Дисертації з теми "Prental diagnosis"

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Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished

Homozygous α0-thalassemia is a serious autosomal recessive disorder with poor fetal outcome and severe maternal complications. Conventionally, prenatal diagnosis is performed by an invasive test. A non-invasive approach using serial ultrasonography can effectively reduce the need for invasive tests in unaffected pregnancies. For two-dimensional ultrasound prediction, a total of 777 at-risk fetuses were studied from 12 to 20 weeks between 1995 and 2006. At 12–15 weeks’ gestation, the highest sensitivity (98.3%) was achieved by the combination of fetal cardiothoracic ratio (CTR) and/or middle cerebral artery peak systolic velocity (MCA-PSV) at a false-positive rate of 15.8%. At 16–20 weeks’ gestation, the sensitivity of CTR was 100.0%, but the false-positive rate was 5.2%. In contrast, the false-positive rate of MCA-PSV alone was 1.4% and that of the combination of CTR and MCA-PSV was 0%, although their sensitivities were less than 65%. In a cross-sectional retrospective study of 546 samples at-risk and control (268 fetal and 278 neonatal cord blood), the degree of anemia was only mild in 27.5% of the affected fetuses (see chapter 3 for definition of mild anemia). Because MCA-PSV is not very predictive of mild anemia, this may be one of the reasons why MCA-PSV is not very sensitive in predicting an affected pregnancy. A total of 832 at-risk pregnancies were studied using same noninvasive approach at Maternal and Neonatal Hospital of Guangzhou (MNH) and Tsan Yuk Hospital (TYH). The overall sensitivity and specificity of the noninvasive approach was 100% and 95.6% respectively. At MNH, the need for an invasive test was reduced by 78.6%, and all the affected pregnancies were diagnosed before 24 weeks’ gestation. After adequate training and monitoring the quality of the subsequent ultrasound examinations, the results achieved at MNH were comparable to TYH, with at-risk pregnancies including the affected ones being seen at a more advanced gestation at MNH. In a retrospective review of 361 women at risk of carrying an affected fetus, 311 (86.2%) opted for the non-invasive approach using CTR and/or placenta. The cost saving of this non-invasive approach was relatively small (HK$ 2,651) in comparison to the cost of the whole prenatal screening program. On the other hand, the non-invasive approach was more expensive than the direct invasive approach for low MCV couples, as well as couples discordant for α-thalassemia and β-thalassemia. ages. These results support the adoption of non-invasive approach in which routine invasive test or karyotyping is no longer performed. A total of 106 at-risk pregnancies and normal controls were prospectively studied using three-dimensional ultrasonography. Placental volume (PV) at 11-14 weeks, and PV/CRL quotient at 9-14 weeks’ gestation of affected pregnancies were significantly greater than unaffected pregnancies (P<0.05). Using a cut-off point of 1.2ml/mm for PV/CRL quotient to predict an affected pregnancy, the sensitivity, and specificity was 96.2%, and 100.0% respectively.
published_or_final_version
Obstetrics and Gynaecology
Master
Doctor of Medicine

Technological advances in prenatal screening and diagnosis mean that it is now possible to test for a wide range of congenital conditions (Hewison et al., 2007). Traditionally testing has been carried out during pregnancy (prenatal diagnosis, PND). However, advances in technology have made it possible for diagnosis of an embryo created through in vitro fertilisation, prior to implantation into the womb (pre-implantation genetic diagnosis, PGD). This means that women can avoid the birth of a child with a genetic condition without the stress of terminating a pregnancy. This raises questions about what women want from reproductive technologies, as it means they are making decisions based not only on the condition diagnosed but also on the technology used to test. Two studies were carried out to examine this further. In the first study, 216 participants completed a questionnaire either based on PND or PGD. Participants were asked whether they would terminate a pregnancy (PND condition) or avoid implantation (PGD condition) following diagnosis of five different genetic conditions, ranging in severity. The results suggest an interaction between the technology (PND or PGD) and the severity of the genetic condition diagnosed, such that for the most and least severe conditions, the number of people choosing to terminate/avoid implantation was similar for the PND and PGD groups. However for conditions in the middle range of severity significantly more people said they would avoid implantation. A within subjects interview study was carried out to explore this further and thematic analysis identified a number of themes that influenced participants’ responses. Overall, the results suggest that PGD may be more acceptable for women in some cases. Women considering diagnoses are likely to benefit from detailed information about both PND and PGD in order to make a fully informed decision as to which is best for them.

