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.

Protocol for the Gut Bugs in Autism Trial: a double-blind randomised placebo-controlled trial of faecal microbiome transfer for the treatment of gastrointestinal symptoms in autistic adolescents and adults.

INTRODUCTION: Autism (formally autism spectrum disorder) encompasses a group of complex neurodevelopmental conditions, characterised by differences in communication and social interactions. Co-occurring chronic gastrointestinal symptoms are common among autistic individuals and can adversely affect their quality of life. This study aims to evaluate the efficacy of oral encapsulated faecal microbiome transfer (FMT) in improving gastrointestinal symptoms and well-being among autistic adolescents and adults. METHODS AND ANALYSIS: This double-blind, randomised, placebo-controlled trial will recruit 100 autistic adolescents and adults aged 16-45 years, who have mild to severe gastrointestinal symptoms (Gastrointestinal Symptoms Rating Scale (GSRS) score ≥2.0). We will also recruit eight healthy donors aged 18-32 years, who will undergo extensive clinical screening. Recipients will be randomised 1:1 to receive FMT or placebo, stratified by biological sex. Capsules will be administered over two consecutive days following an overnight bowel cleanse with follow-up assessments at 6, 12 and 26 weeks post-treatment. The primary outcome is GSRS score at 6 weeks. Other assessments include anthropometry, body composition, hair cortisol concentration, gut microbiome profile, urine/plasma gut-derived metabolites, plasma markers of gut inflammation/permeability and questionnaires on general well-being, sleep quality, physical activity, food diversity and treatment tolerability. Adverse events will be recorded and reviewed by an independent data monitoring committee. ETHICS AND DISSEMINATION: Ethics approval for the study was granted by the Central Health and Disability Ethics Committee on 24 August 2021 (reference number: 21/CEN/211). Results will be published in peer-reviewed journals and presented to both scientific and consumer group audiences. TRIAL REGISTRATION NUMBER: ACTRN12622000015741.

Horizontal gene transfer after faecal microbiota transplantation in adolescents with obesity.

BACKGROUND: Horizontal gene transfer (HGT) describes the transmission of DNA outside of direct ancestral lineages. The process is best characterised within the bacterial kingdom and can enable the acquisition of genetic traits that support bacterial adaptation to novel niches. The adaptation of bacteria to novel niches has particular relevance for faecal microbiota transplantation (FMT), a therapeutic procedure which aims to resolve gut-related health conditions of individuals, through transplanted gut microbiota from healthy donors. RESULTS: Three hundred eighty-one stool metagenomic samples from a placebo-controlled FMT trial for obese adolescents (the Gut Bugs Trial) were analysed for HGT, using two complementary methodologies. First, all putative HGT events, including historical HGT signatures, were quantified using the bioinformatics application WAAFLE. Second, metagenomic assembly and gene clustering were used to assess and quantify donor-specific genes transferred to recipients following the intervention. Both methodologies found no difference between the level of putative HGT events in the gut microbiomes of FMT and placebo recipients, post-intervention. HGT events facilitated by engrafted donor species in the FMT recipient gut at 6 weeks post-intervention were identified and characterised. Bacterial strains contributing to this subset of HGT events predominantly belonged to the phylum Bacteroidetes. Engraftment-dependent horizontally transferred genes were retained within recipient microbiomes at 12 and 26 weeks post-intervention. CONCLUSION: Our study suggests that novel microorganisms introduced into the recipient gut following FMT have no impact on the basal rate of HGT within the human gut microbiome. Analyses of further FMT studies are required to assess the generalisability of this conclusion across different FMT study designs and for the treatment of different gut-related conditions. Video Abstract.

A Multisource Process Evaluation of a Community-Based Healthy Lifestyle Programme for Child and Adolescent Obesity.

Whanau Pakari is a healthy lifestyle assessment and intervention programme for children and adolescents with obesity in Taranaki (Aotearoa/New Zealand), which, in this region, replaced the nationally funded Green Prescription Active Families (GRxAF) programme. We compared national referral rates from the GRxAF programme (age 5-15 years) and the B4 School Check (B4SC, a national preschool health and development assessment) with referral rates in Taranaki from Whanau Pakari. We retrospectively analysed 5 years of clinical data (2010-2015), comparing referral rates before, during, and after the Whanau Pakari clinical trial, which was embedded within the programme. We also surveyed programme referrers and stakeholders about their experiences of Whanau Pakari, analysing their responses using a multiple-methods framework. After the Whanau Pakari trial commenced, Taranaki GRxAF referral rates increased markedly (2.3 pretrial to 7.2 per 1000 person-years), while NZ rates were largely unchanged (1.8-1.9 per 1000 person-years) (p < 0.0001 for differences during the trial). Post-trial, Taranaki GRxAF referral rates remained higher irrespective of ethnicity, being 1.8 to 3.2 times the national rates (p < 0.001). Taranaki B4SC referrals for obesity were nearly complete at 99% in the last trial year and 100% post-trial, compared with national rates threefold lower (31% and 32%, respectively; p < 0.0001), with Taranaki referral rates for extreme obesity sustained at 80% and exceeding national rates for both periods (58% and 62%, respectively; p < 0.01). Notably, a referral was 50% more likely for referrers who attended a Whanau Pakari training half-day (RR = 1.51; p = 0.009). Stakeholders credited the success of Whanau Pakari to its multidisciplinary team, family-centred approach, and home-based assessments. However, they highlighted challenges such as navigating multidisciplinary collaboration, engaging with families with complex needs, and shifting conventional healthcare practices. Given its favourable referral trends and stakeholder endorsement, Whanau Pakari appears to be a viable contemporary model for an accessible and culturally appropriate intervention on a national and potentially international scale.

