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The epidemics of obesity and diabetes are two of the leading threats to health in the 21st century. Maternal obesity complicates a large and increasing minority of pregnancies, and pre-existing diabetes is one of the most common maternal chronic health complications of pregnancy. This Doctoral Statement presents a portfolio of six published articles that draw on the North of England’s long-standing population-based registries of maternal and perinatal health to investigate the effects of pre-pregnancy obesity and diabetes on a range of serious adverse pregnancy outcomes. The first two articles examined a cohort of pregnant women who delivered in five of the region’s hospitals during 2003-2005 to explore the associations between maternal body mass index and the risks of, 1) congenital anomaly and 2) fetal and infant death. The next three examined a cohort of pregnant women with pre-existing diabetes who delivered during 1996-2008 to explore the effects of the condition on, 1) congenital anomaly, 2) birth weight, and 3) fetal and infant death. The final article examined women with pre-existing diabetes who had delivered two successive pregnancies to explore the influences of recurrent adverse pregnancy outcome. Maternal pre-pregnancy obesity and diabetes were both associated with increased risks of congenital anomaly, stillbirth, and infant death, with stronger effects for diabetes than obesity. In diabetes, peri-conception glycaemic control was strongly associated with birthweight and the risks of congenital anomaly, stillbirth, and infant death, and previous adverse outcome was associated with a doubled risk in the second pregnancy. For each article I provide a contemporary analysis of its contribution to the literature and critique of the methodology. The wider relevance of the research is also considered by discussing the evidence for causality, potential mechanisms, and implications for public health. Finally, I reflect on my individual contributions and my development towards an independent epidemiologist.

Obstetric care decisions fundamentally rely upon accurate estimation of gestational age (GA). Ultrasound- (US) based measurements provide reliable estimates of GA, if performed early in pregnancy. However, in low-income settings, the lack of appropriately trained sonographers and the tendency for women to present for care late in pregnancy are barriers to the use of US for dating purposes. In this thesis, we propose to exploit sonographic image patterns associated with dynamic fetal brain development to predict GA. We designed an algorithm which automatically estimates GA from an US scan collected from a single visit, thereby enabling clinically useful estimates of GA to be made even in the third trimester of pregnancy: a period complicated by biological variation and unreliable size-based estimates. The presented model was conceived on the basis that fetal brain development follows a precise spatiotemporal pattern, with folds emerging and disappearing on the surface of the brain (cerebral cortex) at fixed time points during pregnancy. This timing is so precise that post-mortem neuroanatomical and MRI evidence suggest that the 'developmental maturation' of the fetal brain may be a better predictor for GA than traditional size-based estimates. We capitalize on these age-related patterns to develop, for the first time, a unified model which combines sonographic image features and clinical measurements to predict GA and brain maturation. The framework benefits from a manifold surface representation of the fetal head which delineates the inner skull boundary and serves as a common coordinate system based on cranial position. This allows for fast and efficient sampling of anatomically-corresponding brain regions to achieve like-for-like structural comparison of different developmental stages. Bespoke features capture neurosonographic patterns in 3D images, and using a regression forest classifier, we characterize structural brain development both spatially and temporally to capture the natural variation existing in a healthy population (n=448) over an age range of active brain maturation (18 to 34 weeks). Our GA prediction results on a high-risk clinical dataset (n=187) strongly correlate with true GA (r=0.98, accurate within ± 6.10 days), confirming the link between maturational progression and neurosonographic activity observable across gestation. Our model also outperforms current clinical methods, particularly in the third trimester. Through feature selection, the model successfully identified regional biomarkers of neurodevelopmental progression over gestation. Guided by these regions, we present a novel approach for defining and testing hypotheses associated with neuropathological deviations.

Background The pathogenetic mechanisms behind placental dysfunction-related complications like preeclampsia and intrauterine growth restriction have remained perplexing till now, in part because of lack of well-defined structural and functional molecular characterisation. There is growing evidence that links trophoblast debris and the existence of syncytial nuclear aggregates (SNA) to the pathogenesis of gestational diseases. Characterisation and quantification of structural and functional parameters of placental dysfunction may give researchers a clearer picture of the mechanisms underlying the development of high risk pregnancy. Methods Placental samples were obtained from normal term pregnancies, preterm controls, as well as from pregnancies complicated by preeclampsia (PET), intrauterine growth restriction (IUGR) and PET-IUGR. Formalin-fixed, paraffin-embedded sections were visualised with H&E, stained using immunohistochemistry (IHC) and digitally scanned. Using stereological methodology, volumes of placental SNAs, trophoblasts, villi and capillaries were measured. Three dimensional (3D) volume reconstructions of terminal placental villi with SNAs and fibrinoid degenerations were created. IHC-labelled slides were analysed by image analysis algorithms. Differential expression of placental genes and miRNAs, hypothesised to regulate cell death in placental dysfunction, were quantified using RT-qPCR. BeWo cell lines were carried out for in vitro validation of the effects miRNAs regulating programmed cell death (PCD) using flow cytometry and western blotting. Results Specific morphometric patterns of villous, trophoblasts, SNA and capillary volumes were demonstrated with characteristic higher SNAs and lower capillary volumes in PET placentae with reciprocal patterns in IUGR placentae showing a negative correlation pattern between nuclear aggregates and capillary volumes. Image analysis of immune-labelled slides showed a higher autophagy marker expression in PET and a positive correlation to SNAs as well as a balanced reciprocal expression patterns with apoptosis. Moreover, miR-204 transfected BeWo cells showed a similar balanced reciprocal regulation of autophagy and apoptosis expressions. Conclusion We have demonstrated that applying stereology-based and image analysis on digitised placental sections can be useful in quantifying and dissecting structural and functional patterns in normal and abnormal placental function. 3D reconstruction model are a novel approach towards placental characterisation in normal and complicated pregnancies. The study also showed that miR-204 plays a vital role in the regulation of placental autophagy and apoptosis, critical in the pathophysiology of placental dysfunction.

