association between mode of delivery and nutrient composition of HM in the first 4 months of life. Design: Milk samples were obtained from 317 healthy lactating mothers as part of an exploratory analyses within a multicenter European longitudinal cohort (ATLAS cohort) to study the HM composition, and its potential association with the mode of delivery. We employed traditional mixed models to study individual nutrient associations adjusted for mother's country, infant birth weight, parity, and gestational age, and complemented it, for the first time, with a multidimensional data analyses approach (non-negative tensor factorization, NTF) to examine holistically how patterns of multiple nutrients and changes over time are associated with the delivery mode. Results: Over the first 4 months, nutrient profiles in the milk of mothers who delivered vaginally (n = 237) showed significantly higher levels of palmitoleic acid (16:1n-7), stearic acid (18:0), oleic acid (18:1n-9), arachidic acid (20:0), alpha-linolenic acid (18:3n-3), eicosapentaenoic acid (20:5n-3), docosahexenoic acid (22:6n-3), erucic acid (22:1n-9), monounsaturated fatty acids (MUFA)%, calcium, and phosphorus, whereas the ratios of arachidonic acid/docosahexaenoic acid (ARA/DHA) and n-6/n-3, as well as polyunsaturated fatty acids (PUFA)% were higher in milk from women who had C-sections, in the unadjusted analyses (p < 0.05 for all), but did not retain significance when adjusted for confounders in the mixed models. Using a complementary multidimension data analyses approach (NTF), we show few similar patterns wherein a group of mothers with a high density of C-sections showed increased values for PUFA%, n-6/n-3, and ARA/DHA ratios, but decreased values of MUFA%, 20:1n-9, iodine, and fucosyl-sialyl-lacto-N-tetraose 2 during the first 4 months of lactation. Conclusion: Our data provide preliminary insights on differences in concentrations of several HM nutrients (predominantly fatty acids) among women who delivered via C-section. Although these effects tend to disappear after adjustment for confounders, given the similar patterns observed using two different data analytical approaches, these preliminary findings warrant further confirmation and additional insight on the biological and clinical effects related to such differences early in life.