Impact of preconception and antenatal supplementation with myo-inositol, probiotics, and micronutrients on offspring BMI and weight gain over the first 2 years.

BACKGROUND: Nutritional intervention preconception and throughout pregnancy has been proposed as an approach to promoting healthy postnatal weight gain in the offspring but few randomised trials have examined this. METHODS: Measurements of weight and length were obtained at multiple time points from birth to 2 years among 576 offspring of women randomised to receive preconception and antenatally either a supplement containing myo-inositol, probiotics, and additional micronutrients (intervention) or a standard micronutrient supplement (control). We examined the influence on age- and sex-standardised BMI at 2 years (WHO standards, adjusting for study site, sex, maternal parity, smoking and pre-pregnancy BMI, and gestational age), together with the change in weight, length, BMI from birth, and weight gain trajectories using latent class growth analysis. RESULTS: At 2 years, there was a trend towards lower mean BMI among intervention offspring (adjusted mean difference [aMD] - 0.14 SD [95% CI 0.30, 0.02], p = 0.09), and fewer had a BMI > 95th percentile (i.e. > 1.65 SD, 9.2% vs 18.0%, adjusted risk ratio [aRR] 0.51 [95% CI 0.31, 0.82], p = 0.006). Longitudinal data revealed that intervention offspring had a 24% reduced risk of experiencing rapid weight gain > 0.67 SD in the first year of life (21.9% vs 31.1%, aRR 0.76 [95% CI 0.58, 1.00], p = 0.047). The risk was likewise decreased for sustained weight gain > 1.34 SD in the first 2 years of life (7.7% vs 17.1%, aRR 0.55 [95% CI 0.34, 0.88], p = 0.014). From five weight gain trajectories identified, there were more intervention offspring in the "normal" weight gain trajectory characterised by stable weight SDS around 0 SD from birth to 2 years (38.8% vs 30.1%, RR 1.29 [95% CI 1.03, 1.62], p = 0.029). CONCLUSIONS: Supplementation with myo-inositol, probiotics, and additional micronutrients preconception and in pregnancy reduced the incidence of rapid weight gain and obesity at 2 years among offspring. Previous reports suggest these effects will likely translate to health benefits, but longer-term follow-up is needed to evaluate this. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02509988 (Universal Trial Number U1111-1171-8056). Registered on 16 July 2015.

Maternal B-vitamin and vitamin D status before, during, and after pregnancy and the influence of supplementation preconception and during pregnancy: Prespecified secondary analysis of the NiPPeR double-blind randomized controlled trial.