This thesis uses data from three cohort studies in order to investigate the effects of foetal and infant growth on respiratory disease in preterm-born children, and the onward effects of this disease on measures of physical activity. Firstly, I investigated change in foetal growth using biometry obtained from antenatal ultrasounds scans, and related this to rates of respiratory symptoms obtained from the Respiratory and Neurological Outcomes of Children Born Preterm Study. I followed-up this work by reporting the effect of accelerated weight gain during infancy on the respiratory health of preterm-born children. The second half of my thesis then used measures of lung function, as well as data on respiratory symptoms, to investigate whether the decrements associated with preterm birth manifested as reduced participation in objectively measured physical activity. Data from the Avon Longitudinal Study of Parents and Children, and from the Millennium Cohort Study, were used in these analyses. My results noted that change in foetal growth trajectory (acceleration or deceleration) between the trimesters of pregnancy was associated with increased respiratory symptoms in preterm-born children. Accelerated infant weight gain was also associated with increased odds of wheeze; this was in a dose-dependent manner across the spectrum of gestation, with the effect being the greatest at ≤32 weeks’ gestation. Moreover, maternal smoking, as well as gestation, were noted to be a mediator of the relationship between infant weight gain and childhood respiratory health. A reduction in moderate-to-vigorous physical activity at 7 years of age was noted in boys who were born at ≤32 weeks’ gestation. This reduction remained after inclusion of other explanatory variables. No differences were noted at the ages of 11 and 15 years. The reduction in physical activity over the course of childhood may explain this observation.

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The reduction of maternal and child mortality has been central to international development efforts over the past twenty years, spurred on by global initiatives such as the Millennium Development Goals. Whereas a significant decrease in mortality rates has been achieved in mothers and the under-five, the fetal and early neonatal period has received less attention resulting in slower progress. Resource-poor settings suffer from the highest stillbirth, maternal and early neonatal death rates, with 99% occurring in low- and middle income countries. Causes of fetal and maternal compromise can be manifold, both infrastructural and pathophysiological. Common problems remain a scarcity of skilled healthcare personnel leading to low health risk detection, referral and ultimately intervention rates. In the absence of sophisticated equipment fetal compromise may go unnoticed, such as fetal growth restriction, one of the primary causes of poor health outcome. To work towards improved fetal and maternal risk assessment enabling timely and appropriate referral, this thesis proposes a low-cost mHealth monitoring platform for use in low-resource settings. The analysis of the fetal cardiac activity, prerequisite in hospitals in developed nations, may provide important insights on fetal stress levels and more specifically growth retardation. The fetal cardiac signal is accessible and obtained at low-cost with the help of a Doppler transducer. This thesis in healthcare innovation investigates the feasibility of introducing such technology in communities not familiar with their application, proposes a novel signal quality algorithm suitable for implementation on the phone, develops a classifier based on fetal heart rate variability to distinguish growth restricted from normal babies, and introduces the design of the mHealth platform, results of a pilot deployment in rural Guatemala and the design and implementation of a full randomised control trial.

Aims: This review aimed to evaluate the literature that examines factors (maternal age, ethnicity, antenatal depressive symptoms and support) in relation to Postpartum Depressive (PPD) symptomatology in adolescent mothers. Methods: A systematic literature search was conducted using databases PsychINFO, MEDLINE, EMBASE, CINAHL and Maternity and Infant Care. After inclusion and exclusion criteria were applied, 17 studies were identified as suitable for this review. Results: Results showed antenatal depressive (AND) symptoms and support to be associated with PPD symptoms, but not maternal age or ethnicity. Studies highlighted parental competence and conflict as potentially accounting for the relationship between support and PPD symptoms. Contributing factors to this relationship were relationship status, living arrangement, antenatal expectation and socioeconomic status. Due to most studies being part of a larger project, a broad range of other variables were measured often with limited rationale for their inclusion. Conclusion: The current literature indicates AND symptoms and support are related to PPD symptoms. However, there remains a lack of specificity to these relationships. Further research is needed to improve our understanding of the interaction between the relevant factors involved.

Aims: It has been demonstrated that online and offline measures of maternal mentalization use relatively distinct neurological systems. As the unique influence of each on infant attachment classification has not yet been investigated, this study aims to compare the two. Method: A combined sample of “referred” and “non-referred” mother-infant pairs were coded for reflective functioning and representational risk at time one, and reflective functioning, representational risk, infant attachment style and mind-mindedness at time two, 12 months later. The relationships between these measures were investigated using correlation and regression analyses. Results: Reflective function and mind-mindedness were concurrently and predictively related, but with a shared variance of only 6%. Reflective function was not associated with attachment classification and mind-mindedness was associated with attachment security, but in the opposite direction than predicted. Conclusion: Reflective function and mind-mindedness may capture different aspects of mentalizing (explicit vs. implicit). Relationships between the measures of mentalization and infant attachment classification were not as predicted.