Nutrition, growth and body composition in preterm infants

The goal of neonatal nutrition in the preterm infant is to achieve postnatal growth and body composition approximating that of a normal fetus of the same postmenstrual age and to obtain a functional outcome comparable to infants born at term. However, in clinical practice such a pattern is seldom achieved, with growth failure and altered body composition being extensively reported. The BabyGrow preterm nutrition study was a longitudinal, prospective, observational study designed to investigate nutrition and growth in 59 preterm infants following the implementation of evidence-based nutrition guidelines in the neonatal unit at Cork University Maternity Hospital. Nutrient delivery was precisely measured during the entire hospital stay and intakes were compared with current international recommendations. Barriers to nutrient delivery were identified across the phases of nutritional support i.e. exclusive parenteral nutrition and transition (establishment of enteral feeds) phases of nutrition and nutritional strategies to optimise nutrient delivery were proposed according to these phases. Growth was measured from birth up to 2 months corrected age and body composition was assessed in terms of fat mass and lean body mass by air displacement plethysmography (PEA POD) at 34 weeks gestation, term corrected age and 2 months corrected age. Anthropometric and body composition data in the preterm cohort were compared with a term reference group from the Cork BASELINE Birth Cohort Study (n=1070) at similar time intervals. The clinical and nutritional determinants of growth and body composition during the neonatal period were reported for the first time. These data have international relevance, informing authoritative agencies developing evidence-based practice guidelines for neonatal nutritional support. In the future, the nutritional management of preterm infants may need to be individualised to consider gestational age, birth weight as well as preterm morbidity.

Improving the care of preterm infants: before, during, and after, stabilisation in the delivery room

Introduction Up to 10% of infants require stabilisation during transition to extrauterine life. Enhanced monitoring of cardiorespiratory parameters during this time may improve stabilisation outcomes. In addition, technology may facilitate improved preparation for delivery room stabilisation as well as NICU procedures, through educational techniques. Aim To improve infant care 1) before birth via improved training, 2) during stabilisation via enhanced physiological monitoring and improved practice, and 3) after delivery, in the neonatal intensive care unit (NICU), via improved procedural care. Methods A multifaceted approach was utilised including; a combination of questionnaire based surveys, mannequin-based investigations, prospective observational investigations, and a randomised controlled trial involving preterm infants less than 32 weeks in the delivery room. Forms of technology utilised included; different types of mannequins including a CO2 producing mannequin, qualitative end tidal CO2 (EtCO2) detectors, a bespoke quantitative EtCO2 detector, and annotated videos of infant stabilisation as well as NICU procedures Results Manual ventilation improved with the use of EtCO2 detection, and was positively assessed by trainees. Quantitative EtCO2 detection in the delivery room is feasible, EtCO2 increased over the first 4 minutes of life in preterm infants, and EtCO2 was higher in preterm infants who were intubated. Current methods of heart rate assessment were found to be unreliable. Electrocardiography (ECG) application warrants further evaluation. Perfusion index (PI) monitoring utilised in the delivery room was feasible. Video recording technology was utilised in several ways. This technology has many potential benefits, including debriefing and coaching in procedural healthcare, and warrants further evaluation. Parents would welcome the introduction of webcams in the NICU. Conclusions I have evaluated new methods of improving infant care before, during, and after stabilisation in the DR. Specifically, I have developed novel educational tools to facilitate training, and evaluated EtCO2, PI, and ECG during infant stabilisation. I have identified barriers in using webcams in the NICU, to now be addressed prior to webcam implementation.

Infant nutrition and the gut microbiota

Establishment of the intestinal microbiota commences at birth and this colonisation is influenced by a number of factors including mode of delivery, gestational age, mode of feeding, environmental factors and host genetics. As this initial establishment may well influence the health of an individual later in life, it is imperative to understand this process. Therefore, this thesis set out to investigate how early infant nutrition influences the development of a healthy gut microbiota. As part of the INFANTMET project, the intestinal microbiota of 199 breastfed infants was investigated using both culture-dependent and culture-independent approaches. This study revealed that delivery mode and gestational age had a significant impact on early microbial communities. In order to understand host genotype-microbiota interactions, the gut microbiota composition of dichorionic triplets was also investigated. The results suggested that initially host genetics play a significant role in the composition of an individual’s gut microbiota, but by month 12 environmental factors are the major determinant. To investigate the origin of hydrogen sulphide in a case of nondrug- induced sulfhemoglobinemia in a preterm infant, the gut microbiota composition was determined. This analysis revealed the presence of Morganella morganii, a producer of hydrogen sulphide and hemolysins, at a relative abundance 38%, which was not detected in control infants. Following on from this, the negative and short term consequences of intrapartum antibiotic prophylaxis exposure on the early infant intestinal microbiota composition were demonstrated, particularly in breast-fed infants, which are recovered by day 30. Finally, the composition of the breast milk microbiota over the first three months of life was characterised. A core of 12 genera were identified amongst women and the remainder comprised some 195 genera which were individual specific and subject to variations over time. The results presented in this thesis have demonstrated that the development of the infant gut microbiota is complex and highly individual. Clear alterations in the intestinal microbiota establishment process in C-section delivered, preterm and antibiotic exposed infants were shown. Taken together, long-term health benefits for infants, particularly those vulnerable groups, may be conferred through the design of probiotic and prebiotic food ingredients and supplements.