BACKGROUND: Maternal vitamin status preconception and during pregnancy has important consequences for pregnancy outcome and offspring development. Changes in vitamin status from preconception through early and late pregnancy and postpartum have been inferred from cross-sectional data, but longitudinal data on vitamin status from preconception throughout pregnancy and postdelivery are sparse. As such, the influence of vitamin supplementation on vitamin status during pregnancy remains uncertain. This study presents one prespecified outcome from the randomized controlled NiPPeR trial, aiming to identify longitudinal patterns of maternal vitamin status from preconception, through early and late pregnancy, to 6 months postdelivery, and determine the influence of vitamin supplementation. METHODS AND FINDINGS: In the NiPPeR trial, 1,729 women (from the United Kingdom, Singapore, and New Zealand) aged 18 to 38 years and planning conception were randomized to receive a standard vitamin supplement (control; n = 859) or an enhanced vitamin supplement (intervention; n = 870) starting in preconception and continued throughout pregnancy, with blinding of participants and research staff. Supplement components common to both treatment groups included folic acid, ß-carotene, iron, calcium, and iodine; components additionally included in the intervention group were riboflavin, vitamins B6, B12, and D (in amounts available in over-the-counter supplements), myo-inositol, probiotics, and zinc. The primary outcome of the study was glucose tolerance at 28 weeks' gestation, measured by oral glucose tolerance test. The secondary outcome reported in this study was the reduction in maternal micronutrient insufficiency in riboflavin, vitamin B6, vitamin B12, and vitamin D, before and during pregnancy. We measured maternal plasma concentrations of B-vitamins, vitamin D, and markers of insufficiency/deficiency (homocysteine, hydroxykynurenine-ratio, methylmalonic acid) at recruitment, 1 month after commencing intervention preconception, in early pregnancy (7 to 11 weeks' gestation) and late pregnancy (around 28 weeks' gestation), and postdelivery (6 months after supplement discontinuation). We derived standard deviation scores (SDS) to characterize longitudinal changes among participants in the control group and measured differences between the 2 groups. At recruitment, the proportion of patients with marginal or low plasma status was 29.2% for folate (<13.6 nmol/L), 7.5% and 82.0% for riboflavin (<5 nmol/L and ≤26.5 nmol/L, respectively), 9.1% for vitamin B12 (<221 pmol/L), and 48.7% for vitamin D (<50 nmol/L); these proportions were balanced between the groups. Over 90% of all participants had low or marginal status for one or more of these vitamins at recruitment. Among participants in the control group, plasma concentrations of riboflavin declined through early and late pregnancy, whereas concentrations of 25-hydroxyvitamin D were unchanged in early pregnancy, and concentrations of vitamin B6 and B12 declined throughout pregnancy, becoming >1 SDS lower than baseline by 28 weeks gestation. In the control group, 54.2% of participants developed low late-pregnancy vitamin B6 concentrations (pyridoxal 5-phosphate <20 nmol/L). After 1 month of supplementation, plasma concentrations of supplement components were substantially higher among participants in the intervention group than those in the control group: riboflavin by 0.77 SDS (95% CI 0.68 to 0.87, p < 0.0001), vitamin B6 by 1.07 SDS (0.99 to 1.14, p < 0.0001), vitamin B12 by 0.55 SDS (0.46 to 0.64, p < 0.0001), and vitamin D by 0.51 SDS (0.43 to 0.60, p < 0.0001), with higher levels in the intervention group maintained during pregnancy. Markers of vitamin insufficiency/deficiency were reduced in the intervention group, and the proportion of participants with vitamin D insufficiency (<50 nmol/L) during late pregnancy was lower in the intervention group (35.1% versus 8.5%; p < 0.0001). Plasma vitamin B12 remained higher in the intervention group than in the control group 6 months postdelivery (by 0.30 SDS (0.14, 0.46), p = 0.0003). The main limitation is that generalizability to the global population is limited by the high-resource settings and the lack of African and Amerindian women in particular. CONCLUSIONS: Over 90% of the trial participants had marginal or low concentrations of one or more of folate, riboflavin, vitamin B12, or vitamin D during preconception, and many developed markers of vitamin B6 deficiency in late pregnancy. Preconception/pregnancy supplementation in amounts available in over-the-counter supplements substantially reduces the prevalence of vitamin deficiency and depletion markers before and during pregnancy, with higher maternal plasma vitamin B12 maintained during the recommended lactational period. TRIAL REGISTRATION: ClinicalTrials.gov NCT02509988; U1111-1171-8056.

A nutritional supplement taken during preconception and pregnancy influences human milk macronutrients in women with overweight/obesity and gestational diabetes mellitus.

Rational: Maternal overweight/obesity and gestational diabetes mellitus (GDM) are associated with an increased risk of their offspring developing overweight/obesity or type 2 diabetes later in life. However, the impacts of maternal overweight/obesity and dysglycemia on human milk (HM) macronutrient composition are not well understood. Objective: Through a double-blind randomised controlled trial, we investigated the effects of maternal supplementation from preconception throughout pregnancy until birth on HM macronutrient concentrations, in association with maternal and infant factors including maternal pre-pregnancy body mass index (BMI) and GDM status. In addition, we aimed to characterise longitudinal changes in HM macronutrients. Methods: The control supplement contained calcium, iodine, iron, ß-carotene, and folic acid. The intervention supplement additionally contained zinc, vitamins B2, B6, B12, and D3, probiotics, and myo-inositol. HM samples were collected across seven time points from 1 week to 12 months from Singapore and/or New Zealand. HM macronutrient concentrations were measured using a MIRIS Human Milk Analyser. Potential differences in HM macronutrient concentrations were assessed using linear mixed models with a repeated measures design. Results: Overall, HM macronutrient concentrations were similar between control and intervention groups. Among the control group, overweight/obesity and GDM were associated with higher HM fat and energy concentrations over the first 3 months. Such associations were not observed among the intervention group. Of note, mothers with GDM in the intervention group had lower HM fat by 10% (p = 0.049) and energy by 6% (p = 0.029) than mothers with GDM in the control group. Longitudinal changes in HM macronutrient concentrations over 12 months of lactation in New Zealand showed that HM fat and energy decreased in the first 6 months then increased until 12 months. HM lactose gradually decreased from 1 week to 12 months while crude protein decreased from 1 week to 6 months then remained relatively constant until 12 months of lactation. Conclusion: Maternal overweight/obesity or GDM were associated with increased HM fat and energy levels. We speculate the intervention taken during preconception and pregnancy altered the impact of maternal BMI or GDM status on HM macronutrient composition. Further studies are required to identify the mechanisms underlying altered HM macronutrient concentration in the intervention group and to determine any long-term effects on offspring health. Clinical trial registration: ClinicalTrials.gov, NCT02509988, Universal Trial Number U1111-1171-8056. Registered on 16 July 2015. This is an academic-led study by the EpiGen Global Research Consortium.

