Introduction: Conventional ultrasound has been used in the management of early pregnancy complications. Common clinical situations that are encountered include pregnancies of unknown location (PUL) defined as a woman with a positive pregnancy test, but when no intra or extra-uterine pregnancy is visualised on transvaginal sonography (TVS); intra-uterine pregnancies of uncertain viability (IPUV) defines as when an intrauterine gestational sac (<20mm mean diameter) is seen on ultrasonography with no visible yolk sac or embryo, or an embryo of <7mm crown- rump length with no visible heart activity; and recurrent pregnancy losses (RPL). Emerging evidence suggests that novel strategies may be developed to predict early pregnancy complications such as miscarriage using B mode ultrasound imaging and advanced three-dimensional 3D technology, alongside early pregnancy biochemical parameters. These strategies can be assessed prior to conception, at implantation and subsequently in the early stages of pregnancy. In this thesis we describe a series of studies to evaluate the role of ultrasound and biochemical markers for the prediction of early pregnancy complications in relation to these three time periods. Methods: Pre-conception, we used 3D ultrasound to study longitudinal changes in endometrial morphology and vascularity, the influence of physical injury to the endometrium on these parameters and their relationship with implantation success. We investigated the relationship between the ovulation-implantation (OI) time interval and subsequent implantation or early pregnancy failure. Post-conception, we studied PUL and IPUV. In the PUL group, ultrasonography in combination with serum biochemical markers were used to validate the role of mathematical logistic regression models for predicting pregnancy location and viability. We investigated the performance of biochemical markers in urine to assess whether measurements of urine markers can replace serum markers for the management of PUL. In the IPUV group, we established ultrasound criteria that can be used to definitively diagnose miscarriage. In addition, we studied the growth of these pregnancies and its relationship with pregnancy viability and the appearance of early embryonic structures in the gestational sac. Results: We have provided evidence to support the view that endometrial biopsy enhances endometrial vascularity in women with a history of RPL. We have suggested a safe approach to characterise PUL and have shown that logistic regression-based prediction models can reliably be used and further developed to predict the outcome in PUL, independent of the timing of serum biochemistry. In addition, we have shown a potential role for urine pregnancy biochemistry in the management of PUL. We have developed new reliable definitions to diagnose miscarriage, which have now been adopted both in the UK and internationally. Furthermore, we found that, gestation sac growth is not a safe indicator of pregnancy viability, although cutoff values for embryo growth can be suggested below which a miscarriage can be predicted. Conclusion: The studies described in this thesis have introduced a number of novel findings in relation to the use of ultrasound and biochemistry for predicting, and optimising the management of, early pregnancy complications from the preconception phase, through early implantation, to the post conception phase.

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Breastfeeding in infancy, when compared with formula feeding, is associated with a reduced incidence of components of the metabolic syndrome later in life. One potential mechanism is via an effect on lipid metabolism and storage, manifesting as altered adiposity and ectopic lipid deposition. I have examined the null hypothesis: no association is detectable between infant feeding and adiposity or ectopic lipid in infancy, through a meta-analysis of published studies and a prospective cohort study of healthy infants employing gold standard direct measurement techniques (magnetic resonance imaging and spectroscopy). Eleven studies were identified for meta-analysis: in formula-fed compared to breastfed infants, fat mass was lower at 3-4 months [mean difference (95% confidence interval)]: [-0.09 kg (-0.18, -0.01 kg)] and 6 months [-0.18 kg (- 0.34, -0.01 kg)]. Conversely, at 12 months, fat mass was higher in formula-fed infants [0.29 kg (-0.03, 0.61 kg)] than in breastfed infants. Eighty-seven infants were included in a prospective cohort, of which 73 were investigated at two time points. In healthy, term, breastfed infants adipose tissue accretion between birth and 2-3 months ages was predominantly within subcutaneous rather than internal adipose tissue compartments, and a significant increase in intrahepatocellular lipid was detected: median [interquartile range] 0.653 [0.367-1.900] after birth and 1.837 [1.408-2.429] at 2-3 months. Comparing breastfed with formula fed infants within this cohort no significant differences were detected in total adipose tissue, adipose tissue distribution or intrahepatocellular lipid between birth and 2-3 months. Significant associations were detected between maternal BMI, rate of weight gain in early infancy and gender, and adipose tissue partitioning at 2-3 months. While method of feeding is associated with altered infant fat mass up to 6 months, no association is detectable with adipose tissue partitioning or ectopic hepatic lipid at 2-3 months.