The current state of preimplantation genetic diagnosis technology is presented, as are the biological principles and medical procedures that make it possible. The arguments of both proponents and those with social and ethical reservations about the broader implications of the technique are carefully reviewed, and the limitations of the dominant medical model approach to the technique are exposed. A discussion of reproductive autonomy in light of emerging testing applications of PGD not directly related to the avoidance of serious genetic abnormalities in the resulting child demonstrates the complexity of both clinical decision-making and public policy formulation with regard to PGD. Recently proposed legislation in Canada reflects such complexities, and highlights the lack of social consensus on the appropriate uses of, and restrictions on, PGD. A variety of "soft law" instruments, notably professional codes of practice and research guidelines implemented by institutional ethics committees, may mitigate some of the uncertainty surrounding PGD in Canada, but their limited applicability and espousal of the medical model approach render questionable their capacity to reconcile tolerance of pluralism with respect for human life, diversity, and reproductive autonomy.

For this project I describe the socio-historical development of a particular application of genetic prenatal diagnosis, in terms of changing social relations that govern an ethics of reproductive choice. I examine ways that medicine and government articulate prenatal diagnosis to problematise the maternal body and govern women's reproductive choices about chromosomal abnormality in the fetus. Since its introduction in the early 1970s, the major use of prenatal diagnosis has been to detect chromosomal abnormalities-in particular, Down syndrome-in the fetus. Medico-scientific knowledge claims negotiated in everyday practices in the genetic counselling clinic between health professionals and their clients are situated within broader social relations. Negotiations between medicine and government have produced technoscientific possibilities, realised with greater or lesser success in the co-construction of a workable prenatal diagnosis standardised package. I describe how these socio-technical relations have produced similarities and differences across time, and national and professional boundaries. My analysis draws on observations in three genetic counselling clinics, and of the health professionals' other work activities. I also draw on interviews with them and other actors in that arena, as well as claims made about prenatal diagnosis technologies in the medico-scientific literature. I analyse my data using concepts developed in social worlds/arenas theory within a Foucauldian framework of social relations that govern the body. Since the early formation of a standardised package of genetic counselling about amniocentesis, ethical decisions about prenatal diagnosis have identified multiple parts of the self to be governed. This ethics has relied on a duty to make genetically responsible decisions as a particular way to relate to oneself, although it has been expressed in different ways. Newer technologies have articulated greater ethical possibilities for governing the self by co-constructing new ways of assembling the constituent components. Throughout, there have been tensions between two major aims for governing the self: that of giving birth to a healthy baby, and that of managing maternal rationality in order to act as an autonomous rational individual. I have thus described how a woman's use of prenatal diagnosis is not simply one of individual choice. Her decision is a complex ethical one that is historically and socially contingent on relations between medicine and government that present the maternal body in certain ways for her to act upon herself.