Prediction of fat-free mass in young children using bioelectrical impedance spectroscopy.

BACKGROUND: Bioimpedance devices are practical for measuring body composition in preschool children, but their application is limited by the lack of validated equations. OBJECTIVES: To develop and validate fat-free mass (FFM) bioimpedance prediction equations among New Zealand 3.5-year olds, with dual-energy X-ray absorptiometry (DXA) as the reference method. METHODS: Bioelectrical impedance spectroscopy (SFB7, ImpediMed) and DXA (iDXA, GE Lunar) measurements were conducted on 65 children. An equation incorporating weight, sex, ethnicity, and impedance was developed and validated. Performance was compared with published equations and mixture theory prediction. RESULTS: The equation developed in ~70% (n = 45) of the population (FFM [kg] = 1.39 + 0.30 weight [kg] + 0.39 length2/resistance at 50 kHz [cm2/Ω] + 0.30 sex [M = 1/F = 0] + 0.28 ethnicity [1 = Asian/0 = non-Asian]) explained 88% of the variance in FFM and predicted FFM with a root mean squared error of 0.39 kg (3.4% of mean FFM). When internally validated (n = 20), bias was small (40 g, 0.3% of mean FFM), with limits of agreement (LOA) ±7.6% of mean FFM (95% LOA: -0.82, 0.90 kg). Published equations evaluated had similar LOA, but with marked bias (>12.5% of mean FFM) when validated in our cohort, likely due to DXA differences. Of mixture theory methods assessed, the SFB7 inbuilt equation with personalized body geometry values performed best. However, bias and LOA were larger than with the empirical equations (-0.43 kg [95% LOA: -1.65, 0.79], p < 0.001). CONCLUSIONS: We developed and validated a bioimpedance equation that can accurately predict FFM. Further external validation of the equation is required.

An open-label pilot trial of faecal microbiome transfer to restore the gut microbiome in anorexia nervosa: protocol.

INTRODUCTION: Individuals with anorexia nervosa (AN) harbour distinct gut microbiomes compared with healthy individuals, which are sufficient to induce weight loss and anxiety-like behaviours when transplanted into germ-free mice. We hypothesise that faecal microbiome transfer (FMT) from healthy donors would help restore the gut microbiome of individuals with AN, which in turn, may aid patient recovery. METHODS: We aim to conduct an open-label pilot study in 20 females aged 16-32 years in Auckland, New Zealand who meet the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria for AN and have a body mass index 13-19 kg/m2. We will recruit four healthy, lean, female donors, aged 18-32 years, who will undergo extensive clinical screening prior to stool donation. Faecal microbiota will be harvested from donors and double encapsulated in delayed release, acid-resistant capsules. All participants will receive a single course of 20 FMT capsules (five from each donor) which they can choose to take over two or four consecutive days. Stool and blood samples will be collected from participants over a period of 3 months to assess their gut microbiome profile, metabolome, levels of intestinal inflammation and nutritional status. Our primary outcome is a shift in the gut microbiome composition at 3 weeks post-FMT (Bray-Curtis dissimilarity). We will also monitor participants' body composition (whole-body dual-energy X-ray absorptiometry scans), eating disorder psychopathology, mental health and assess their views on, and tolerability of, treatment. All adverse events will be recorded and reviewed by an independent data monitoring committee. ETHICS AND DISSEMINATION: Ethics approval was provided by the Central Health and Disability Ethics Committee (Ministry of Health, New Zealand, 21/CEN/212). Results will be published in peer-reviewed journals and presented to both scientific and consumer group audiences. TRIAL REGISTRATION NUMBER: ACTRN12621001504808.

The effect of a preconception and antenatal nutritional supplement on children's BMI and weight gain over the first 2 years of life: findings from the NiPPeR randomised controlled trial.

