Currently there is no test to accurately predict stillbirth. It is proposed that better identification of placental disease in utero may aid stillbirth prediction and prevention. Pregnancies complicated by reduced fetal movement (RFM) have increased risk of stillbirth. We hypothesised that RFM is a symptom of placental dysfunction associated with adverse pregnancy outcome (APO) and that this placental abnormality can be detected antenatally and used to identify fetuses at highest-risk of APO. We tested this hypothesis by: 1) comparison of ex vivo placental structure and function between APO RFM pregnancies and their normal outcome RFM counterparts, 2) comparison of in utero estimates of placental size, vascularity, vascular and endocrine functions obtained from placental ultrasound, Doppler waveform analysis and maternal circulating placentally-derived hormone concentrations, to their ex vivo correlates and 3) examination of the predictive potential of placental biomarkers at the time of RFM.Ex vivo placentas from APO RFM pregnancies, compared to normal outcome RFM counterparts, were smaller (diameter, area, weight and volume, p<0.0001), less vascular (vessel number and density, p≤0.002), with arteries that were less responsive to sodium nitroprusside (p<0.05), and with aberrant endocrine function (reduced tissue content and/or release of human chorionic gonadotrophin (hCG), human placental lactogen (hPL) and soluble fms-like Tyrosine Kinase-1 (sFlt-1), p<0.03). Placental volume (PV) ex vivo correlated with sonographic estimated PV (p<0.004), hPL, hCG and placental growth factor (PlGF) concentrations in the maternal circulation (p<0.03). Ex vivo villous vessel number and density correlated with Doppler impedance at the umbilical artery free-loop (UAD-F, p=0.02) and intraplacental arteries (p<0.0001) respectively, whilst UAD-F impedance correlated with arterial thromboxane sensitivity (p<0.04). Examination of placental structure and function at the time of presentation with RFM identified 15 independently-predictive biomarkers. Three potential predictive models, incorporating measures of placental size (PlGF), endocrine function (sFlt-1), arterial thromboxane sensitivity and villous vascularity (UAD-F), were proposed. Using these models, sensitivity for APO was improved from 8.9% with baseline care (assessment of fetal size and gestation) to up to 37.5% at a fixed specificity of 99% (p<0.05). This series of studies shows that antenatal placental examination is possible and improves identification of pregnancies at highest risk of stillbirth in a high-risk population by up to 29%. Therefore such tests merit further development to prospectively assess their ability to predict and prevent stillbirth itself.

Fetal growth restriction (FGR) is a common pregnancy complication resulting in increased neonatal mortality and morbidity. The aetiology of fetal growth restriction is not fully understood, but abnormalities in placental development are, leading to abnormalities in placental structure which are thought to affect supply of oxygen to the fetus. The source of fetal hypoxia is unknown due to the difficulty in obtaining oxygenation data in the context of pregnancy using existing techniques. There is also an absence of data relating to oxygenation in FGR pregnancies. Oxygen-Enhanced MRI (OE-MRI) and Blood Oxygen-Level Dependent (BOLD) MRI permit noninvasive acquisition of data related to changes in the concentration of dissolved oxygen (pO2) and changes in hemoglobin saturation (sO2) under air- and oxygen- breathing (hyperoxic challenge).The aim of this project was to determine whether MRI methods can provide information relating to placental oxygenation in normal and FGR-compromised pregnancy, to investigate fetal brain oxygenation and to assess the potential confound of placental perfusion changes under hyperoxic challenge. After optimization of sequences in non-pregnant volunteers, similar pO2 and sO2 increases under hyperoxic challenge were seen in normal and FGR pregnancy. This suggested placental oxygenation was similar and that fetal extraction of oxygen may be a likelier cause of fetal hypoxia. Normal fetal brain oxygenation was found not to increase under hyperoxic challenge, which may be due to hemodynamic adaptation to limit cerebral hyperoxygenation. Finally, the robustness of these oxygenation results was supported by the lack of placental perfusion changes observed under hyperoxia using Arterial Spin Labeling (ASL).In conclusion, MRI methods successfully provided information on placental and fetal oxygenation in normal and abnormal pregnancy, obtaining novel data informing the aetiology of FGR and the physiology of the fetal brain.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22744号 / 医博第4662号 / 新制||医||1046(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙折 晃史, 教授 竹内 理, 教授 近藤 玄 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: Pregnancy substance use is linked to low birth weight. However, less is known about relative contributions of various substances and whether effects are due to decreased gestational duration, restriction of fetal growth, or both. The study goal was to use causal modeling to evaluate the individual impact of alcohol, tobacco, cocaine, and marijuana on gestational duration and fetal growth. Methods: Participants were 3164 urban black women recruited at entry to prenatal care and followed to delivery, with all gestational dating ultrasound supported. Pregnancy substance use was assessed via self-report (alcohol, tobacco, cocaine, and marijuana). Results: Alcohol, cigarette, and cocaine use were all individually and negatively related to gestational age at delivery. However, only alcohol, cigarette, and marijuana use predicted fetal growth, with effects for alcohol and cigarette greater and more discrepant for older women. Overall, heavy cigarette smoking had the greatest individual impact on birth weight (up to 431 g). Heavy levels of use of all 4 substances by older women decreased birth weight by 26% (806 g). Conclusions: For perhaps the first time, reduced birth weight is apportioned both by type of substance and mechanism of effect. The use of alcohol and/or cigarettes was clearly more harmful to fetal growth than cocaine use. Findings demonstrate the need for continued emphasis on intervention efforts to address legal and illicit pregnancy substance use.