Introduction: Prenatal diagnosis for genetic conditions has been available in Pakistan since 1994, however very little is known about this population's attitudes toward prenatal diagnosis or termination of affected pregnancies for different conditions. Advances in molecular biology mean it is possible to offer prenatal diagnosis for an increasing number of conditions and therefore, it is important to assess these attitudes. Objective: To explore Pakistani parents' attitudes toward prenatal diagnosis and termination of affected pregnancies for a range of conditions and the factors that contribute towards such attitudes in parents with and without children affected with conditions. Methodology: Attitudes of 400 parents (200 with affected and 200 with unaffected children) towards diagnosis and termination of pregnancy for 30 different genetic conditions were explored, using a UK questionnaire (Hewison et al., 2007). Factors that affect parents' attitudes towards diagnosis and termination of pregnancy for different genetic conditions were also explored through interviews with 40 parents (20 with affected and 20 with unaffected children). Results: Parents held favourable attitudes to prenatal diagnosis and termination of pregnancy for different conditions. Only 3% of parents wanted no prenatal diagnosis and 13.8% did not want termination of pregnancy at all. Mothers and fathers had similar attitudes towards prenatal diagnosis and termination of pregnancy but mothers had higher acceptability of prenatal diagnosis and termination of pregnancy than fathers. Similarly, parents with affected children were more in favour of prenatal diagnosis and termination of pregnancy than parents with unaffected children. The variation in parents' attitudes showed that there was more acceptability for prenatal diagnosis and termination of pregnancy for conditions perceived to be more severe. The most important factors in most parents' decision about termination of pregnancy were suffering of the child and the family, negative attitudes of society, availability of required resources to care for an affected child and and religious beliefs. There was lack of awareness about Islam's stance on termination of pregnancy. The role of family members and health care providers in decision making related to prenatal diagnosis and termination of pregnancy was considered important by some but not all parents. Conclusion: The findings challenged the stereotypes about the non acceptance of termination of pregnancy for genetic conditions in Muslim populations. There is a need to raise awareness of genetic conditions, Islam's stance on termination of pregnancy and availability of screening and prevention services of genetic conditions in Pakistan. The study also highlighted the need for a comprehensive policy on the offer of testing and termination for genetic conditions in Pakistan to ensure easy access to at-risk parents. Furthermore, clinical guidelines should be developed for healthcare providers to facilitate autonomous decision making through the provision of information for parents on testing and termination issues. Technological advances in the field of genetic testing are not only providing more reproductive choices to parents but are also presenting them with more dilemmas.

Thesis: S.M. in Science Writing, Massachusetts Institute of Technology, Department of Humanities, Graduate Program in Science Writing, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 38-40).
Prenatal diagnosis has given doctors the ability to predict problems before a child is even born. But what happens when the information gleaned from these tests is that the child is fatally sick? Doctors call these "futile" pregnancies. The increasing sophistication and prevalence of prenatal diagnostic tests means that prospective parents and their doctors are grappling with ethical questions unheard of just half a century ago. Legislators try to demarcate what choices are "good" and "bad". However, there is no good choice when it comes to a fatally ill infant. While archival research is used to frame modem perspectives, this thesis aims to explore the different choices women make and the difficulties they must grapple with in this day and age.
by Emma Sconyers.
S.M. in Science Writing

INTRODUCTION: Advances in molecular biology will soon make it possible to offer parents prenatal testing for a large number of different genetic disorders. The tests that have been offered to date are available because of technology, not because of the burden or prevalence of the condition. Parents' attitudes to different genetic disorders need to be evaluated, because little is known about how people's attitudes to testing for one disorder relate to their views on testing for other disorders. AIMS: To assess the attitudes of Saudi parents with and without an affected child, towards prenatal diagnosis and termination of pregnancy for a range of different genetic disorders, and the factors that affect their attitudes. METHODS: The study was conducted using structured questionnaires and semi-structured interviews. 400 Saudi parents with and without affected children completed a structured questionnaire and forty of these were then interviewed. The questionnaires were designed to assess parents' attitudes towards prenatal diagnosis and termination of the pregnancy, for thirty different conditions. The interviews were designed to explore the factors that affect parents' attitudes. FINDINGS: Parents had different attitudes to different conditions. Overall, there was an unexpectedly high level of acceptance of prenatal diagnosis and termination of pregnancy for a range of different conditions in this Muslim sample. It was also found that parents with an affected child held more favourable attitudes towards termination of the pregnancy than parents without an affected child. Fathers without an affected child held the least favourable attitudes towards termination of pregnancy. DISCUSSION: The evidence suggests that parents perceive genetic conditions differently according to their individual experience. Islam is not the main factor that influences Muslim parents toward prenatal diagnosis and termination of the pregnancy. New technologies provide parents with more reproductive choices but also present them with more dilemmas. Further investigation about factors associated with testing and termination choices is recommended.