BACKGROUND: Nutritional intervention before and throughout pregnancy might promote healthy infant weight gain; however, clinical evidence is scarce. Therefore, we examined whether preconception and antenatal supplementation would affect the body size and growth of children in the first 2 years of life. METHODS: Women were recruited from the community before conception in the UK, Singapore, and New Zealand, and randomly allocated to either the intervention (myo-inositol, probiotics, and additional micronutrients) or control group (standard micronutrient supplement) with stratification by site and ethnicity. Measurements of weight and length were obtained from 576 children at multiple timepoints in the first 2 years of life. Differences in age and sex standardised BMI at age 2 years (WHO standards) and the change in weight from birth were examined. Written informed consent was obtained from the mothers, and ethics approval was granted by local committees. The NiPPeR trial was registered with ClinicalTrials.gov (NCT02509988) on July 16, 2015 (Universal Trial Number U1111-1171-8056). FINDINGS: 1729 women were recruited between Aug 3, 2015, and May 31, 2017. Of the women randomised, 586 had births at 24 weeks or more of gestation between April, 2016, and January, 2019. At age 2 years, adjusting for study site, infant sex, parity, maternal smoking, maternal prepregnancy BMI, and gestational age, fewer children of mothers who received the intervention had a BMI of more than the 95th percentile (22 [9%] of 239 vs 44 [18%] of 245, adjusted risk ratio 0·51, 95% CI 0·31-0·82, p=0·006). Longitudinal data revealed that the children of mothers who received the intervention had a 24% reduced risk of experiencing rapid weight gain of more than 0·67 SD in the first year of life (58 [21·9%] of 265 vs 80 [31·1%] of 257, adjusted risk ratio 0·76, 95% CI 0·58-1·00, p=0·047). Risk was likewise decreased for sustained weight gain of more than 1·34 SD in the first 2 years (19 [7·7%] of 246 vs 43 [17·1%] of 251, adjusted risk ratio 0·55, 95% CI 0·34-0·88, p=0·014). INTERPRETATION: Rapid weight gain in infancy is associated with future adverse metabolic health. The intervention supplement taken before and throughout pregnancy was associated with lower risk of rapid weight gain and high BMI at age 2 years among children. Long-term follow-up is required to assess the longevity of these benefits. FUNDING: National Institute for Health Research; New Zealand Ministry of Business, Innovation and Employment; Société Des Produits Nestlé; UK Medical Research Council; Singapore National Research Foundation; National University of Singapore and the Agency of Science, Technology and Research; and Gravida.

Fish oil supplementation during pregnancy and postpartum in mothers with overweight and obesity to improve body composition and metabolic health during infancy: A double-blind randomized controlled trial.

BACKGROUND: Maternal obesity during pregnancy is associated with an increased risk of obesity and metabolic disease in the offspring. Supplementation with fish oil (FO), which is insulin sensitizing, during pregnancy in mothers with overweight or obesity may prevent the development of greater adiposity and metabolic dysfunction in their children. OBJECTIVES: To determine the effects of FO supplementation throughout the second half of pregnancy and lactation in mothers with overweight or obesity on infant body composition and metabolism. METHODS: A double-blind randomized controlled trial of 6 g FO (3.55 g/d of n-3 PUFAs) compared with olive oil (control) from mid-pregnancy until 3 mo postpartum. Eligible women had singleton pregnancies at 12-20 wk of gestation, and BMI ≥ 25 kg/m2. The primary outcome was the infant body fat percentage (DXA scans) at 2 wk of age. Secondary outcomes included maternal metabolic markers during pregnancy, infant anthropometry at 2 wk and 3 mo of age, and metabolic markers at 3 mo. RESULTS: A total of 129 mothers were randomized, and 98 infants had a DXA scan at 2 wk. PRIMARY OUTCOME: Imputed and nonimputed analyses showed no effects of FO supplementation on infant body fat percentage at age 2 wk. SECONDARY OUTCOMES: There were no treatment effects on infant outcomes at 2 wk, but FO infants had a higher BMI z-score (P = 0.025) and ponderal index (P = 0.017) at age 3 mo. FO supplementation lowered maternal triglycerides by 17% at 30 wk of pregnancy (P = 0.0002) and infant triglycerides by 21% at 3 mo of age (P = 0.016) but did not affect maternal or infant insulin resistance. The rate of emergency cesarean section was lower with FO supplementation [aRR = 0.38 (95%CI 0.16, 0.90); P = 0.027]. CONCLUSIONS: FO supplementation of mothers with overweight or obesity during pregnancy did not impact infant body composition. There is a need to follow up the offspring to determine whether the observed metabolic effects persist. CLINICAL TRIAL REGISTRY NUMBER: This study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617001078347p). In addition, the Universal Trial Number, WHO, was obtained (U1111-1199-5860).

Time-to-conception and clinical pregnancy rate with a myo-inositol, probiotics, and micronutrient supplement: secondary outcomes of the NiPPeR randomized trial.

