Structure-function relationships in the feto-placental circulation from in silico interpretation of micro-CT vascular structures

A well-functioning placenta is critical for healthy fetal development, as the placenta brings fetal blood in close contact with nutrient rich maternal blood, enabling exchange of nutrients and waste between mother and fetus. The feto-placental circulation forms a complex branching structure, providing blood to fetal capillaries, which must receive sufficient blood flow to ensure effective exchange, but at a low enough pressure to prevent damage to placental circulatory structures. The branching structure of the feto-placental circulation is known to be altered in complications such as fetal growth restriction, and the presence of regions of vascular dysfunction (such as hypovascularity or thrombosis) are proposed to elevate risk of placental pathology. Here we present a methodology to combine micro-computed tomography and computational model-based analysis of the branching structure of the feto-placental circulation in ex vivo placentae from normal term pregnancies. We analyse how vascular structure relates to function in this key organ of pregnancy; demonstrating that there is a 'resilience' to placental vascular structure-function relationships. We find that placentae with variable chorionic vascular structures, both with and without a Hyrtl's anastomosis between the umbilical arteries, and those with multiple regions of poorly vascularised tissue are able to function with a normal vascular resistance. Our models also predict that by progressively introducing local heterogeneity in placental vascular structure, large increases in feto-placental vascular resistances are induced. This suggests that localised heterogeneities in placental structure could potentially provide an indicator of increased risk of placental dysfunction

Perinatal Outcomes in fetuses with early-onset fetal growth restriction at Chris Hani Baragwanath Academic Hospital (CHBAH) and accuracy of Doppler findings in predicting outcomes

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfilment of the requirements for the degree of the Master of Medicine in Obstetrics and Gynaecology. MMed (O&G) Johannesburg, December 2016.Background: Intrauterine growth restriction (IUGR) is a pregnancy-related complication that is diagnosed more frequently due to improved antenatal surveillance with greater access to ultrasound equipment and training in ultrasound and it affects 3-5% of all pregnancies. The addition of Doppler surveillance in high risk pregnancies has been found to decrease morbidity and mortality by 29%. Methods: This was a prospective cross-sectional descriptive study that took place at Chris Hani Baragwaneth Academic Hospital (CHBAH), a tertiary hospital in Soweto, Johannesburg, which conducts an average of 23,000 deliveries a year. Study participants were collected over a 15 month period and early-onset IUGR was defined as an abdominal circumference of less than the 5th percentile for a given gestation and diagnosed between 26+0 and 32+0 weeks of gestation. Multivessel Doppler surveillance was performed to monitor these fetuses and optimally time delivery. Pregnancy and neonatal outcomes were followed up. Results: A total of 60 women were included in the study. Detailed data on outcomes was available for 47 study participants. Nineteen babies (40.6%) were discharged home after an average hospital stay of 62.6 days and 52.6% of these babies fulfilled the criteria for major morbidity. Twenty eight babies (59.4%) were mortalities, with 9 intrauterine fetal deaths, 2 medical terminations of pregnancy for maternal indications, 3 fresh still births, 9 early neonatal deaths, 3 late neonatal deaths and 2 infant deaths. The average birth weight of babies that survived was 969g and the gestation was 29 weeks and 2 days, while in the group that demised, the average birth weight was 775.8g and the mean gestation was 28weeks and 4 days. All study participants had abnormalities on Doppler studies, with 38 of the 48 study participants having abnormalities in more than one vessel. Abnormalities in the Ductus Venosus, as well as a low birth weight, were shown to be independent risk factors for perinatal mortality. Conclusion Babies born with IUGR at CHBAH tend to have severe, early onset IUGR at the time of diagnosis, with many compounding factors affecting their outcomes, the most important of which is their birth weight and the presence of an abnormal Ductus Venosus Doppler.LG201

