Late-onset vitamin K deficiency bleeding in an extremely preterm infant fed an exclusively human milk-based diet.

All newborns need extra phylloquinone (vitamin K1; K1) to prevent vitamin K deficiency bleeding (VKDB). In preterm babies, the main sources are prophylactic K1 given at birth and parenteral and/or enteral feeding thereafter. Preterm babies are at risk of late-onset VKDB if ongoing K1 supplementation is inadequate. For extremely preterm infants fed an exclusive human milk diet, the low K1 content of human milk may predispose them to vitamin K deficiency. Human milk fortification with either bovine milk-derived fortifier or human milk-based fortifier (HMF) made from pooled donor milk is a widely used strategy to improve the micronutrient and growth status of preterm infants. However, the K1 content of HMF is markedly lower than that of bovine-based preparations. We present an unusual case of late-onset VKDB in an extremely preterm infant who received an exclusive human milk diet and HMF and quantify total K1 intake prior to the bleeding.

Effect of an Exclusive Human Milk Diet on the Gut Microbiome in Preterm Infants: A Randomized Clinical Trial.

Importance: The effect of using an exclusive human milk diet compared with one that uses bovine products in preterm infants is uncertain, but some studies demonstrate lower rates of key neonatal morbidities. A potential mediating pathway is the gut microbiome. Objective: To determine the effect of an exclusive human milk diet on gut bacterial richness, diversity, and proportions of specific taxa in preterm infants from enrollment to 34 weeks' postmenstrual age. Design, Setting, and Participants: In this randomized clinical trial conducted at 4 neonatal intensive care units in the United Kingdom from 2017 to 2020, microbiome analyses were blind to group. Infants less than 30 weeks' gestation who had only received own mother's milk were recruited before 72 hours of age. Statistical analysis was performed from July 2019 to September 2021. Interventions: Exclusive human milk diet using pasteurized human milk for any shortfall in mother's own milk supply and human milk-derived fortifiers (intervention) compared with bovine formula and bovine-derived fortifier (control) until 34 weeks' postmenstrual age. Fortifier commenced less than 48 hours of tolerating 150 mL/kg per day. Main Outcomes and Measures: Gut microbiome profile including alpha and beta diversity, and presence of specific bacterial taxa. Results: Of 126 preterm infants enrolled in the study, 63 were randomized to control (median [IQR] gestation: 27.0 weeks [26.0-28.1 weeks]; median [IQR] birthweight: 910 g [704-1054 g]; 32 [51%] male) and 63 were randomized to intervention (median [IQR] gestation: 27.1 weeks [25.7-28.1 weeks]; median [IQR] birthweight: 930 g [733-1095 g]; 38 [60%] male); 472 stool samples from 116 infants were analyzed. There were no differences in bacterial richness or Shannon diversity over time, or at 34 weeks between trial groups. The exclusive human milk diet group had reduced relative abundance of Lactobacillus after adjustment for confounders (coefficient estimate, 0.056; P = .03), but not after false discovery rate adjustment. There were no differences in time to full feeds, necrotizing enterocolitis, or other key neonatal morbidities. Conclusions and Relevance: In this randomized clinical trial in preterm infants using human milk-derived formula and/or fortifier to enable an exclusive human milk diet, there were no effects on overall measures of gut bacterial diversity but there were effects on specific bacterial taxa previously associated with human milk receipt. These findings suggest that the clinical impact of human milk-derived products is not modulated via microbiomic mechanisms. Trial Registration: ISRCTN trial registry identifier: ISRCTN16799022.

Randomised controlled trial of human derived breast milk fortifier versus bovine milk fortifier on body composition in very preterm babies.

