Evidence from 3-month-old infants shows that a combination of postnatal feeding and exposures in utero shape lipid metabolism

Abstract: We tested the hypothesis that both postnatal feeding and conditions in utero affect lipid metabolism in infants. Infants who experienced restrictive growth conditions in utero and others exposed to maternal hyperglycaemia were compared to a control group with respect to feeding mode. Dried blood spots were collected from a pilot subset of infant participants of the Cambridge Baby Growth Study at 3mo. Groups: (a) a normal gestation (control, n = 40), (b) small for gestational age (SGA, n = 34) and (c) whose mothers developed hyperglycaemia (n = 59). These groups were further stratified by feeding mode; breastfed, formula-fed or received a mixed intake. Their phospholipid, glyceride and sterol fractions were profiled using direct infusion mass spectrometry. Statistical tests were used to identify molecular species that indicated differences in lipid metabolism. The abundance of several phospholipids identified by multivariate analysis, PC(34:1), PC(34:2) and PC-O(34:1), was 30–100% higher across all experimental groups. SM(39:1) was around half as abundant in in utero groups among breastfed infants only. The evidence from this pilot study shows that phospholipid metabolism is modulated by both conditions in utero and postnatal feeding in a cohort of 133 Caucasian infants, three months post partum

Reduced size at birth and persisting reductions in adiposity in recent, compared with earlier, cohorts of infants born to mothers with gestational diabetes mellitus

Funder: National Institute for Health Research Cambridge Biomedical Research CentreFunder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265; Grant(s): Unit programme: MC_UU_12015/2Abstract: Aims/hypothesis: This study aimed to explore the infancy growth trajectories of ‘recent’ and ‘earlier’ offspring of mothers with gestational diabetes mellitus (OGDM), each compared with the same control infants, and investigate whether ‘recent’ OGDM still exhibit a classical phenotype, with macrosomia and increased adiposity. Methods: Within a prospective observational birth cohort, 98 ‘earlier’ OGDM born between 2001 and 2009 were identified using 75 g oral glucose tolerance testing at 28 weeks gestation, 122 recent OGDM born between 2011 and 2013 were recruited postnatally through antenatal diabetes clinics, and 876 normal birthweight infants of mothers with no history of diabetes were recruited across the full study period as the control group. All infants followed the same study protocol (measurements at birth, 3, 12 and 24 months, including weight, length and skinfold thickness indicating adiposity, and detailed demographic data). In all cases, GDM was defined using the International Association of Diabetes and Pregnancy Study Group criteria. Results: Earlier OGDM had higher birthweight SD scores (SDS) than control infants. Conversely, recent OGDM had similar birthweight- and length SDS to control infants (mean ± SD, 0.1 ± 1.0 and− 0.1 ± 0.9, respectively), but lower mean skinfold thickness SDS (−0.4 ± 0.6 vs 0.0 ± 0.9; p < 0.001). After birth, earlier OGDM showed reduced gains in weight and length between 3 and 12 months. In contrast, recent OGDM had increased weight and skinfold thickness gains until 3 months, followed by reduced gains in those variables from 3 to 12 months, compared with control infants. At 24 months, recent OGDM had lower adiposity than control infants (mean skinfold thickness SDS −0.3 ± 0.7 vs 0.0 ± 0.8; p < 0.001). At all time points recent OGDM had lower growth measurements than earlier OGDM. Conclusions/interpretation: Recent OGDM showed different growth trajectories to the earlier group, namely normalisation of birthweight and reduced adiposity at birth, followed by initial rapid weight gain but subsequent reduced adiposity postnatally. While avoidance of macrosomia at birth may be advantageous, the longer-term health implications of these changing growth trajectories are uncertain

Extensive Study of Breast Milk and Infant Growth: Protocol of the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF).