A review of feto-placental vasculature flow modelling

The placenta provides the vital nutrients and removal of waste products required for fetal growth and development. Understanding and quantifying the differences in structure and function between a normally functioning placenta compared to an abnormal placenta is vital to provide insights into the aetiology and treatment options for fetal growth restriction and other placental disorders. Computational modelling of blood flow in the placenta allows a new understanding of the placental circulation to be obtained. This structured review discusses multiple recent methods for placental vascular model development including analysis of the appearance of the placental vasculature and how placental haemodynamics may be simulated at multiple length scales

Machine learning from fetal flow waveforms to predict adverse perinatal outcomes: A study protocol

Background: In Pakistan, stillbirth rates and early neonatal mortality rates are amongst the highest in the world. The aim of this study is to provide proof of concept for using a computational model of fetal haemodynamics, combined with machine learning. This model will be based on Doppler patterns of the fetal cardiovascular, cerebral and placental flows with the goal to identify those fetuses at increased risk of adverse perinatal outcomes such as stillbirth, perinatal mortality and other neonatal morbidities.Methods: This will be prospective one group cohort study which will be conducted in Ibrahim Hyderi, a peri-urban settlement in south east of Karachi. The eligibility criteria include pregnant women between 22-34 weeks who reside in the study area. Once enrolled, in addition to the performing fetal ultrasound to obtain Dopplers, data on socio-demographic, maternal anthropometry, haemoglobin and cardiotocography will be obtained on the pregnant women.Discussion: The machine learning approach for predicting adverse perinatal outcomes obtained from the current study will be validated in a larger population at the next stage. The data will allow for early interventions to improve perinatal outcomes

Dynamic modeling of uteroplacental blood flow in IUGR indicates vortices and elevated pressure in the intervillous space - a pilot study

Ischemic placental disease is a concept that links intrauterine growth retardation (IUGR) and preeclampsia (PE) back to insufficient remodeling of uterine spiral arteries. The rheological consequences of insufficient remodeling of uterine spiral arteries were hypothesized to mediate the considerably later manifestation of obstetric disease. However, the micro-rheology in the intervillous space (IVS) cannot be examined clinically and rheological animal models of the human IVS do not exist. Thus, an in silico approach was implemented to provide in vivo inaccessible data. The morphology of a spiral artery and the inflow region of the IVS were three-dimensionally reconstructed to provide a morphological stage for the simulations. Advanced high-end supercomputing resources were used to provide blood flow simulations at high spatial resolution. Our simulations revealed turbulent blood flow (high-velocity jets and vortices) combined with elevated blood pressure in the IVS and increased wall shear stress at the villous surface in conjunction with insufficient spiral artery remodeling only. Post-hoc histological analysis of uterine veins showed evidence of increased trophoblast shedding in an IUGR placenta. Our data support that rheological alteration in the IVS is a relevant mechanism linking ischemic placental disease to altered structural integrity and function of the placenta

Machine Learning in Fetal Cardiology: What to Expect

In fetal cardiology, imaging (especially echocardiography) has demonstrated to help in the diagnosis and monitoring of fetuses with a compromised cardiovascular system potentially associated with several fetal conditions. Different ultrasound approaches are currently used to evaluate fetal cardiac structure and function, including conventional 2-D imaging and M-mode and tissue Doppler imaging among others. However, assessment of the fetal heart is still challenging mainly due to involuntary movements of the fetus, the small size of the heart, and the lack of expertise in fetal echocardiography of some sonographers. Therefore, the use of new technologies to improve the primary acquired images, to help extract measurements, or to aid in the diagnosis of cardiac abnormalities is of great importance for optimal assessment of the fetal heart. Machine leaning (ML) is a computer science discipline focused on teaching a computer to perform tasks with specific goals without explicitly programming the rules on how to perform this task. In this review we provide a brief overview on the potential of ML techniques to improve the evaluation of fetal cardiac function by optimizing image acquisition and quantification/segmentation, as well as aid in improving the prenatal diagnoses of fetal cardiac remodeling and abnormalities