BACKGROUND: Preterm infants receiving a diet of exclusive human milk compared to predominantly preterm formula have lower weight and non-adipose tissue mass by term. Human milk fortification is recommended. However, it is not known if the protein source affects body composition. AIMS: To compare the effect of an exclusive human milk based diet (intervention) with a diet containing cow milk products (control) on body composition. PARTICIPANTS: Infants born below 30 weeks gestation. STUDY DESIGN: Randomised multicentre, open label, controlled trial. Infants preferentially received their own mother's milk. Infants were randomised to either an exclusive human milk diet (human milk formula to make up a shortfall in own mother's milk and human milk derived fortifier) or cow milk-based supplementation (preterm formula to make up a shortfall in own mother's milk and cow milk-based fortifier). Fortification began at an enteral intake of 150 ml/kg/day. Infants underwent whole-body magnetic resonance imaging at term. PRIMARY OUTCOME: Body composition (adipose tissue (ATM) and non-adipose tissue mass (N-ATM)) at term. RESULTS: We randomly assigned 38 infants to intervention (n = 19) and control arms (n = 19). Primary outcomes were analysed in 15 infants in the intervention arm and 12 in the control arm. The estimates of the effect of the intervention following adjustment for length and sex, were non-significant (ATM (kg): 0.137, 95 % confidence interval (CI) -0.01, 0.29; N-ATM: -0.137; -0.01, 0.29). CONCLUSIONS: We identified no clinically relevant differences in body composition in preterm babies <30 weeks gestation receiving a macronutrient-equivalent exclusive human milk diet compared with a diet containing cow milk products.

Less-Invasive Surfactant Administration for Neonatal Respiratory Distress Syndrome: A Consensus Guideline.

INTRODUCTION: Less-invasive surfactant administration (LISA) is a method of surfactant delivery to preterm infants for treating respiratory distress syndrome (RDS), which can reduce the composite risk of death or bronchopulmonary dysplasia and the time on mechanical ventilation. METHODS: A systematic literature search of studies published up to April 2021 on minimally invasive catheter surfactant delivery in preterm infants with RDS was conducted. Based on these studies, with parental feedback sought via an online questionnaire, 9 UK-based specialists in neonatal respiratory disease developed their consensus for implementing LISA. Recommendations were developed following a modified, iterative Delphi process using a questionnaire employing a 9-point Likert scale and an a priori level of agreement/disagreement. RESULTS: Successful implementation of LISA can be achieved by training the multidisciplinary team and following locally agreed guidance. From the time of the decision to administer surfactant, LISA should take <30 min. The comfort of the baby and requirements to maintain non-invasive respiratory support are important. While many infants can be managed without requiring additional sedation/analgesia, fentanyl along with atropine may be considered. Parents should be provided with sufficient information about medication side effects and involved in treatment discussions. CONCLUSION: LISA has the potential to improve outcomes for preterm infants with RDS and can be introduced as a safe and effective part of UK-based neonatal care with appropriate training.

Prophylactic Paracetamol After Meningococcal B Vaccination Reduces Postvaccination Fever and Septic Screens in Hospitalized Preterm Infants.

BACKGROUND: Following the introduction of the 4CMenB (Bexsero, GlaxoSmithKline, Rixensart, Belgium) vaccine against Meningococcal B into the UK vaccination schedule, Public Health England advised paracetamol to be given prophylactically with the vaccine. This was based on observations of increased postvaccination febrile reactions in term infants. Evidence in preterm infants was lacking. We aimed to evaluate whether (i) 4CmenB is associated with an increase in adverse events (AEs) in the 48 hours after vaccination in preterm infants and (ii) the impact of prophylactic paracetamol on AEs. METHODS: Retrospective case-note review of preterm infants, within a UK level 3 neonatal unit, receiving first or second 4CMenB vaccination, within 3 periods; (i) period 1 (pre-4CMenB): September 2014-September 2015; (ii) period 2 (4CMenB without prophylactic paracetamol): September 2015-March 2016 and (iii) period 3 (4CMenB with prophylactic paracetamol): June 2016-May 2018. Data were collected on a predefined list of postvaccination AEs within 48 hours of vaccination: (i) number (%) of infants with temperature >37.5°C; (ii) highest temperature (°C); (iii) number (%) of infants receiving evaluation for sepsis and (iv) number (%) of infants receiving intravenous antibiotics. RESULTS: Ninety-five vaccination episodes were included. Compared with the pre-4CMenB (period 1), more infants developed temperature >37.5°C, needed partial septic screens and had intravenous antibiotics when 4CMenB was introduced without paracetamol prophylaxis (period 2). Paracetamol prophylaxis (period 3) with 4CMenB resulted in fewer infants experiencing postvaccination fever and antibiotic administration comparable to period 1. CONCLUSIONS: 4CMenB is associated with AEs in hospitalized preterm infants. Prophylactic paracetamol administration attenuates this.