Assisted reproduction technology is increasingly used for treatment of couples with subfertility. These women are usually of more advanced maternal age and carry a higher risk of fetal Down syndrome. Results from early publications showed that biochemical markers for screening of fetal Down syndrome in the second trimester were different between pregnancies from in vitro fertilization (IVF) and natural conception. This could potentially increase the false positive rate and result in unnecessary invasive diagnostic procedures. Questions were raised as to whether the alterations were related to ovarian stimulation. This laid the fundamentals of a series of studies presented in this thesis with an aim to address the variations in the concentrations of markers of fetal Down syndrome and the fetal growth profile of pregnancies conceived following different assisted reproduction treatments. Studies were conducted on maternal serum and amniotic fluid alpha fetoprotein (AFP) and human chorionic gonadotrophin (hCG) in the second trimester in pregnancies conceived by assisted reproduction. A reduced level of AFP in maternal serum in pregnancies with fresh embryos together with an elevated level of hCG in both maternal serum and amniotic fluid in pregnancies with frozen thawed embryos were found. This pioneer piece of data showing the raised hCG in frozen thawed embryo pregnancies with unstimulated treatment cycles spoke against the ovarian driven hypothesis, but suggested placental dysfunction be a possible underlying pathophysiology. For markers adopted in the first trimester, the level of pregnancy associated protein A (PAPP-A) was significantly reduced in pregnancies from assisted reproduction. The data on free βhCG was heterogeneous. Apart from biochemical markers, the nuchal translucency was also increased in these singleton pregnancies but not in dichorionic twins. As the direction of deviations of these markers in unaffected pregnancies from assisted reproduction resembled those observed in pregnancies affected by Down syndrome, appropriate adjustment was necessary to reduce the false positive rate for these women. Altered biochemical markers, notably a low PAPP-A level, were also associated with adverse obstetric outcomes. The changes observed in pregnancies from assisted reproduction might be a manifestation of an intrinsic placental insufficiency or fetal developmental delay. A longitudinal study was performed to examine the intrauterine fetal growth profile in these pregnancies. The rate of increment in the mean sac size, which could represent an adaptive compensatory mechanism, was significantly greater in pregnancies from assisted reproduction compared to natural conception. We concluded that pregnancies conceived after assisted reproduction technology were different from pregnancies from natural conception in terms of the concentrations of biochemical and ultrasound markers of Down syndrome. Due to the wide variation in treatment protocols and patients’ background demographics, the exact underlying pathophysiology might be difficult to be explored. Couples undergoing assisted reproduction treatment should be counseled on the increased risk of adverse pregnancy course and perinatal outcome.
published_or_final_version
Medicine
Master
Doctor of Medicine

This thesis presents findings from a qualitative study of the emergence and early clinical translation of non-invasive prenatal diagnosis (NIPD) in the UK. Drawing from interviews with a range of experts and users I track the enrolment and translation of this new prenatal testing technology across a variety of clinical and social spaces. I show how encounters with NIPD prompt deep critical examination of the moral, social and political implications - not only of the technology - but of the established clinical practices (routine and specialised prenatal testing) and specific policy contexts (prenatal screening programmes) within which NIPD has begun to sediment. I explore how, as NIPD advances at a rapid pace and emerges within a culturally and politically complex context, the technology both aligns with and disrupts routine practices of prenatal screening and diagnosis. I show how, as the technology divides into two major strands - NIPD and NIPT - at an early stage of development, and before becoming naturalised/normalised within the clinic, scientists, clinicians and policy makers attempt to pin down, define and ‘fix’ the technology, drawing upon and engaging in substantive practices of division, categorisation and classification. I explore ambiguities present within such accounts, highlighting dissenting voices and moments of problematisation, and following this, I show how the ‘troubling’ of boundaries prompts much examination of ethical and social concerns. As a location within which interviewees explored more contentious issues, I show how abortion emerged as central to the discussion of NIPD. I proceed to show how institutionalised, professionalised bioethical debate dominates mainstream discourse, and I explain how a particular construction of the informed, individual choice-maker is mobilised in order to locate moral and political responsibility for testing in the hands of individuals, and to distance political/organisational structures from entanglement with problematic concerns. I explore how clinicians and patients respond to this positioning in multiple ways, both assimilating and questioning the mainstream discourse of ‘informed choice’. In conclusion, I highlight the broader (bio)political aspects of NIPD’s emergence and translation within prenatal screening and diagnosis.