The relationship between 25-hydroxyvitamin D concentration in early pregnancy and pregnancy outcomes in a large, prospective cohort

Vitamin D insufficiency and deficiency have been associated with an increased risk of adverse pregnancy outcomes. Controversy remains as findings have been inconsistent between disparate populations. The aim of this study was to investigate the relationship between vitamin D status and pregnancy outcomes in a large, prospective pregnancy cohort. 25-Hydroxyvitamin D concentration was analysed in serum samples collected at 15 weeks of gestation from 1710 New Zealand women participating in a large, observational study. Associations between vitamin D status and pre-eclampsia, preterm birth, small for gestational age (SGA) and gestational diabetes were investigated. The mean 25-hydroxyvitamin D concentration was 72·9 nmol/l. In all, 23 % had 25-hydroxyvitamin D concentrations <50 nmol/l, and 5 % of participants had concentrations <25 nmol/l. Women with 25-hydroxyvitamin D concentrations <75 nmol/l at 15 weeks of gestation were more likely to develop gestational diabetes mellitus than those with concentrations >75 nmol/l (OR 2·3; 95 % CI 1·1, 5·1). However, this effect was not significant when adjustments were made for BMI and ethnicity (OR 1·8; 95 % CI 0·8, 4·2). 25-Hydroxyvitamin D concentration at 15 weeks was not associated with development of pre-eclampsia, spontaneous preterm birth or SGA infants. Pregnancy complications were low in this largely vitamin D-replete population.

Establishment and development of infant gut microbiota

The nascent gut microbiota at birth is established in concert with numerous developmental parameters. Here, in the INFAMTET study, we chronicled the impact of some factors which are key determinants of the infant gut microbiota, namely; mode of birth, gestational age, and type of feeding. We determined that the aggregated microbiota profile of naturally delivered, initially breastfed infants are relatively stable from one week to six months of age and are not significantly altered by increased duration of breastfeeding. Contrastingly, there is significant development of the microbiota profile of C-section delivered infants, and this development is significantly influenced by breastfeeding duration. Preterm infants, born by either mode of birth, initially have a high proportion of Proteobacteria, and demonstrate significant development of the gut microbiota from week 1 to later time-points. The microbiota is still slightly, but significantly, affected by birth mode at one year of age although no specific genera were found to be significantly altered in relative abundance. By two years of age, there is no effect of either birth mode or gestational age. However this does not preclude the possibility that symptoms developed later in life, which are associated with preterm or C-section birth, are as a result of the early perturbation of the neonatal gut microbiota. It is likely that the combination of relatively low exposure (breast fed), high exposure (formula fed) or delayed exposure (C-section and preterm) to specific antigens and the resulting inflammatory responses, in this crucial window of host-microbiota interaction, influence systemic health of the individual throughout life.

Treatment trials for neonatal seizures: the effect of design on sample size

Neonatal seizures are common in the neonatal intensive care unit. Clinicians treat these seizures with several anti-epileptic drugs (AEDs) to reduce seizures in a neonate. Current AEDs exhibit sub-optimal efficacy and several randomized control trials (RCT) of novel AEDs are planned. The aim of this study was to measure the influence of trial design on the required sample size of a RCT. We used seizure time courses from 41 term neonates with hypoxic ischaemic encephalopathy to build seizure treatment trial simulations. We used five outcome measures, three AED protocols, eight treatment delays from seizure onset (Td) and four levels of trial AED efficacy to simulate different RCTs. We performed power calculations for each RCT design and analysed the resultant sample size. We also assessed the rate of false positives, or placebo effect, in typical uncontrolled studies. We found that the false positive rate ranged from 5 to 85% of patients depending on RCT design. For controlled trials, the choice of outcome measure had the largest effect on sample size with median differences of 30.7 fold (IQR: 13.7–40.0) across a range of AED protocols, Td and trial AED efficacy (p<0.001). RCTs that compared the trial AED with positive controls required sample sizes with a median fold increase of 3.2 (IQR: 1.9–11.9; p<0.001). Delays in AED administration from seizure onset also increased the required sample size 2.1 fold (IQR: 1.7–2.9; p<0.001). Subgroup analysis showed that RCTs in neonates treated with hypothermia required a median fold increase in sample size of 2.6 (IQR: 2.4–3.0) compared to trials in normothermic neonates (p<0.001). These results show that RCT design has a profound influence on the required sample size. Trials that use a control group, appropriate outcome measure, and control for differences in Td between groups in analysis will be valid and minimise sample size.