Funder: Medical Research Council; Grant(s): Unit programmes: MC_UU_12015/2 and MC_UU_00006/2Funder: Wellcome TrustGrowth and nutrition during early life have been strongly linked to future health and metabolic risks. The Cambridge Baby Growth Study (CBGS), a longitudinal birth cohort of 2229 mother-infant pairs, was set up in 2001 to investigate early life determinant factors of infant growth and body composition in the UK setting. To carry out extensive profiling of breastmilk intakes and composition in relation to infancy growth, the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) was established upon the original CBGS. The strict inclusion criteria were applied, focusing on a normal birth weight vaginally delivered infant cohort born of healthy and non-obese mothers. Crucially, only infants who were exclusively breastfed for the first 6 weeks of life were retained in the analysed study sample. At each visit from birth, 2 weeks, 6 weeks, and then at 3, 6, 12, 24, and 36 months, longitudinal anthropometric measurements and blood spot collections were conducted. Infant body composition was assessed using air displacement plethysmography (ADP) at 6 weeks and 3 months of age. Breast milk was collected for macronutrients and human milk oligosaccharides (HMO) measurements. Breast milk intake volume was also estimated, as well as sterile breastmilk and infant stool collection for microbiome study

Human Milk Short-Chain Fatty Acid Composition is Associated with Adiposity Outcomes in Infants.

BACKGROUND: Presumed benefits of human milk (HM) in avoiding rapid infancy weight gain and later obesity could relate to its nutrient composition. However, data on breast milk composition and its relation with growth are sparse. OBJECTIVE: We investigated whether short-chain fatty acids (SCFAs), known to be present in HM and linked to energy metabolism, are associated with infancy anthropometrics. METHODS: In a prospective birth cohort, HM hindmilk samples were collected from 619 lactating mothers at 4-8 wk postnatally [median (IQR) age: 33.9 (31.3-36.5) y, body mass index (BMI) (kg/m2): 22.8 (20.9-25.2)]. Their offspring, born at 40.1 (39.1-41.0) wk gestation with weight 3.56 (3.22-3.87) kg and 51% male, were assessed with measurement of weight, length, and skinfold thickness at ages 3, 12, and 24 mo, and transformed to age- and sex-adjusted z scores. HM SCFAs were measured by 1H-nuclear magnetic resonance spectroscopy (NMR) and GC-MS. Multivariable linear regression models were conducted to analyze the relations between NMR HM SCFAs and infancy growth parameters with adjustment for potential confounders. RESULTS: NMR peaks for HM butyrate, acetate, and formic acid, but not propionate, were detected. Butyrate peaks were 17.8% higher in HM from exclusively breastfeeding mothers than mixed-feeding mothers (P = 0.003). HM butyrate peak values were negatively associated with changes in infant weight (standardized B  = -0.10, P = 0.019) and BMI (B = -0.10, P = 0.018) between 3 and 12 mo, and negatively associated with BMI (B = -0.10, P = 0.018) and mean skinfold thickness (B = -0.10, P = 0.049) at age 12 mo. HM formic acid peak values showed a consistent negative association with infant BMI at all time points (B < = -0.10, P < = 0.014), whereas HM acetate was negatively associated with skinfold thickness at 3 mo (B = -0.10, P = 0.028) and 24 mo (B = -0.10, P = 0.036). CONCLUSIONS: These results suggest that HM SCFAs play a beneficial role in weight gain and adiposity during infancy. Further knowledge of HM SCFA function may inform future strategies to support healthy growth.PP was supported by a Medical Research Council Clinical Training Fellowship (G1001995). The Cambridge Baby Growth Study has been supported by the European Union (QLK4-1999-01422), the World Cancer Research Foundation International (2004/03), the Medical Research Council (7500001180), the NIHR Cambridge Comprehensive Biomedical Research Centre, Newlife - The Charity for Disabled Children (07/20), Mothercare Foundation (RG54608), and Mead Johnson Nutrition. KKO is supported by the Medical Research Council (MC_UU_12015/2)

Metabolic phenotypes of infants with normal birth weight, small-for-gestational-age, or after maternal gestational diabetes mellitus