Introduction: Preeclampsia (PE) and fetal growth restriction (FGR) are common obstetrical complications, often with pathological features of maternal vascular malperfusion (MVM) in the placenta. Current placental clinical pathology methods involve a manual visual examination of histology sections, a practice that can be resource-intensive and demonstrate moderate-to-poor inter-pathologist agreement on diagnostic outcomes, dependant on the degree of pathologist sub-specialty training. Methods: This thesis aims to apply different machine learning (ML) feature extraction methods to classify digital images of placental histopathology specimens, collected from PE, FGR, PE + FGR, and healthy pregnancies, according to the presence or absence of MVM lesions. 166 digital images were captured from histological placental specimens, manually scored for MVM lesions (MVM- or MVM+) and used to develop various support vector machine (SVM) classifier models, differing in feature extraction methods. Classification performance of each model was assessed through accuracy, precision, and recall using confusion matrices. Results: SVM models demonstrated accuracies between 47-73% in MVM classification, with poorest performance observed on images with borderline MVM presence, as determined through manual observation. Data augmentation provided little to no improvement to the accuracies. Conclusion: The results are promising for the integration of ML methods into the placental histopathological examination process. Using this study as a proof-of-concept foundation will lead our group and others to carry ML models further in placental histopathology.

The major physiological function of the carotid body is to respond to a low partial pressure of oxygen in the systemic arterial blood. The structure and functions of the adult carotid body have been extensively investigated over the past fifteen years. However, the carotid body in children has been relatively neglected with only a handful of studies being performed. To date, no study has been undertaken to investigate the effects of intrauterine hypoxia on the carotid body of foetuses. Clinically, intrauterine growth retardation has been ascribed, amongst other causes, to placental insufficiency that results in chronic hypoxia in the fetus. Intrauterine growth retardation can be divided into two types: - Type I (symmetrical) and type II (asymmetrical). In Type II intrauterine growth retardation, growth retardation does not become clinically evident until the third trimester. There is relative brain sparing with a greater deprivation in the size of abdominal organs, such as the liver and the kidneys. Previous studies have shown that there is no correlation between volume of the carotid body and hypoxia in children. However, Heath et al. made the observation that there are three variants of chief cells (progenitor, light and dark) within the carotid body and that an increase in the relative percentage of the dark subtype is an indicator of hypoxia. Using this observation, the present study set out to test two hypotheses: Firstly, whether the carotid body is functional in utero; and secondly whether there are any objective morphological changes in the carotid bodies of fetuses that have been subjected to intrauterine growth retardation. The carotid bodies from 72 fetuses with a gestational age between thirty and forty weeks were removed from the archived autopsy material, and differential cell counts were performed of the various cells present within the carotid bodies, using haematoxylin and eosin stained sections of the carotid bodies. The cases were assigned to three groups: - I) cases that had clinical and pathological evidence of intrauterine growth retardation, 2) negative controls and 3) positive controls. The three main groups were categorised as follows: -: (1) Intrauterine growth retardation (all cases with a weight for gestational age that is below the tenth centile and a brain to liver ratio of greater than four.) (2) Negative controls (all cases in whom there is a normal weight for age, a brain to liver ratio of less than three and no histological evidence of an episode of significant hypoxia before death). (3) Positive controls (all cases in whom there was clinically significant hypoxia present before death). The groups comprised of: 20 hypoxic positive controls, 15 negative controls, and 16 test cases which had suffered from intrauterine growth retardation. The remaining 21 cases were 7 dysmorphic infants, 3 congenital infection cases (congenital syphilis) and 11 cases that fitted the negative control criteria but had suffered significant hypoxia, thus excluding them from that category. The results showed that no significant difference was present in the percentage of sustentacular cells between any of the three groups. The results of the percentage of dark chief cells were as follows: l) mean percentage of dark chief cells in the intrauterine growth retardation group was 21.1 ±10.9%. 