OBJECTIVE: To determine whether a combined myo-inositol, probiotics and micronutrient nutritional supplement impacts time-to-natural-conception and clinical pregnancy rates. DESIGN: Secondary outcomes of a double-blind randomized controlled trial. SETTING: Community recruitment. PATIENTS: Women aged 18 to 38 years planning to conceive in the United Kingdom, Singapore, and New Zealand, excluding those with diabetes mellitus or receiving fertility treatment. INTERVENTION: A standard (control) supplement (folic acid, iron, calcium, iodine, ß-carotene), compared with an intervention additionally containing myo-inositol, probiotics, and other micronutrients (vitamins B2, B6, B12, D, zinc). MAIN OUTCOME MEASURES: Number of days between randomization and estimated date of natural conception of a clinical pregnancy, as well as cumulative pregnancy rates at 3, 6, and 12 months. RESULTS: Of 1729 women randomized, 1437 (83%; intervention, n=736; control, n=701) provided data. Kaplan-Meier curves of conception were similar between intervention and control groups; the time at which 20% achieved natural conception was 90.5 days (95% confidence interval: 80.7, 103.5) in the intervention group compared with 92.0 days (76.0, 105.1) in the control group. Cox's proportional hazard ratios (HRs) comparing intervention against control for cumulative achievement of pregnancy (adjusted for site, ethnicity, age, body mass index, and gravidity) were similar at 3, 6, and 12 months. Among both study groups combined, overall time-to-conception lengthened with higher preconception body mass index, and was longer in non-White than in White women. Among women who were overweight the intervention shortened time-to-conception compared with control regardless of ethnicity (12-month HR=1.47 [1.07, 2.02], P=.016; 20% conceived by 84.5 vs. 117.0 days) and improved it to that comparable to nonoverweight/nonobese women (20% conceived by 82.1 days). In contrast, among women with obesity, time-to-conception was lengthened with intervention compared with control (12-month HR=0.69 [0.47, 1.00]; P=.053; 20% conceived by 132.7 vs. 108.5 days); an effect predominantly observed in non-White women with obesity. CONCLUSIONS: Time-to-natural-conception and clinical pregnancy rates within a year were overall similar in women receiving the intervention supplement compared with control. Overweight women had a longer time-to-conception but there was suggestion that the supplement may shorten their time-to-conception to that comparable to the nonoverweight/nonobese women. Further studies are required to confirm this. CLINICAL TRIAL REGISTRATION NUMBER: clinicaltrials.gov (NCT02509988).

International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood.

This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

A nutritional supplement during preconception and pregnancy increases human milk vitamin D but not B-vitamin concentrations.

BACKGROUND & AIMS: Optimal maternal vitamin status during pregnancy and lactation is essential to support maternal and infant health. For instance, vitamin D3 is involved in infant bone development, and B-vitamins are involved in various metabolic processes, including energy production. Through a double-blind randomised controlled trial, we investigated the effects of maternal supplementation from preconception throughout pregnancy until birth on human milk (HM) concentrations of vitamin D3 and B-vitamins. In addition, we aimed to characterise longitudinal changes in milk concentrations of these vitamins. METHODS: Both control and intervention supplements contained calcium, iodine, iron, ß-carotene, and folic acid, while the intervention also contained zinc, vitamins B2, B6, B12, and D3, probiotics, and myo-inositol. HM samples were collected across 4 time points from 1 week to 3 months post-delivery from 158 mothers in Singapore, and 7 time points from 1 week to 12 months from 180 mothers in New Zealand. HM vitamin D was quantified using supercritical fluid chromatography and B-vitamins with mass spectrometry. Potential intervention effects on HM vitamins D3, B2, B6, and B9, as well as other B-vitamin (B1 and B3) concentrations were assessed using linear mixed models with a repeated measures design. RESULTS: Over the first 3 months of lactation, HM 25-hydroxyvitamin D3 concentrations were 20% (95% CI 8%, 33%, P = 0.001) higher in the intervention group, with more marked effects in New Zealand. There were no observed intervention effects on HM concentrations of vitamins B1, B2, B3, B6, and B9. In New Zealand mothers, longitudinally, vitamin D3 concentrations gradually increased from early lactation up to 12 months, while vitamins B1 and B2 peaked at 6 weeks, B3 at 3 weeks, and B6 and B9 at 3 months. CONCLUSIONS: Maternal supplementation during preconception and pregnancy increased HM vitamin D, but not B-vitamin concentrations in lactation. Further studies are required to examine the discrete benefits of vitamin D supplementation starting preconception vs during pregnancy, and to further characterise the effects of supplementation on later offspring health outcomes. CLINICAL TRIAL REGISTRATION: Registered at ClinicalTrials.gov on the 16 July 2015 (identifier NCT02509988); Universal Trial Number U1111-1171-8056. This study was academic-led by the EpiGen Global Research Consortium.

Prediction of fat-free mass in a multi-ethnic cohort of infants using bioelectrical impedance: Validation against the PEA POD.

Background: Bioelectrical impedance analysis (BIA) is widely used to measure body composition but has not been adequately evaluated in infancy. Prior studies have largely been of poor quality, and few included healthy term-born offspring, so it is unclear if BIA can accurately predict body composition at this age. Aim: This study evaluated impedance technology to predict fat-free mass (FFM) among a large multi-ethnic cohort of infants from the United Kingdom, Singapore, and New Zealand at ages 6 weeks and 6 months (n = 292 and 212, respectively). Materials and methods: Using air displacement plethysmography (PEA POD) as the reference, two impedance approaches were evaluated: (1) empirical prediction equations; (2) Cole modeling and mixture theory prediction. Sex-specific equations were developed among ∼70% of the cohort. Equations were validated in the remaining ∼30% and in an independent University of Queensland cohort. Mixture theory estimates of FFM were validated using the entire cohort at both ages. Results: Sex-specific equations based on weight and length explained 75-81% of FFM variance at 6 weeks but only 48-57% at 6 months. At both ages, the margin of error for these equations was 5-6% of mean FFM, as assessed by the root mean squared errors (RMSE). The stepwise addition of clinically-relevant covariates (i.e., gestational age, birthweight SDS, subscapular skinfold thickness, abdominal circumference) improved model accuracy (i.e., lowered RMSE). However, improvements in model accuracy were not consistently observed when impedance parameters (as the impedance index) were incorporated instead of length. The bioimpedance equations had mean absolute percentage errors (MAPE) < 5% when validated. Limits of agreement analyses showed that biases were low (< 100 g) and limits of agreement were narrower for bioimpedance-based than anthropometry-based equations, with no clear benefit following the addition of clinically-relevant variables. Estimates of FFM from BIS mixture theory prediction were inaccurate (MAPE 11-12%). Conclusion: The addition of the impedance index improved the accuracy of empirical FFM predictions. However, improvements were modest, so the benefits of using bioimpedance in the field remain unclear and require further investigation. Mixture theory prediction of FFM from BIS is inaccurate in infancy and cannot be recommended.