Numerous studies have associated both under- and overnutrition during early life with long-term metabolic outcomes. Those conditions are typically represented by two groups of infants in animal and human studies: infants born small-for-gestational-age (SGA; reflecting intrauterine undernutrition) and offspring of mothers with gestational diabetes mellitus (OGDM; reflecting intrauterine overnutrition and hyperglycaemia). However, the underlying mechanism behind this phenomenon is still unknown: how these distinct groups can end up with similar metabolic risks, despite having opposite in utero nutritional conditions. This thesis aims to characterise biological similarities and differences across SGA, OGDM, and a control population from the Cambridge Baby Growth Study (CBGS). The CBGS, set up in 2001, is an ongoing longitudinal cohort aiming to examine the ante- and postnatal determinants of infant growth and body composition, including genetic and environmental factors. While SGA infants in CBGS showed typical rapid postnatal growth patterns, the contemporary OGDM cohort showed a distinct trend to that in earlier cohorts, with normal birth weights but reduced adiposity, which was sustained from birth to 24 months. Preliminary analyses of infant capillary blood spot profiles suggested that pre- and postnatal exposures reflected in SGA and OGDM may share common hormonal and lipidomic signatures during early infancy, independent of feeding practice and other confounding factors. In a CBGS breastmilk (BM) study, higher BM intake volume at 6 weeks conferred protection against subsequent rapid weight gain. Analyses of BM macronutrients also suggested that carbohydrate and protein intakes may have functional relevance to later infant growth and adiposity. This work has characterised in detail the effects of antenatal and postnatal nutritional factors on infant growth, body composition and biochemical profiles. The early infancy metabolic signatures identified here may reflect the continuum of early programming from pre- to early postnatal and might be potentially linked to future metabolic risks.Jardine Foundation - Cambridge Trus

Butyrate in Human Milk: Associations with Milk Microbiota, Milk Intake Volume, and Infant Growth

Butyrate in human milk (HM) has been suggested to reduce excessive weight and adipo-sity gains during infancy. However, HM butyrate&rsquo;s origins, determinants, and its influencing mechanism on weight gain are not completely understood. These were studied in the prospective longitudinal Cambridge Baby Growth and Breastfeeding Study (CBGS-BF), in which infants (n = 59) were exclusively breastfed for at least 6 weeks. Infant growth (birth, 2 weeks, 6 weeks, 3 months, 6 months, and 12 months) and HM butyrate concentrations (2 weeks, 6 weeks, 3 months, and 6 months) were measured. At age 6 weeks, HM intake volume was measured by deuterium-labelled water technique and HM microbiota by 16S sequencing. Cross-sectionally at 6 weeks, HM butyrate was associated with HM microbiota composition (p = 0.036) although no association with the abundance of typical butyrate producers was detected. In longitudinal analyses across all time points, HM butyrate concentrations were overall negatively associated with infant weight and adiposity, and associations were stronger at younger infant ages. HM butyrate concentration was also inversely correlated with HM intake volume, supporting a possible mechanism whereby butyrate might reduce infant growth via appetite regulation and modulation of HM intake

Maternal high body mass index, but not gestational diabetes, is associated with poorer educational attainment in mid-childhood

Background Previous studies suggest that gestational diabetes mellitus (GDM) is associated with poorer cognitive outcomes in children, however confounding factors especially maternal BMI have been poorly accounted for. Objective This study aimed to examine the independent associations between maternal BMI, GDM status and educational outcomes. Study Design Antenatal data from a prospective birth cohort (Pregnancy Outcome Prediction Study; POPS, 2008-2012, Cambridge, UK) was linked to mid-childhood educational outcomes (Department for Education, UK). 3249 children born at term were stratified by maternal GDM status and BMI at booking (<25 kg/m2 vs. ≥25 kg/m2). Regression models adjusted for relevant maternal, child, and socioeconomic factors were used to determine associations with academic outcomes at ages 5-7. Results No differences in educational attainment found between children exposed to GDM vs. non-exposed children. Neither maternal glucose levels measured at 11-14 weeks, 24-28 weeks, or acceleration of the fetal abdominal circumference growth velocity were related to educational attainment between ages 5-7. Children of mothers with booking BMI ≥25kg/m2 vs. <25kg/m2 were ~50% more likely not to meet expected educational standards regardless of GDM status (Age 5: aOR 1.44; 95%CI 1.19-1.74, p<0.001; Age 6: aOR 1.61; 95%CI 1.28-2.02, p<0.001). The association between maternal BMI and offspring educational attainment is dose-dependent and robust to stratification by GDM status and adjustment for socio-economic factors. Conclusions Mid-childhood educational attainment is not associated with maternal glucose status and this may provide important reassurance for pregnant women and clinicians. However maternal BMI is associated with lower childhood educational attainment and may be modifiable with intervention before or during pregnancy.This research was funded by the NIHR Cambridge Biomedical Research Centre, an Action Medical Research grant (GN2788) to CEA, GE and Roche Diagnostics Limited

