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.

L’infection génitale par le Virus du Papillome Humain (VPH) est l’infection transmissible sexuellement la plus fréquente. Sa prévalence la plus élevée est retrouvée chez les femmes en âge de procréer. Bien que la littérature expérimentale s’accorde sur la plausibilité biologique de l’effet du VPH sur les issues négatives de grossesse, les résultats des études observationnelles sont équivoques. Parmi ces issues négatives figure l’accouchement prématuré qui reste une cause majeure de mortalité périnatale et de morbidité à vie dans le monde. La présente thèse avait alors pour but de faire la lumière sur la qualité de la littérature actuelle sur les issues négatives de grossesse en lien avec le VPH en général et d’approfondir l’association entre le VPH et l’accouchement prématuré en particulier. À cette fin, trois objectifs de recherche étaient visés, à savoir: 1) évaluer systématiquement l’ampleur de l’association entre l’infection VPH et les issues négatives de grossesse dans la littérature et la qualité des évidences sur ces relations, 2) estimer l’association entre l’infection VPH pendant la grossesse et l’accouchement prématuré et 3) identifier les déterminants de la transmission du VPH dans le placenta chez les femmes infectées par le VPH au niveau vaginal. Trois analyses ont été menées pour répondre à chacun des objectifs. D’abord, nous avons effectué une revue systématique et des méta-analyses pour chacune des issues négatives de grossesse suivantes: avortement spontané, rupture prématurée et/ou préterme et des membranes, accouchement prématuré, faible poids de naissance, retard de croissance intra-utérine, troubles hypertensifs gestationnels et mortinaissance. Ensuite, en utilisant les données des femmes éligibles de la cohorte prospective HERITAGE (n=899), nous avons estimé l’association entre l’infection VPH (pendant la grossesse et dans le placenta) et l’accouchement prématuré. Dans un modèle de régression logistique, un ajustement pour la confusion a été assuré par pondération par l’inverse de probabilité de l’infection VPH au premier trimestre en fonction des caractéristiques maternelles. Enfin, l’analyse des déterminants du VPH dans le placenta a été réalisée sur l’échantillon de la cohorte de femmes positives au VPH au premier trimestre de grossesse (n=354) en utilisant un modèle d’équations d’estimation généralisée. La revue systématique et les méta-analyses ont montré que l’infection VPH est associée à plusieurs issues négatives de grossesse dont l’accouchement prématuré. Cependant, ces résultats doivent être interprétés avec prudence, compte tenu des limites dans certaines études en raison d’erreur de mesure de l’exposition au VPH, d’une détection du VPH en dehors de la période de grossesse, et d’un contrôle insuffisant pour la confusion. Les résultats de notre étude de cohorte prospective ont montré que la persistance des VPH16/18 pendant la grossesse et la présence du VPH dans le placenta sont associées à l’accouchement prématuré avec un odds ratio ajusté (aOR) de 3,72 (IC 95% 1,47-9,39) et 2,53 (IC 95% 1,06- 6,03) respectivement. Cet effet est indépendant des antécédents de traitement de dysplasies cervicales. Par ailleurs, la présence du VPH dans le placenta est associée à l’origine ethnique autre que blanc (aOR 1,78; IC 95% 1,08-2,96), aux anomalies cervicales (aOR 1,92; IC 95% 1,14-3,24), à l’infection génitale ou urinaire (aOR 2,32; IC 95% 1,15-4,68), à la coinfection VPH au 1er trimestre (aOR 2,56; IC 95% 1,72-3,83), à la persistance d’un VPH à haut risque autre que les génotypes 16/18 (2,31; IC 95% 1,20-4,45) et à la persistance des VPH-16/18 pendant la grossesse (aOR 4,55; IC 95% 2,40-8,66). Dans l’ensemble, les résultats de cette thèse apportent de nouvelles connaissances sur l’infection VPH vaginale pendant la grossesse et dans le placenta. L’association entre l’accouchement prématuré et la persistance du VPH-16/18 en cours de grossesse ou l’infection VPH dans le placenta indique qu’un certain nombre d’accouchements prématurés, jusque-là inexpliqués, pourraient être en lien avec le VPH. Cet effet direct de l’infection VPH sur l’accouchement prématuré vient s’ajouter