Direct Single-Cell Analysis of Human Polar Bodies and Cleavage-Stage Embryos Reveals No Evidence of the Telomere Theory of Reproductive Ageing in Relation to Aneuploidy Generation.

Reproductive ageing in women, particularly after the age of 35, is associated with an exponential increase in the proportion of chromosomally abnormal oocytes produced. Several hypotheses have attempted to explain this observation, including the 'limited oocyte pool' hypothesis and the 'two-hit' hypothesis, the latter explaining that a depletion in oocyte quality with age results from the multiple opportune stages for errors to occur in meiosis. Recently however, the telomere theory of reproductive ageing in women has been proposed. This suggests that shortened telomeres in oocytes of women of advanced maternal age render oocytes unable to support fertilization and embryogenesis. Despite a credible rationale for the telomere theory of reproductive ageing in women, very few studies have assessed telomere length directly in human oocytes or preimplantation embryos. Therefore, we directly assessed relative telomere length in first polar bodies and blastomeres from cleavage stage (day 3) embryos. In both cell types we tested the hypothesis that (1) older women have shorter telomeres and (2) chromosomally abnormal (aneuploid) gametes/embryos have shorter telomeres. In all cases, we found no evidence of altered telomere length associated with age-related aneuploidy.

Telomere Biology and Human Phenotype.

Telomeres are nucleoprotein structures that cap the end of each chromosome arm and function to maintain genome stability. The length of telomeres is known to shorten with each cell division and it is well-established that telomere attrition is related to replicative capacity in vitro. Moreover, telomere loss is also correlated with the process of aging in vivo. In this review, we discuss the mechanisms that lead to telomere shortening and summarise telomere homeostasis in humans throughout a lifetime. In addition, we discuss the available evidence that shows that telomere shortening is related to human aging and the onset of age-related disease.

Preterm infants have significantly longer telomeres than their term born counterparts.

There are well-established morbidities associated with preterm birth including respiratory, neurocognitive and developmental disorders. However several others have recently emerged that characterise an 'aged' phenotype in the preterm infant by term-equivalent age. These include hypertension, insulin resistance and altered body fat distribution. Evidence shows that these morbidities persist into adult life, posing a significant public health concern. In this study, we measured relative telomere length in leukocytes as an indicator of biological ageing in 25 preterm infants at term equivalent age. Comparing our measurements with those from 22 preterm infants sampled at birth and from 31 term-born infants, we tested the hypothesis that by term equivalent age, preterm infants have significantly shorter telomeres (thus suggesting that they are prematurely aged). Our results demonstrate that relative telomere length is highly variable in newborn infants and is significantly negatively correlated with gestational age and birth weight in preterm infants. Further, longitudinal assessment in preterm infants who had telomere length measurements available at both birth and term age (n = 5) suggests that telomere attrition rate is negatively correlated with increasing gestational age. Contrary to our initial hypothesis however, relative telomere length was significantly shortest in the term born control group compared to both preterm groups and longest in the preterm at birth group. In addition, telomere lengths were not significantly different between preterm infants sampled at birth and those sampled at term equivalent age. These results indicate that other, as yet undetermined, factors may influence telomere length in the preterm born infant and raise the intriguing hypothesis that as preterm gestation declines, telomere attrition rate increases.

Pilot evaluation of parental and professional views regarding consent in neonatal medicine by telephone interviews and questionnaires.