Association between antenatal diagnosis of late fetal growth restriction and educational outcomes in mid-childhood: A UK prospective cohort study with long-term data linkage study.

Funder: NIHR Cambridge Biomedical Research Centre; funder-id: http://dx.doi.org/10.13039/501100018956BACKGROUND: Fetal growth restriction (FGR) is associated with a suboptimal intrauterine environment, which may adversely impact fetal neurodevelopment. However, analysing neurodevelopmental outcomes by observed birthweight fails to differentiate between true FGR and constitutionally small infants and cannot account for iatrogenic intervention. This study aimed to determine the relationship between antenatal FGR and mid-childhood (age 5 to 7 years) educational outcomes. METHODS AND FINDINGS: The Pregnancy Outcome Prediction Study (2008-2012) was a prospective birth cohort conducted in a single maternity hospital in Cambridge, United Kingdom. Clinicians were blinded to the antenatal diagnosis of FGR. FGR was defined as estimated fetal weight (EFW) <10th percentile at approximately 36 weeks of gestation, plus one or more indicators of placental dysfunction, including ultrasonic markers and maternal serum levels of placental biomarkers. A total of 2,754 children delivered at term were divided into 4 groups: FGR, appropriate-for-gestational age (AGA) with markers of placental dysfunction, healthy small-for-gestational age (SGA), and healthy AGA (referent). Educational outcomes (assessed at 5 to 7 years using UK national standards) were assessed with respect to FGR status using regression models adjusted for relevant covariates, including maternal, pregnancy, and socioeconomic factors. Compared to healthy AGA (N = 1,429), children with FGR (N = 250) were at higher risk of "below national standard" educational performance at 6 years (18% versus 11%; aOR 1.68; 95% CI 1.12 to 2.48, p = 0.01). By age 7, children with FGR were more likely to perform below standard in reading (21% versus 15%; aOR 1.46; 95% CI 0.99 to 2.13, p = 0.05), writing (28% versus 23%; aOR 1.46; 95% CI 1.02 to 2.07, p = 0.04), and mathematics (24% versus 16%; aOR 1.49; 95% CI 1.02 to 2.15, p = 0.03). This was consistent whether FGR was defined by ultrasound or biochemical markers. The educational attainment of healthy SGA children (N = 126) was comparable to healthy AGA, although this comparison may be underpowered. Our study design relied on linkage of routinely collected educational data according to nationally standardised metrics; this design allowed a high percentage of eligible participants to be included in the analysis (75%) but excludes those children educated outside of government-funded schools in the UK. Our focus on pragmatic and validated measures of educational attainment does not exclude more subtle effects of the intrauterine environment on specific aspects of neurodevelopment. CONCLUSIONS: Compared to children with normal fetal growth and no markers of placental dysfunction, FGR is associated with poorer educational attainment in mid-childhood

A comparative analyses of lipid ratios representing desaturase enzyme activity between preterm and term infants within the first ten weeks of life.