à celui, déjà montré, du traitement cervical des lésions dysplasiques. Le VPH placentaire est associé aux marqueurs d’une réponse immunitaire inadéquate contre le VPH vaginal. Nos résultats plaident en faveur de la couverture vaccinale optimale contre le VPH dans le but d’alléger le fardeau des naissances prématurées. / Human Papillomavirus (HPV) genital infection is the most common sexually transmitted infection. Its highest prevalence is found in women of childbearing age. Although experimental studies agree on the biological plausibility of detrimental effect of HPV on pregnancy outcomes, observational studies yielded contradictory findings. Among these negative outcomes there is preterm delivery, which remains a major cause of perinatal mortality and lifelong morbidity worldwide. Therefore, this thesis aimed to shed light on the quality of the current literature on negative outcomes related to HPV in general and specifically to further investigate the association between HPV and preterm birth. We targeted three research objectives: 1) systematic assessment of the association between HPV infection and negative pregnancy outcomes in the literature and the quality of the evidence on these relationships, 2) estimate the association between HPV infection during pregnancy and preterm delivery; and 3) to identify the determinants of HPV transmission in the placenta in women infected with in the first trimester. Three analyzes were carried out to meet each of the objectives. We performed a systematic review and meta-analyzes for each of the following negative pregnancy outcomes: spontaneous abortion, premature and / or preterm rupture and membranes, preterm birth, low birth weight, intra-uterine growth retardation, pregnancy induced hypertensive disorders and stillbirth. Using data from eligible women in the HERITAGE prospective cohort (n = 899), we assessed the association between HPV infection (during pregnancy and in the placenta) and preterm birth. In a logistic regression model, we adjusted for confounding by inverse propensity treatment weighting of HPV infection in the first trimester based on maternal characteristics. Finally, the analysis of the determinants of HPV in the placenta was performed on the sample of the cohort of HPV positive women in the first trimester of pregnancy (n = 354) using a generalized estimation equations model. The systematic review and meta-analyzes showed that HPV infection is associated with several negative pregnancy outcomes including preterm birth. However, these results should be interpreted with caution, given the limitations in some studies regarding misclassification of HPV exposure, inappropriate HPV time-point detection, and insufficient control for confusion. Our prospective cohort study showed that the persistence of HPV16/18 during pregnancy and the presence of any HPV in the placenta are associated with preterm birth with an adjusted odds ratio (aOR) of 3.72 (CI 95 % 1.47-9.39) and 2.53 (95% CI 1.06-6.03) respectively. These findings are independent of the history of cervical dysplasia treatment. In addition, the presence of any HPV in the placenta is associated with ethnic origin other than white (aOR 1.78; 95% CI 1.08-2.96), cervical abnormalities (aOR 1.92; 95% CI 1.14-3.24), genital or urinary infection (aOR 2.32; 95% CI 1.15-4.68), HPV coinfection in the 1st trimester (aOR 2.56; 95% CI 1.72-3.83), persistence of high-risk HPV other than genotypes 16/18 (2.31; 95% CI 1.20-4.45) and persistence of HPV-16/18 during pregnancy (aOR 4.55; 95% CI 2.40-8.66). Overall, our findings provide new evidence on vaginal HPV infection during pregnancy and in the placenta. The association between preterm birth and persistence of HPV-16/18 during pregnancy or any HPV infection in the placenta indicates that a number of unexplained preterm deliveries may be related to HPV. This direct effect of HPV infection on preterm birth is in addition to that already shown of cervical treatment of dysplastic lesions. Placental HPV is associated with markers of an inadequate immune response against vaginal HPV. Our results argue in favor of an increase in vaccine coverage against HPV in order to reduce the burden of preterm births.