Fish oil supplementation of rats fed a high fat diet during pregnancy improves offspring insulin sensitivity.

Introduction: In rats, a maternal high-fat diet (HFD) leads to adverse metabolic changes in the adult offspring, similar to the children of mothers with obesity during pregnancy. Supplementation with a high dose of fish oil (FO) to pregnant rats fed a HFD has been shown to prevent the development of insulin resistance in adult offspring. However, the effects of supplementation at a translationally relevant dose remain unknown. Aim: To determine whether supplementation with a human-relevant dose of FO to pregnant rats can prevent the long-term adverse metabolic and cardiovascular effects of a maternal HFD on adult offspring. Methods: Female rats (N = 100, 90 days of age) were assigned to HFD (45% kcal from fat) or control diet (CD) for 14 days prior to mating and throughout pregnancy and lactation. Following mating, dams received a gel containing 0.05 ml of FO (human equivalent 2-3 ml) or a control gel on each day of pregnancy. This produced 4 groups, CD with control gel, CD with FO gel, HFD with control gel and HFD with FO gel. Plasma and tissue samples were collected at day 20 of pregnancy and postnatal day 2, 21, and 100. Adult offspring were assessed for insulin sensitivity, blood pressure, DXA scan, and 2D echocardiography. Results: There was an interaction between maternal diet and FO supplementation on insulin sensitivity (p = 0.005) and cardiac function (p < 0.01). A maternal HFD resulted in impaired insulin sensitivity in the adult offspring (p = 0.005 males, p = 0.001 females). FO supplementation in the context of a maternal HFD prevented the reduction in insulin sensitivity in offspring (p = 0.05 males, p = 0.0001 females). However, in dams consuming CD, FO supplementation led to impaired insulin sensitivity (p = 0.02 males, p = 0.001 females), greater body weight and reduced cardiac ejection fraction. Conclusion: The effects of a human-relevant dose of maternal FO on offspring outcomes were dependent on the maternal diet, so that FO was beneficial to the offspring if the mother consumed a HFD, but deleterious if the mother consumed a control diet. This study suggests that supplementation with FO should be targeted to women expected to have abnormalities of metabolism such as those with overweight and obesity.

Oral diazoxide versus placebo for severe or recurrent neonatal hypoglycaemia: Neonatal Glucose Care Optimisation (NeoGluCO) study - a randomised controlled trial.

INTRODUCTION: Infants with severe or recurrent transitional hypoglycaemia continue to have high rates of adverse neurological outcomes and new treatment approaches are needed that target the underlying pathophysiology. Diazoxide is one such treatment that acts on the pancreatic ß-cell in a dose-dependent manner to decrease insulin secretion. METHODS AND ANALYSIS: Phase IIB, double-blind, two-arm, parallel, randomised trial of diazoxide versus placebo in neonates ≥35 weeks' gestation for treatment of severe (blood glucose concentration (BGC)<1.2 mmol/L or BGC 1.2 to <2.0 mmol/L despite two doses of buccal dextrose gel and feeding in a single episode) or recurrent (≥3 episodes <2.6 mmol/L in 48 hours) transitional hypoglycaemia. Infants are loaded with diazoxide 5 mg/kg orally and then commenced on a maintenance dose of 1.5 mg/kg every 12 hours, or an equal volume of placebo. The intervention is titrated from the third maintenance dose by protocol to target BGC in the range of 2.6-5.4 mmol/L. The primary outcome is time to resolution of hypoglycaemia, defined as the first point at which the following criteria are met concurrently for ≥24 hours: no intravenous fluids, enteral bolus feeding and normoglycaemia. Groups will be compared for the primary outcome using Cox's proportional hazard regression analysis, expressed as adjusted HR with a 95% CI. ETHICS AND DISSEMINATION: This trial has been approved by the Health and Disability Ethics Committees of New Zealand (19CEN189). Findings will be disseminated in peer-reviewed journals, to clinicians and researchers at local and international conferences and to the public. TRIAL REGISTRATION NUMBER: ACTRN12620000129987.

Cross-calibration of two dual-energy X-ray absorptiometry devices for the measurement of body composition in young children.