BACKGROUND: Desaturase enzymes play a key role in several pathways including biosynthesis of poly- and mono- unsaturated fatty acids (PUFAs, MUFA). In preterm infants, desaturase enzyme activity (DA) may be a rate-limiting step in maintaining PUFAs levels during this critical developmental window and impact on long term metabolic health. The study tested the hypothesis that DA is altered in preterm infants compared to term infants in early life and may be a marker of risk or contribute to later alterations in metabolic health. METHODS: Lipidomic analyses were conducted using blood samples from two established UK-based cohorts, involving very preterm (n = 105) and term (n = 259) infants. Blood samples were taken from term infants at birth, two and six weeks and from preterm infants when established on enteral feeds and at term corrected age. DA of the 2 groups of infants were estimated indirectly from product/precursor lipids ratios of phosphatidylcholine (PC) and triglycerides (TG) species and reported according to their postmenstrual and postnatal ages. RESULTS: There were changes in lipid ratios representing desaturase enzyme activity in preterm infants in the first weeks of life with higher delta 6 desaturases (D6D) triglyceride (TG) indices but significantly lower delta 9 desaturase (D9D) and D6D(PC) indices. In comparison to term infants, preterm have lower delta 5 desaturase (D5D) but higher D6D indices at all postnatal ages. Although point levels of desaturase indices were different, trajectories of changes in these indices over time were similar in preterm and term infants. CONCLUSIONS: This study findings suggest the patterns of desaturase indices in preterm infants differ from that of term infants but their trajectories of change in the first 10 weeks of life were similar. These differences of DA if they persist in later life could contribute to the mechanism of diseases in preterm adulthood and warrant further investigations.The CBGS-BF has been funded by the Medical Research Council [7500001180, G1001995], European Union Framework 5 [QLK4- 1999?01422], the Mothercare Charitable Foundation [RG54608], Newlife Foundation for Disabled Children (07/20), and the World Cancer Research Fund International (2004/03). The authors acknowledge the support of The National Institute for Health Research Cambridge Biomedical Research Centre. We want to thank the financial support of the Biotechnology and Biological Sciences Research Council (BB/P028195/1) for SGS and the NIHR Cambridge Biomedical Research Centre (146281) for Albert Koulman

Associations between maternal iron supplementation in pregnancy and offspring growth and cardiometabolic risk outcomes in infancy and childhood.

Funder: NIHR BioResourceIt was previously observed that maternal iron supplementation in pregnancy was associated with increased offspring size and adiposity at birth, possibly mediated through increased risk of gestational diabetes. In this study we investigated potential long-term associations of maternal iron supplementation in pregnancy with offspring growth in infancy, and growth and cardiometabolic risk factors in mid-childhood to seek evidence of nutritional programming. Using a nested case-control format, markers of growth and adiposity were measured at 3, 12 and 24 months of age in 341 infants from the Cambridge Baby Growth Study whose mothers supplemented with iron in pregnancy and 222 infants whose mothers did not. Measures of growth, glucose tolerance (using a 30 minute 1.75 g glucose/kg body weight oral glucose tolerance test), insulin sensitivity (HOMA IR) and blood pressure were collected in 122 and 79 of these children, respectively, at around 9.5 years of age. In infancy adiposity-promoting associations with maternal iron supplementation in pregnancy were evident at 3 months of age (e.g. mean difference in skinfold thickness: β = +0.15 mm, p = 0.02, in n = 341 whose mothers supplemented versus 222 that did not; waist circumference: β = +0.7 cm, p = 0.04, in n = 159 and 78, respectively) but differences lessened after this time (e.g. 3-12 month change in mean difference in skinfold thickness: β = -0.2 mm, p = 0.03, in n = 272 and 178, respectively). At ~9.5 years of age children whose mothers supplemented with iron in pregnancy had lower mean arterial blood pressures (β = -1.0 mmHg, p = 0.03, in n = 119 and 78, respectively). There were no apparent differences in markers of growth or other cardiometabolic factors. These results suggest that most of the associations of maternal iron supplementation in pregnancy on growth and adiposity evident at birth disappear during infancy, but there may be some evidence of long-term nutritional programming of blood pressure in mid-childhood.This analysis was funded by the Medical Research Council (7500001180, G1001995, U106179472); the European Union Framework 5 (QLK4-1999-01422); the Newlife Foundation for Disabled Children (07/20); the World Cancer Research Fund International (2004/03) and the Mothercare Charitable Foundation (RG54608). We also acknowledge support from National Institute for Health Research Cambridge Biomedical Research Centre. KKO is supported by the Medical Research Council (Unit Programme numbers: MC_UU_12015/2 and MC_UU_00006/2)