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Background/Objectives: Adequate folate intake is required in preterm infants for rapid growth and development, but there is little evidence to back recommendations. We aimed to assess folate status in preterm infants at discharge and in early infancy, according to exposure to folate sources, particularly in those exclusively/predominantly breastfed. Methods: A prospective, multicenter, observational cohort study was conducted in the UK, involving 45 preterm infants <33 weeks' gestational age (GA) exclusively/predominantly fed human milk when approaching NICU (Neonatal Intensive Care Unit) discharge. Serum folate levels were measured near NICU discharge (T1) and at 2–3 months corrected age (T2). Folate status was categorized per WHO (World Health Organization) guidelines: deficiency (<6.8 nmol/L), possible deficiency (6.8–13.4 nmol/L), normal (13.5–45.3 nmol/L), and elevated (>45.3 nmol/L). Nutritional information on feed and supplements was collected from hospital notes and maternal interviews. Results: Thirty-two infants (71%) received parenteral nutrition. Twelve infants (32%) remained exclusively breastfed at T2. No infant from the whole cohort had a serum folate concentration <13.5 nmol/L at either time point. A proportion of infants had serum folate concentrations >45.3 nmol/L: 14/45 (31%) at T1, 19/37 (42%) at T2, and 7/37 (16%) at both time points. Elevated concentrations were seen particularly in infants who received folic acid supplements or nutrition containing folic acid, such as parenteral nutrition and breastmilk fortifiers. Conclusions: Folate deficiency was not observed in this cohort; folate concentrations were high and in line with those observed in healthy term infants. Further research is needed to assess the high folate concentrations in premature babies and whether they may have any adverse clinical impact. [ABSTRACT FROM AUTHOR]

Human milk adipokines in term babies seem partially determined by maternal factors and affect infant's development. We aimed to describe bioactive peptide concentration in very preterm human milk and associations to maternal characteristics and postnatal growth. Mothers delivering ≤32 weeks of gestation and their infant/s were recruited. At 4 weeks of lactation, an aliquot of 24‐h‐pooled milk was collected for exclusively breastfeeding dyads. Insulin, leptin, adiponectin, and milk fat globule epidermal growth factor‐8 (MFG‐E8) were measured by enzyme‐linked immunoabsorbent assay in skimmed milk. One hundred mothers (28.8 ± 2.3 weeks at delivery) provided a milk sample. Milk insulin was related to gestational age, pre‐pregnancy body mass index (BMI), and galactagogue treatment (final model: adjusted R2: 0.330, p < 0.0001; adjusted β coefficients: galactagogue treatment: 0.348, p 0.001; pre‐pregnancy BMI: 0.274, p 0.009; gestational age: −0.290, p 0.007). Adiponectin was higher in mothers with gestational diabetes (30.7 ± 6.5 vs. 24.8 ± 8 ng/mL, p 0.044). Leptin was associated with pre‐pregnancy BMI (Spearman's ρ: 0.648, p < 0.0001) and MFG‐E8 to presence of labor and multiple pregnancy (final linear regression model, R2: 0.073, p 0.028, adjusted β coefficients: presence of labor −0.229, p 0.050; twins: −0.192, p 0.099). Milk adiponectin was associated with a greater decrease in length z‐scores from birth to 28 days (Pearson's r: −0.225, p 0.032) and to discharge (Pearson's r: −0.290, p 0.003). Milk MFG‐E8 was lower in milk of mothers whose babies experienced late‐onset sepsis (13.3 ± 5.8 vs. 16.8 ± 6.3 μg/mL, p 0.023). Adipokines levels in preterm human milk are partially related to maternal metabolic status. Milk peptide concentration associates with early neonatal growth trajectories. [ABSTRACT FROM AUTHOR]

Postnatal growth restriction remains one of the most common problems of very preterm infants (VPI). Chorioamnionitis is a frequent cause of prematurity. Both have been related to worse postnatal outcomes. To evaluate the influence of histological chorioamnionitis (CA) on postnatal growth in very premature infants. Retrospective one-to-one matched cohort study assessing growth in infants born at or below 32.0 weeks gestation from mothers for whom histological examination of the placenta was available. Newborns with histological CA were matched and compared with those without it. Postnatal growth was recorded at admission, 14 days of life, 28 days of life and 36 weeks postmenstrual age (PMA). Nutritional support and clinical outcomes were used as covariables. Eighty-eight patients were included: 44 with fetal or/and maternal placental inflammation, and 44 without histological CA (41% with vasculopathy findings and 59% without). Baseline characteristics were similar between the groups. Change in weight z-scores at 14 days of life, 28 days of life, 36 weeks PMA or at discharge were similar in both groups, with a steady fall and no signs of catch-up. No differences were found in enteral and parenteral nutritional intakes between groups. Histological CA did not affect postnatal growth of very preterm infants after matching for birth weight z-scores with non-CA newborns. [ABSTRACT FROM AUTHOR]

