Obstetric mode of delivery and child psychological development

Background/aims: Objective of the current thesis is to investigate the potential impact of birth by Caesarean section (CS) on child psychological development, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), behavioural difficulties and school performance. Structure/methods: Published literature to date on birth by CS, ASD and ADHD was reviewed (Chapter 2). Data from the UK Millennium Cohort Study (MCS) were analysed to determine the association between CS and ASD, ADHD and parent-reported behavioural difficulties (Chapter 3). The Swedish National Registers were used to further assess the association with ASD, ADHD and school performance (Chapters 4-6). Results: In the review, children born by CS were 23% more likely to be diagnosed with ASD after controlling for potential confounders. Only two studies reported adjusted estimates on the association between birth by CS and ADHD, results were conflicting and limited. CS was not associated with ASD, ADHD or behavioural difficulties in the UK MCS. In the Swedish National Registers, children born by CS were more likely to be diagnosed with ASD or ADHD. The association with elective CS did not persist when compared amongst siblings. There was little evidence of an association between birth by elective CS and poor school performance. Children born by elective CS had slight reduction in school performance. Conclusions: The lack of association with the elective CS in the sibling design studies indicates that the association in the population is most probably due to confounding. A small but significant association was found between birth by CS and school performance. However, the effect may have been due to residual confounding or confounding by indication and should be interpreted with caution. The overall conclusion is that birth by CS does not appear to have a causal relationship with the aspects of child psychological development investigated.

Nutritional status of lactating mothers and their children 6-23 months of age in pre- and post-harvest seasons in two agro-ecological zones of rural Ethiopia

The objective of this study was to assess seasonal variation in nutritional status and feeding practices among lactating mothers and their children 6-23 months of age in two different agro-ecological zones of rural Ethiopia (lowland zone and midland zone). Food availability and access are strongly affected by seasonality in Ethiopia. However, there are few published data on the effects of seasonal food fluctuations on nutritional status and dietary diversity patterns of mothers and children in rural Ethiopia. A longitudinal study was conducted among 216 mothers in two agro-ecological zones of rural Ethiopia during pre and post-harvest seasons. Data were collected on many parameters including anthropometry, blood levels of haemoglobin and ferritin and zinc, urinary iodine levels, questionnaire data regarding demographic and household parameters and health issues, and infant and young child feeding practices, 24 h food recall to determine dietary diversity scores, and household use of iodized salt. Chi-square and multivariable regression models were used to identify independent predictors of nutritional status. A wide variety of results were generated including the following highlights. It was found that 95.4% of children were breastfed, of whom 59.7% were initially breastfed within one hour of birth, 22.2% received pre-lacteal feeds, and 50.9% of children received complementary feedings by 6 months of age. Iron deficiency was found in 44.4% of children and 19.8% of mothers. Low Zinc status was found in 72.2% of children and 67.3% of mothers. Of the study subjects, 52.5% of the children and 19.1% of the mothers were anaemic, and 29.6% of children and 10.5% of mothers had iron deficiency anaemia. Among the mothers with low serum iron status, 81.2% and 56.2% of their children had low serum zinc and iron, respectively. Similarly, among the low serum zinc status mothers, 75.2% and 45.3% of their children had low serum in zinc and iron, respectively. There was a strong correlation between the micronutrient status of the mothers and the children for ferritin, zinc and haemoglobin (P <0.001). There was also statistically significant difference between agro-ecological zones for micronutrient deficiencies among the mothers (p<0.001) but not for their children. The majority (97.6%) of mothers in the lowland zone were deficient in at least one micronutrient biomarker (zinc or ferritin or haemoglobin). Deficiencies in one, two, or all three biomarkers of micronutrient status were observed in 48.1%, 16.7% and 9.9% of mothers and 35.8%, 29.0%, and 23.5%, of children, respectively. Additionally, about 42.6% of mothers had low levels of urinary iodine and 35.2% of lactating mothers had goitre. Total goitre prevalence rates and urinary iodine levels of lactating mothers were not significantly different across agro-ecological zones. Adequately iodised salt was available in 36.6% of households. The prevalence of anaemia increased from post-harvest (21.8%) to pre-harvest seasons (40.9%) among lactating mothers. Increases were from 8.6% to 34.4% in midland and from 34.2% to 46.3% in lowland agro-ecological zones. Fifteen percent of mothers were anaemic during both seasons. Predictors of anaemia were high parity of mother and low dietary diversity. The proportion of stunted and underweight children increased from 39.8% and 27% in post-harvest season to 46.0% and 31.8% in pre-harvest season, respectively. However, wasting in children decreased from 11.6% to 8.5%. Major variations in stunting and underweight were noted in midland compared to lowland agroecological zones. Anthropometric measurements in mothers indicated high levels of undernutrition. The prevalence of undernutrition in mothers (BMI <18.5kg/m2) increased from 41.7 to 54.7% between post- and pre-harvest seasons. The seasonal effect was generally higher in the midland community for all forms of malnutrition. Parity, number of children under five years and regional variation were predictors of low BMI among lactating mothers. There were differences in minimum meal frequency, minimum acceptable diet and dietary diversity in children in pre-harvest and post-harvest seasons and these parameters were poor in both seasons. Dietary diversity among mothers was higher in lowland zone but was poor in both zones across the seasons. In conclusion, malnutrition and micronutrient deficiencies are very prevalent among lactating mothers and their children 6-23 months old in the study areas. There are significant seasonal variations in malnutrition and dietary diversity, in addition to significant differences between lowland and midland agro-ecological zones. These findings suggest a need to design effective preventive public health nutrition programs to address both the mothers’ and children’s needs particularly in the preharvest season.