This study aimed to cross-calibrate body composition measures from the GE Lunar Prodigy and GE Lunar iDXA in a cohort of young children. 28 children (mean age 3.4 years) were measured on the iDXA followed by the Prodigy. Prodigy scans were subsequently reanalysed using enCORE v17 enhanced analysis ("Prodigy enhanced"). Body composition parameters were compared across three evaluation methods (Prodigy, Prodigy enhanced, iDXA), and adjustment equations were developed. There were differences in the three evaluation methods for all body composition parameters. Body fat percentage (%BF) from the iDXA was approximately 1.5-fold greater than the Prodigy, whereas bone mineral density (BMD) was approximately 20% lower. Reanalysis of Prodigy scans with enhanced software attenuated these differences (%BF: - 5.2% [95% CI - 3.5, - 6.8]; and BMD: 1.0% [95% CI 0.0, 1.9]), although significant differences remained for all parameters except total body less head (TBLH) total mass and TBLH BMD, and some regional estimates. There were large differences between the Prodigy and iDXA, with these differences related both to scan resolution and software. Reanalysis of Prodigy scans with enhanced analysis resulted in body composition values much closer to those obtained on the iDXA, although differences remained. As manufacturers update models and software, researchers and clinicians need to be aware of the impact this may have on the longitudinal assessment of body composition, as results may not be comparable across devices and software versions.

Peripartum outcomes after combined myo-inositol, probiotics, and micronutrient supplementation from preconception: the NiPPeR randomized controlled trial.

BACKGROUND: Evidence that nutritional supplementation before and during pregnancy improves peripartum outcomes is sparse. In the Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism and Offspring Health (NiPPeR) trial, we previously reported that a combined myo-inositol, probiotics, and micronutrient supplement started at preconception showed no difference in the primary outcome of gestational glycemia, but did reduce the risk of preterm delivery, preterm prelabor rupture of membranes, and major postpartum hemorrhage. OBJECTIVE: This study aimed to examine the hypothesis that a reduction in major postpartum hemorrhage following a combined nutritional (myo-inositol, probiotics, and micronutrients) intervention is linked with promotion of labor progress and reduced operative delivery. STUDY DESIGN: This double-blind randomized controlled trial recruited 1729 women from the United Kingdom, Singapore, and New Zealand, aged 18 to 38 years, and planning conception between 2015 and 2017. The effects of the nutritional intervention compared with those of a standard micronutrient supplement (control), taken at preconception and throughout pregnancy, were examined for the secondary outcomes of peripartum events using multinomial, Poisson, and linear regression adjusting for site, ethnicity, and important covariates. RESULTS: Of the women who conceived and progressed beyond 24 weeks' gestation with a singleton pregnancy (n=589), 583 (99%) provided peripartum data. Between women in the intervention (n=293) and control (n=290) groups, there were no differences in rates of labor induction, oxytocin augmentation during labor, instrumental delivery, perineal trauma, and intrapartum cesarean delivery. Although duration of the first stage of labor was similar, the second-stage duration was 20% shorter in the intervention than in the control group (adjusted mean difference, -12.0 [95% confidence interval, -22.2 to -1.2] minutes; P=.029), accompanied by a reduction in operative delivery for delayed second-stage progress (adjusted risk ratio, 0.61 [0.48-0.95]; P=.022). Estimated blood loss was 10% lower in the intervention than in the control group (adjusted mean difference, -35.0 [-70.0 to -3.5] mL; P=.047), consistent with previous findings of reduced postpartum hemorrhage. CONCLUSION: Supplementation with a specific combination of myo-inositol, probiotics, and micronutrients started at preconception and continued in pregnancy reduced the duration of the second stage of labor, the risk of operative delivery for delay in the second stage, and blood loss at delivery.

Caregiver Perception of Weight Status in 5-Year-Old Children From a Community of High Socioeconomic Deprivation in New Zealand.

Background: Early childhood obesity is highly prevalent in Aotearoa New Zealand (NZ). Little is known about caregiver perception of children's weight status among those living in areas of high socioeconomic deprivation, particularly Maori and Pacific children. Aims: To explore caregiver perception of weight status among children starting school in areas of high socioeconomic deprivation and examine potential associations between the child's body mass index (BMI) z-score and their caregiver's perception of their child's body size or health. Methods: Participants were 5-year-old children living in a community of high socioeconomic deprivation and their caregivers. Children had their weight and height measured. BMI z-scores were calculated according to World Health Organization standards. Caregivers were asked to assess their child's BMI and health status, and choose a silhouette that best represented their child's body size. Results: One hundred and six children (>75% Maori or Pacific) were included. Over half (58%) had overweight or obesity, with only 16% correctly perceived by their caregiver as overweight. These children tended to have higher BMI z-scores than those not correctly perceived as overweight. Caregivers chose larger silhouettes to represent children's body sizes as children's BMI z-scores increased. There was no discernible association between children's BMI z-scores and caregiver perception of children's health. Conclusions: Caregivers appeared to judge their child's body size in comparison to other children. The normalization of childhood obesity and infrequent caregiver recognition of this condition in children in communities with a high prevalence may impact the uptake and efficacy of intervention initiatives.