OBJECTIVE: The objectives of the study were to determine (1) parental and professional views regarding the type of consent required for common neonatal interventions and (2) whether there has been a change in professional understanding regarding the requirements of consent since the last UK survey in 2003. DESIGN: Cohort study of (1) parents of babies admitted to a single-centre tertiary neonatal unit and (2) healthcare professionals. METHODS: The views of 8 parents of former neonatal patients and 69 neonatal professionals were sought using online and telephone survey methodology regarding 20 neonatal interventions and whether implied consent, explicit verbal consent or explicit written consent should be obtained. RESULTS: Agreement, defined as both parental and professional consensus on the type of consent required, was present in 12/20 of the interventions. Comparison between professional views in 2003 demonstrated a change regarding type of consent for 50% of interventions with a shift towards obtaining explicit written consent certain treatments. CONCLUSIONS: The study indicates areas of consensus that exist between parents and professionals regarding consent for common neonatal interventions and a change in professional views regarding consent since the last UK survey in 2003. These data might help inform the development of national guidance for how professionals should obtain consent in neonatology.

Telomere length analysis and preterm infant health: the importance of assay design in the search for novel biomarkers.

Preterm infants develop an 'aged' phenotype in comparison with term-born infants, one component of which is adverse metabolic health and, therefore, long-term health follow-up is warranted to identify morbidity. In light of this, the identification and use of biomarkers to aid with prognosis would be a welcome development. Telomeres are repeat sequences at the ends of each chromosome arm known to shorten as a consequence of cellular aging, and in relation to several disease conditions. The hypothesis that expreterm infants manifest alterations in telomere attrition rate is, therefore, one of interest. Analysis of telomere length maybe a plausible technique to predict prognosis in relation to preterm birth, and early life environmental and nutritional exposures. In this article, we review the literature on telomere length analysis in the preterm infant population and examine the tools available to measure telomere length.

Preterm nutritional intake and MRI phenotype at term age: a prospective observational study.

OBJECTIVE: To describe (1) the relationship between nutrition and the preterm-at-term infant phenotype, (2) phenotypic differences between preterm-at-term infants and healthy term born infants and (3) relationships between somatic and brain MRI outcomes. DESIGN: Prospective observational study. SETTING: UK tertiary neonatal unit. PARTICIPANTS: Preterm infants (<32 weeks gestation) (n=22) and healthy term infants (n=39) MAIN OUTCOME MEASURES: Preterm nutrient intake; total and regional adipose tissue (AT) depot volumes; brain volume and proximal cerebral arterial vessel tortuosity (CAVT) in preterm infants and in term infants. RESULTS: Preterm nutrition was deficient in protein and high in carbohydrate and fat. Preterm nutrition was not related to AT volumes, brain volume or proximal CAVT score; a positive association was noted between human milk intake and proximal CAVT score (r=0.44, p=0.05). In comparison to term infants, preterm infants had increased total adiposity, comparable brain volumes and reduced proximal CAVT scores. There was a significant negative correlation between deep subcutaneous abdominal AT volume and brain volume in preterm infants (r=-0.58, p=0.01). CONCLUSIONS: Though there are significant phenotypic differences between preterm infants at term and term infants, preterm macronutrient intake does not appear to be a determinant. Our preliminary data suggest that (1) human milk may exert a beneficial effect on cerebral arterial vessel tortuosity and (2) there is a negative correlation between adiposity and brain volume in preterm infants at term. Further work is warranted to see if our findings can be replicated and to understand the causal mechanisms.

Dilated neonatal cisterna magna and Marfan syndrome.

The authors report the incidental finding of a dilated cisterna magna with an abnormal configuration to the falx in a newborn infant with Marfan syndrome who was recruited to a research study involving whole body MRI. To our knowledge, dilation of the cisterna magna has not previously been reported in patients with Marfan syndrome. Potential implications for antenatal diagnosis, the ethics of recruiting healthy volunteers for research and directions for future work are discussed.

Assessing the impact of preterm nutrition.

Growth is the traditional means of assessing the impact of newborn nutrition. We argue that this approach is flawed as the optimum pattern of postnatal growth after extremely preterm birth is unknown and both growth restraint and growth acceleration are associated with beneficial as well as adverse outcomes. Clinical trials examining nutritional regimens should be designed to achieve specific patterns of postnatal growth. Clinical practice should include the systematic capture of neonatal nutritional intake. As the ultimate goals are adult health and wellbeing, long-term follow-up is essential.