Introduction: Evidences indicate that human immuno-deficiency virus (HIV) and diabetes (DM) impact pregnancy outcomes but no experience on the integrated service delivery of HIV, DM and pregnancy care. This study explored the domains and levels of integration among DM, HIV and pregnancy care to prepare a service delivery model in Ethiopia. Methods: A sequential exploratory mixed method and the integration theoretical framework guided the study. An exploratory qualitative phase used focused group discussion, in-depth interview and observation to explore the level of integration and to refine a questionnaire for the quantitative phase. The data were transcribed and coded for theme-based analysis. The descriptive quantitative phase described HIV, DM and pregnancy care services, and determined the burden of DM among HIV patients and the prevalence of pregnancy and pregnancy outcomes. Data was analysed using Epi-info. The findings were triangulated, discussed and interpreted. Results: Seven themes were generated: joint plan, shared budget, monitoring system, structural location, the need of policy guide, the practice of integrated service delivery and suggested integration approaches. A coordinated HIV and pregnancy care services were noted. There was a linkage between diabetes and HIV, and diabetes and pregnancy care. The 1.5% of diabetes among HIV, the low number of pregnancies per a mother in diabetes (1.8) and HIV (1.3); the high adverse pregnancy outcomes among HIV (13.4% abortion, 12.4% low birth weight (LBW), 3.5% pre-term birth, 2.1% congenital malformation) and diabetes (3.2% big baby, 3.2% LBW, 3.1% Cesarean-section); the respective absent and low (16.2%) diabetes screening service at anti-natal and HIV clinics, the absent pregnancy care service for diabetic females justified the development of the tripartite integrated service delivery model of diabetes, HIV and pregnancy care. Conclusions: The model suggests active diabetes screening, evaluation and treatment at HIV and antenatal clinics. It considers the coordination between non-communicable diseases (NCD), HIV and maternal health units. Pregnancy care could be coordinated at HIV and NCD units. Full integration can be practiced between HIV and pregnancy care units. Preparing policy guide, building the capacity of health providers, advocating and piloting the model may be prioritized before the implementation of the model. / Health Studies / D. Litt. et Phil. (Health Studies)

Σκοπός της παρούσας προοπτικής µελέτης είναι η διερεύνηση της σχέσης µεταξύ των επιπέδων της α-φετοπρωτείνης και της β-hCG στον ορό της µητέρας κατά το β' τρίµηνο της κύησης και της δυσµενούς έκβασης της κύησης σε τυχαίο δείγµα εγκύων γυναικών της Νοτιο-Δυτικής Ελλάδος. Υλικό - Μέθοδος: 130 υγιείς γυναίκες ελληνικής καταγωγής µε αυτόµατη έναρξη της εγκυµοσύνης µελετήθηκαν για τα επίπεδα της AFP και της β-hCG στον ορό τους µεταξύ της 13ης-24ης εβδοµάδας της κύησης και παρακολουθήθηκαν για δυσµενή έκβαση της εγκυµοσύνης. Επίπεδα AFP καθώς και επίπεδα β-hCG στον ορό της εγκύου 2 φορές µεγαλύτερα του µέσου όρου για την ηλικία της κύησης θεωρήθηκαν µη φυσιολογικά. Η στατιστική ανάλυση έγινε µε τη δοκιµασία Pearson's x2. Αποτέλεσµα: Αυξηµένα επίπεδα AFP στον ορό της µητέρας βρέθηκαν σε 27 από τις 130 γυναίκες που µελετήθηκαν (20,7%). Μεταξύ αυτών µόνο 4 γυναίκες (14,8%) ανέπτυξαν επιπλοκές της κύησης. Επίσης αυξηµένα επίπεδα β-hCG βρέθηκαν σε 14 από τις 130 γυναίκες που µελετήθηκαν (10,77%). Όµως µεταξύ αυτών καµία γυναίκα δεν ανέπτυξε επιπλοκές κατά τη διάρκεια της παρούσας κύησης. Συµπέρασµα: Ένας πολυπαραγοντικός έλεγχος της λειτουργίας του πλακούντα κατά το β' τρίµηνο της εγκυµοσύνης µε Doppler των µητριαίων αρτηριών, µε έλεγχο της µορφολογίας του πλακούντα, µε έλεγχο των επιπέδων της AFP και της β-hCG στον ορό της εγκύου δυνατό να µας επιτρέψει την αναγνώριση εκείνων των εγκύων µε αυξηµένο κίνδυνο να αναπτύξουν σοβαρή πλακουντιακή ανεπάρκεια και επιπλοκές της κύησης. / In our prospective study, we investigated the association between midtrimester maternal serum AFP (ms-AFP) and midtrimester maternal serum β-hCG (ms-β- hCG) levels and adverse pregnancy outcome, in the South-Western Greek population. Materials and Methods: 130 healthy Greek women with spontaneous pregnancies, investigated for ms-AFP levels between 13th-24th weeks of gestation and followed for adverse pregnancy outcome. AFP levels > 2,0 multiples αnd β-hCG levels>2,0 multiples of the median value for gestation, were considered abnormal. Statistical analysis was performed by Pearson's chi-square test. Results: Elevated ms-AFP levels were detected in a total of 27 from the 130 women studied (20,7%). Among them, only 4 women (14,8%) developed pregnancy complications. Elevated ms-b-hCG levels were detected in total of 14 from the 130 women studied (10,77%). Νοne of them developed pregnancy complications. Conclusion: Multiparameter testing of placental function in the mid-trimester uterine artery Doppler, placental morphology, ms-AFP and ms-hCG screening may allow us to identify women with increased risk to develop severe placental insufficiency and pregnancy complications.