Doutoramento em Química
O trabalho apresentado nesta tese teve como principais objectivos contribuir para o conhecimento da composição do líquido amniótico humano (LA), colhido no 2º trimestre de gravidez, assim como investigar possíveis alterações na sua composição devido à ocorrência de patologias pré-natais, recorrendo à metabonómica e procurando, assim, definir novos biomarcadores de doenças da grávida e do feto. Após uma introdução descrevendo o estado da arte relacionado com este trabalho (Capítulo 1) e os princípios das metodologias analíticas usadas (Capítulo 2), seguida de uma descrição dos aspectos experimentais associados a esta tese (Capítulo 3), apresentam-se os resultados da caracterização da composição química do LA (gravidez saudável) por espectroscopia de ressonância magnética nuclear (RMN), assim como da monitorização da sua estabilidade durante o armazenamento e após ciclos de congelamento-descongelamento (Capítulo 4). Amostras de LA armazenadas a -20°C registaram alterações significativas, tornando-se estas menos pronunciadas (mas ainda mensuráveis) a -70°C, temperatura recomendada para o armazenamento de LA. Foram também observadas alterações de composição após 1-2 ciclos de congelamento-descongelamento (a ter em conta aquando da reutilização de amostras), assim como à temperatura ambiente (indicando um período máximo de 4h para a manipulação e análise de LA). A aquisição de espectros de RMN de 1H de alta resolução e RMN acoplado (LC-NMR/MS) permitiu a detecção de 75 compostos no LA do 2º trimestre, 6 dos quais detectados pela primeira vez no LA. Experiências de difusão (DOSY) permitiram ainda a caracterização das velocidades de difusão e massas moleculares médias das proteínas mais abundantes. O Capítulo 5 descreve o estudo dos efeitos de malformações fetais (FM) e de cromossomopatias (CD) na composição do LA do 2º trimestre de gravidez. A extensão deste trabalho ao estudo dos efeitos de patologias no LA que ocorrem no 3º trimestre de gravidez é descrita no Capítulo 6, nomeadamente no que se refere ao parto pré-termo (PTD), pré-eclampsia (PE), restrição do crescimento intra-uterino (IUGR), ruptura prematura de membranas (PROM) e diabetes mellitus gestacional (GDM). Como complemento a estes estudos, realizou-se uma análise preliminar da urina materna do 2º trimestre para o estudo de FM e GDM, descrita no Capítulo 7. Para interpretação dos dados analíticos, obtidos por espectroscopia RMN de 1H, cromatografia líquida de ultra eficiência acoplada a espectrometria de massa (UPLC-MS) e espectroscopia do infravermelho médio (MIR), recorreu-se à análise discriminante pelos métodos dos mínimos quadrados parciais e o método dos mínimos quadrados parciais ortogonal (PLS-DA e OPLS-DA) e à correlação espectral. Após análise por validação cruzada de Monte-Carlo (MCCV), os modelos PLS-DA de LA permitiram distinguir as FM dos controlos (sensibilidades 69-85%, especificidades 80-95%, taxas de classificação 80-90%), revelando variações metabólicas ao nível do metabolismo energético, dos metabolismos dos aminoácidos e glícidos assim como possíveis alterações ao nível do funcionamento renal. Observou-se também um grande impacto das FM no perfil metabólico da urina materna (medido por UPLC-MS), tendo no entanto sido registados modelos PLS-DA com menor sensibilidade (40-60%), provavelmente devido ao baixo número de amostras e maior variabilidade da composição da urina (relativamente ao LA). Foram sugeridos possíveis marcadores relacionados com a ocorrência de FM, incluindo lactato, glucose, leucina, valina, glutamina, glutamato, glicoproteínas e conjugados de ácido glucurónico e/ou sulfato e compostos endógenos e/ou exógenos (<1 M) (os últimos visíveis apenas na urina). No LA foram também observadas variações metabólicas devido à ocorrência de vários tipos de cromossomopatias (CD), mas de menor magnitude. Os perfis metabólicos de LA associado a pré- PTD produziram modelos que, apesar do baixo poder de previsão, sugeriram alterações precoces no funcionamento da unidade fetoplacentária, hiperglicémia e stress oxidativo. Os modelos obtidos para os grupos pré- IUGR pré- PE, pré- PROM e pré-diagnóstico GDM (LA e urina materna) registaram baixo poder de previsão, indicando o pouco impacto destas condições na composição do LA e/ou urina do 2º trimestre. Os resultados obtidos demonstram as potencialidades da análise dos perfis metabólicos do LA (e, embora com base em menos estudos, da urina materna) do 2º trimestre para o desenvolvimento de novos e complementares métodos de diagnóstico, nomeadamente para FM e PTD.