Investigating metabolomic biomarkers of hypoxic ischaemic encephalopathy

Background An early objective biomarker to predict the severity of hypoxic-ischaemic encephalopathy (HIE) and identify infants suitable for intervention remains elusive. This thesis aims to progress metabolomic markers of HIE through a pipeline of biomarker discovery and validation by employing a novel untargeted mass spectrometry metabolomic method. Methodology Term infants with perinatal asphyxia were recruited, all having umbilical cord blood (UCB) drawn and biobanked within three hours of birth. HIE was defined by Sarnat score at 24hours and continuous multichannel-EEG. Infant neurodevelopment was assessed at 36-42 months using the Bayley Scales of Infant and Toddler Development Ed. III (BSID-III). Untargeted metabolomic analysis of UCB was performed using direct injection FT-ICR mass spectrometry (DI FT-ICR MS). Putative metabolite annotations and lipid classes were assigned and pathway analysis was performed. Results Untargeted metabolomic analysis: Thirty enrolled infants were diagnosed with HIE, including 17 mild, 8 moderate, and 5 severe cases. Pathway analysis revealed that ΔHIE was associated with a 50% and 75% perturbation of tryptophan and pyrimidine metabolism respectively, alongside alterations in amino acid pathways. Significant metabolite alterations were detected from six putatively identified lipid classes including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids and prenol lipids. Outcome prediction: Metabolite model scores significantly correlated with outcome R=0.429 (model A) and R=0.549 (model B) respectively. Model B demonstrates the potential to predict both severe outcome (AUROC of 0.915) and intact survival (AUROC of 0.800). The effect of haemolysis: On average 5% of polar and 1.5% of non-polar features were altered between paired haemolysed and clean samples. However unsupervised multivariate analysis concluded that the preanalytical variability introduced by haemolysis was negligible compared with the inherent biological inter-individual variability. Conclusion This research has employed untargeted metabolomics to identify potential early cord blood biomarkers of HIE and has performed the technical validation of previously proposed markers.

Postoperative analgesic effect, of preoperatively administered dexamethasone, after operative fixation of fractured neck of femur: randomised, double blinded controlled study.

Background: Fractured neck of femur is a common cause of hospital admission in the elderly and usually requires operative fixation. In a variety of clinical settings, preoperative glucocorticoid administration has improved analgesia and decreased opioid consumption. Our objective was to define the postoperative analgesic efficacy of single dose of dexamethasone administered preoperatively in patients undergoing operative fixation of fractured neck of femur. Methods: Institutional ethical approval was granted and written informed consent was obtained from each patient. Patients awaiting for surgery at Cork University Hospital were recruited between July 2009 and August 2012. Participating patients, scheduled for surgery were randomly allocated to one of two groups (Dexamethasone or Placebo). Patients in the dexamethasone group received a single dose of intravenous dexamethasone 0.1 mg kg -1 immediately preoperatively. Patients in the placebo group received the same volume of normal saline. Patients underwent operative fixation of fractured neck of femur using standardised spinal anaesthesia and surgical techniques. The primary outcome was pain scores at rest 6 h after the surgery. Results: Thirty seven patients were recruited and data from thirty patients were analysed. The groups were similar in terms of patient characteristics. Pain scores at rest 6 h after the surgery (the principal outcome) were lesser in the dexamethasone group compared with the placebo group [0.8(1.3) vs. 3.9(2.9), mean(SD) p = 0.0004]. Cumulative morphine consumption 24 h after the surgery was also lesser in the dexamethasone group [7.7(8.3) vs. 15.1(9.4), mean(SD) mg, p = 0.04]. Conclusions: A single dose of intravenous dexamethasone 0.1 mg kg -1 administered before operative fixation of fractured neck of femur improve significantly the early postoperative analgesia. Trial registration: ClinicalTrials.gov identifier: NCT01550146, date of registration: 07/03/2012

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.