DNA methylation (5-methylcytosine, 5 mC) is involved in many cellular processes and is an epigenetic mechanism primarily associated with transcriptional repression. The recent discovery that 5mC can be oxidized to 5-hydromethylcytosine (5hmC) by TET proteins has revealed the "sixth base" of DNA and provides additional complexity to what was originally thought to be a stable repressive mark. However, our knowledge of the genome-wide distribution of 5hmC in different tissues is currently limited. Here, we sought to define loci enriched for 5hmC in the placenta genome by combining oxidative bisulphite (oxBS) treatment with high-density Illumina Infinium HumanMethylation450 methylation arrays and to compare our results with those obtained in brain. Despite identifying over 17,000 high-confidence CpG sites with consistent 5hmC enrichment, the distribution of this modification in placenta is relatively sparse when compared to cerebellum and frontal cortex. Supported by validation using allelic T4 b-glucosyltransferase assays we identify 5hmC at numerous imprinted loci, often overlapping regions associated with parent-oforigin allelic 5mC in both placenta and brain samples. Furthermore, we observe tissue-specific monoallelic enrichment of 5hmC overlapping large clusters of imprinted snoRNAs-miRNAs processed from long noncoding RNAs (lncRNAs) within the DLK1-DIO3 cluster on chromosome 14 and SNRPN-UBE3A domain on chromosome 15. Enrichment is observed solely on the transcribed alleles suggesting 5hmC is positively associated with transcription at these loci. Our study provides an extensive description of the 5hmC/5mC landscape in placenta with our data available at www.humanimprints.net, which represents the most comprehensive resource for exploring the epigenetic profiles associated with human imprinted genes. [ABSTRACT FROM AUTHOR]

Aim: To analyze different methods to assess postnatal growth in a cohort of very premature infants (VPI) in a clinical setting and identify potential early markers of growth failure. Methods: Study of growth determinants in VPI (≤32 weeks) during hospital stay. Nutritional intakes and clinical evolution were recorded. Growth velocity (GV: g/kg/day), extrauterine growth restriction (%) (EUGR: weight < 10th centile, z-score < −1.28) and postnatal growth failure (PGF: fall in z-score > 1.34) at 36 weeks postmenstrual age (PMA) were calculated. Associations between growth and clinical or nutritional variables were explored (linear and logistic regression). Results: Sample: 197 VPI. GV in IUGR patients was higher than in non-IUGRs (28 days of life and discharge). At 36 weeks PMA 66.0% of VPIs, including all but one of the IUGR patients, were EUGR. Prevalence of PGF at the same time was 67.4% (IUGR patients: 48.1%; non-IUGRs: 70.5% (p = 0.022)). Variables related to PGF at 36 weeks PMA were initial weight loss (%), need for oxygen and lower parenteral lipids in the first week. Conclusions: The analysis of z-scores was better suited to identify postnatal growth faltering. PGF could be reduced by minimising initial weight loss and assuring adequate nutrition in patients at risk. [ABSTRACT FROM AUTHOR]

Genomic imprinting is the parent-of-origin dependent monoallelic expression of genes often associated with regions of germline-derived DNA methylation that are maintained as differentially methylated regions (gDMRs) in somatic tissues. This form of epigenetic regulation is highly conserved in mammals and is thought to have co-evolved with placentation. Tissue-specific gDMRs have been identified in human placenta, suggesting that species-specific imprinting dependent on unorthodox epigenetic establishment or maintenance may be more widespread than previously anticipated. Non-canonical imprinting, reliant on differential allelic H3K27me3 enrichment, has been reported in mouse and rat pre-implantation embryos, often overlapping long terminal repeat (LTR)-derived promoters. These non-canonical imprints lose parental allele-specific H3K27me3 specificity, subsequently gaining DNA methylation on the same allele in extra-embryonic tissues resulting in placenta-specific, somatically acquired maternal DMRs. To determine if similar non-canonical imprinting is present in the human placenta, we interrogated allelic DNA methylation for a selected number of loci, including (i) the human orthologues of non-canonical imprinted regions in mouse and rat, (ii) promoters of human LTR-derived transcripts, and (iii) CpG islands with intermediate placenta-specific methylation that are unmethylated in gametes and pre-implantation embryos. We failed to identify any non-canonical imprints in the human placenta whole villi samples. Furthermore, the assayed genes were shown to be biallelically expressed in human pre-implantation embryos, indicating they are not imprinted at earlier time points. Together, our work reiterates the continued evolution of placenta-specific imprinting in mammals, which we suggest is linked to epigenetic differences during the maternal-to-embryo transition and species-specific integration of retrotransposable elements., (© The Author(s) 2025. Published by Oxford University Press.)

Objectives: While the target of growth of very preterm infants (VPIs) during Neonatal Intensive care unit (NICU) admission is still controversial, the most accepted objective is that they should follow their intrauterine trajectory in terms of growth and body composition (BC). BC is difficult to measure in clinical daily routine but proxies like body ratios and skinfolds have been used. Prenatal and postnatal factors can influence the growth and BC of VPIs in the NICU., Design, Setting and Patients: We conducted a case-control study, including preterm infants born before 32 weeks gestational age at term-corrected age (TCA) and healthy late preterm or term infants as controls and also a retrospective cohort analysis of factors influencing VPI's BC at discharge. Patients had an anthropometric evaluation at discharge including weight, length, head circumference, body circumferences (waist, arm), skinfolds and abdominal ultrasound (US)., Results: 191 VPIs were eligible for discharge visits, but only 83 had a complete evaluation and we collected 26 controls. VPIs at TCA were smaller in weight, length and head circumference but had greater ratios (arm fat-to-circumference and waist-to-length). Abdominal fat assessed by US was smaller in VPIs compared with term infants. Intrauterine growth restriction-VPI remained smaller at TCA but experienced less weight z-score loss. Sex did not seem to influence growth and BC proxies at TCA. Higher nutritional support during the first 2 weeks of life was related to a lower loss of length z-scores, and exclusive human milk feeding correlates with arm fat-to-circumference ratio., Conclusions: Growth and BC of VPIs can be approached using simpler measures in clinical practice. Arm skinfolds and arm circumferences point to a greater adiposity of VPIs at TCA compared with term infants, while US does not show a greater visceral adiposity. Nutritional factors played a small effect in BC at the time of discharge., Competing Interests: Competing interests: There are no competing interests., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)