Fetal heart computational modeling

Treballs Finals de Grau d'Enginyeria Biomèdica. Facultat de Medicina i Ciències de la Salut. Universitat de Barcelona. Curs: 2021-2022. Tutor/Director: Director: Patricia Garcia Cañadilla / Tutor: Fàtima Crispi BrillasAmong infants born with cardiac defects, congenital heart disease (CHD) is the leading congenital abnormality and it origins the majority of newborns death in developed countries. The structural malformations in the heart or great vessels it causes increase the postnatal cardiovascular risk and mortality. In particular, the high incidence of tetralogy of Fallot (ToF) in live births make essential to develop new procedures that enable the study and understanding of this cardiac disorder and the hemodynamic changes it induces. That way, fetal medicine has been constantly evolving in the past years, and computational modeling techniques are becoming more established in the clinical practice and are of growing importance. Nowadays, different 0D lumped parameters models have demonstrated to be useful to evaluate complex cardiac defects in order to aid health workers and find the best management for patients. In this project, a 0D lumped model simulating hemodynamic components and parameters of the fetal heart was developed to study the changes occurring in a ToF heart. Specifically, birth defects of ventricular septal defect (VSD) and pulmonary valve stenosis (PVS) were modeled, allowing the analysis of their effects in fetal circulation. Our results suggested that the designed 0D lumped model can reproduce the blood velocities and pressure waveforms of the fetal heart in healthy conditions after adjusting the values of some model parameters. Despite that, the parameters of the ductus arteriosus (DA) should be better fit since we could not completely reproduce its velocity waveform. Regarding the evaluation of hemodynamic changes of cardiac defects, results suggested that the 0D lumped model can simulate the features present in ToF, such as the right-to-left shunt, characteristic of blood flow in VSD, and the increase of the pressure gradient and peak velocity of the pulmonary artery, indicative of PVS. However, more literature and clinical data of cardiac defects should be used in order to verify these outcomes and ensure their reliability

Computational model of the fetal heart with Coarctation of the Aorta

Treballs Finals de Grau d'Enginyeria Biomèdica. Facultat de Medicina i Ciències de la Salut. Universitat de Barcelona. Curs: 2021-2022. Directors: Patricia Garcia Cañadilla & Bart Bijnens. Tutora: Fátima Crispi.It is thought that altered intrauterine hemodynamics may lead to congenital heart defects, such as aortic arch abnormalities. Coarctation of the aorta (CoA) is one of the most difficult cardiac defects to diagnose before birth, because of the patency of the ductus arteriosus (DA). It consists of a narrowing in the aortic isthmus (AoI) causing a decrease of blood flow. Prenatal diagnosis is important to reduce mortality and morbidity. Nonetheless, prenatal diagnosis has a high rate of false-positive and false-negatives and local hemodynamics in the CoA is not fully understood. The aim of this project was to improve our understanding of the underlying cause of CoA using computational fluid dynamics (CFD) tools. We have implemented a computational model with an idealized geometry of the fetal aorta to investigate the relationship between flow unbalance and wall shear stress (WSS) at the isthmus-ductus. An imbalanced flow was imposed in the ascending aorta (AscAo) and ductus to study if a progressive aortic flow reduction suggests the “flowdependency” of the fetal aortic arch development. As a result, when aortic flow diminished from 50% to 10% progressively, velocity and WSS decreased in the aortic arch and increased in the distal arch. A redistribution of flow could be observed in the model and a “zero flow zone” could be noticed between the brachiocephalic artery and left carotid when the flow decreased to from 50% to 10%. Additionally, another “zero flow zone” could be observed in the AoI when the aortic flow decreased from 50% to 30%

Quantification of Placental Dysfunction in Pregnancy Complications

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

Quantification of Placental Dysfunction in Pregnancy Complications

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