Fetal growth aberrations, including fetal growth restriction (FGR) and macrosomia, convey the highest risk of perinatal mortality and morbidity, as well as increasing the chance of developing chronic disease in later life. Using Metabolic profiling/metabolomics approaches in maternal urine samples collected in a prospective mother-child cohort can provide information on the early-life exposome and can be linked to child health outcomes as well as potentially identify new biomarkers of exposure. The aims of this PhD were to characterise intra and inter-individual variations in maternal urine profiles during pregnancy, predict fetal growth outcomes and identify environmental sources of metabolic variations. We applied an exploratory metabolic profiling approach using 1H nuclear magnetic resonance (NMR) spectroscopy to maternal urine samples at the first (n=806) and third trimesters of gestation (n=886), collected as part of the Infancia y Medio Ambiente (INMA)-Environment and Childhood Study, a large prospective mother-child population-based cohort study cohorts based in eight Spanish cities. An exploratory metabolomics approach was applied using 1H nuclear magnetic resonance (NMR) spectroscopy for profiling and LC-MS/MS for metabolite identification. Metabolites were used to predict longitudinal measures of fetal growth in terms of body weight and head size (estimated at 12th, 20th and 34th gestational weeks and at birth) and placental weight at birth using linear regression adjusting for main confounding factors. To our knowledge the present study represents the largest human investigation (n > 800) in which non-targeted proton nuclear magnetic resonance spectroscopy has been used to understand the progression of normal fetal growth in two different Spanish populations. We identified 10 reproducible metabolic associations at week 34 with estimated fetal weight, birth weight and placental weight. These signatures included pregnancy-related hormone breakdown products that were newly characterised in our study and branched-amino acids (BCAAs) isoleucine, valine and leucine with its catabolic intermediate 3-hyrdoxyisobutyrate. Overall metabolic phenotypes at week 12 could not predict fetal weight at week 34 or at birth, but only at weeks 12 and 20 and with little consistency across the two populations. Unique adverse metabolic signatures at week 12 of fetal growth were found in Sabadell related to mitochondrial oxidative stress, systemic inflammation and renal function. These findings captured the metabolic signatures of a myriad of physiological (both maternal and fetal), environmental, and other lifestyle characteristics associated with fetal growth. Sensitive measures of environmental exposure to HAA toxins were also created using LC-MS, a non-volatile sub-type of water contaminants, using gold-standard urine biomarker (TCAA), in a case-control study for use in future epidemiological studies of fetal growth outcomes. This work provides ground breaking evidence of clinical relevance with the potential to personalise pre-natal care and ensure healthy fetal development.

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This qualitative descriptive study explores what expectations and experiences midwives and lecturers have of the European Master’s in Midwifery Science (MSc). Following the Bologna Process in 1999, which was a pledge by 29 European countries to enhance mobility and employability through the creation of a European space for higher education and the adoption of a standard degree structure which allows degree programmes awarded in one country to be acknowledged and accepted in another international graduate and post graduate degree programmes are being developed. As technology continues to improve new opportunities for midwives and nurses to study together in an international online community, such as the European MSc in Midwifery are becoming possible. Distance learning has increased rapidly over the last two decades but research around nursing or midwifery students, studying on international distance learning programmes is sparse. The search strategy highlighted only ten relevant studies, and only two other international distance learning post graduate programmes have been discovered and been the focus of research studies. Data were collected via individual interviews and one focus group. Five students were interviewed at the beginning of their programme and again following the successful completion of two modules, three past students were interviewed individually and four lecturers from four different collaborating countries were interviewed via a focus group. Data were digitally recorded and transcribed verbatim. A thematic data analysis framework was used from which 5 broad Themes, each with their own sub - themes emerged. The findings highlight the crucial importance of peer and lecturer support and the requirement for students studying in a second language to have clear and written feedback to avoid misunderstandings. Constructivist teaching methods have been shown to increase students’ engagement, improve foreign language skills and enhance the exchange of cross - cultural theory and knowledge.