2) mean percentage of dark chief cells in the negative controls was 12.3 ±7.3%. 3) mean percentage of dark chief cells in the positive controls was 21.2 ±9.8%. A significant difference was present between the intrauterine growth retardation cases and the negative controls p=0.013, and between the positive and negative controls p=0.006. The dark chief cell count in the intrauterine growth retardation group showed no significant difference from the positive controls. No age-related difference appeared to be present in any of the groups. The conclusions reached are: a) Clinical hypoxia correlates with morphological changes in the carotid body, manifesting as an increase in the percentage of dark chief cells. b) intrauterine growth retardation cases show similar morphological changes in the carotid body to cases that have suffered from clinical hypoxia. c) therefore, by deduction intrauterine growth retardation fetuses have probably also been exposed to significant hypoxia while in utero. d) the fact that morphological changes in response to hypoxia are occurring in the carotid bodies of fetuses is an indication that the carotid body may be functional in utero. The results of the study indicate that a dark chief cell percentage of greater than 20% indicates that the fetus has been subjected to significant hypoxia, while a percentage of less than 10% indicates that it has not. A percentage of between 10 and 20% is unhelpful in determining whether hypoxia has taken place. The results of this study indicate that histological examination of the carotid bodies in neonates suspected of intrauterine growth retardation could be a useful additional means of assessment.

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24835号 / 医博第5003号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 浅野, 雅秀, 教授 柳田, 素子, 教授 近藤, 玄 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Ambient air pollution has been associated with restricted fetal growth, which is linked with adverse respiratory health in childhood. We assessed the effect of maternal exposure to low concentrations of ambient air pollution on birthweight. We pooled data from 14 population-based mother-child cohort studies in 12 European countries. Overall, the study population included 74-178 women who had singleton deliveries between Feb 11, 1994, and June 2, 2011, and for whom information about infant birthweight, gestational age, and sex was available. The primary outcome of interest was low birthweight at term (weight <2500 g at birth after 37 weeks of gestation). Mean concentrations of particulate matter with an aerodynamic diameter of less than 2·5 μm (PM2·5), less than 10 μm (PM10), and between 2·5 μm and 10 μm during pregnancy were estimated at maternal home addresses with temporally adjusted land-use regression models, as was PM2·5 absorbance and concentrations of nitrogen dioxide (NO2) and nitrogen oxides. We also investigated traffic density on the nearest road and total traffic load. We calculated pooled effect estimates with random-effects models. A 5 μg/m3 increase in concentration of PM2·5 during pregnancy was associated with an increased risk of low birthweight at term (adjusted odds ratio [OR] 1·18, 95% CI 1·06-1·33). An increased risk was also recorded for pregnancy concentrations lower than the present European Union annual PM2·5 limit of 25 μg/m3 (OR for 5 μg/m3 increase in participants exposed to concentrations of less than 20 μg/m3 1·41, 95% CI 1·20-1·65). PM10 (OR for 10 μg/m3 increase 1·16, 95% CI 1·00-1·35), NO2 (OR for 10 μg/m3 increase 1·09, 1·00-1·19), and traffic density on nearest street (OR for increase of 5000 vehicles per day 1·06, 1·01-1·11) were also associated with increased risk of low birthweight at term. The population attributable risk estimated for a reduction in PM2·5 concentration to 10 μg/m3 during pregnancy corresponded to a decrease of 22% (95% CI 8-33%) in cases of low birthweight at term. Exposure to ambient air pollutants and traffic during pregnancy is associated with restricted fetal growth. A substantial proportion of cases of low birthweight at term could be prevented in Europe if urban air pollution was reduced. / The European Union