The work presented in this thesis aimed to contribute to knowledge of 2nd trimester human amniotic fluid (AF) composition and to investigate the possible metabolic effects of prenatal disorders on AF composition through metabonomics, in order to define new potential disorder biomarkers. After an introduction describing the state-of-the-art (Chapter 1), the analytical methodologies used (Chapter 2) and the description of the experimental details of the work performed (Chapter 3), the results from the chemical characterization of AF (healthy pregnancy) by nuclear magnetic resonance (NMR) spectroscopy are presented, as well as the results of AF stability assessment during storage and after freeze-thaw cycles (Chapter 4). AF samples stored at -20°C registered significant compositional changes, less marked (but still measurable) at -70°C, the latter temperature being then recommended for AF storage. In addition, significant compositional changes were also observed after 1-2 freeze-thaw cycles (to be considered when sample re-usage is necessary), and at room temperature (indicating a maximum period of 4h for handling and analysis of AF). High resolution 1H NMR and hyphenated NMR (LC-NMR/MS) analysis enabled the detection of 75 different compounds in 2nd trimester AF, 6 of which were detected for the first time in AF. Moreover, diffusion-edited spectroscopy (DOSY) experiments allowed the characterization of the main AF proteins in terms of diffusivity and, hence, average molecular weight. Chapter 5 describes the study of the effects of fetal malformations (FM) and chromosomal disorders (CD) on the composition of 2nd trimester AF. In Chapter 6, this approach is extended, to the effects of 3rd trimester disorders, namely preterm delivery (PTD), preeclampsia (PE), intrauterine growth restriction (IUGR), premature rupture of the membranes (PROM) and gestational diabetes mellitus (GDM). These studies were complemented by a preliminary analysis of 2nd trimester maternal urine to study FM and GDM (Chapter 7). Interpretation of the analytical data obtained by 1H NMR spectroscopy, ultra performance liquid chromatography-mass spectrometry (UPLC-MS) and mid-infrared spectroscopy (MIR) was performed through partial least squares and orthogonal partial least squares - discriminant analysis (PLS-DA and OPLS-DA) and statistical correlation spectroscopy. Monte-Carlo cross-validated (MCCV) PLS-DA models of AF revealed separation of FM cases from controls (sensitivities 69-85%, 80-95% specificities, classification rates: 80-90%), revealing disturbances in energy metabolism, amino acids and sugar metabolisms and possibly abnormal kidney function. A high impact of FM on maternal urine was also observed (by UPLC-MS), however, the models obtained were of lower sensitivity (40-60%), probably due to the low sample numbers and higher variability of urine composition (in relation to AF). Possible markers of FM were suggested including lactate, glucose, leucine, valine, glutamine, glutamate, glycoproteins and conjugation products of glucuronic acid and/or sulfate with endogenous and/or exogenous metabolites (<1 M). In addition, metabolite variations were found in AF related to the occurrence of several types of chromosomal disorders (CD), although of smaller magnitude. Second trimester AF profiling associated with pre-PTD produced models, which, despite their low predictive power, enabled the detection of metabolite variations suggestive of early fetal-placental dysfunction, hyperglycaemia and oxidative stress. The models obtained for pre-IUGR, pre-PE, pre-PROM and pre-diagnostic GDM (both AF and urine) showed low predictive power, reflecting the small impact of these disorders in 2nd trimester AF and/or urine composition. The results presented demonstrate the potential of metabolic profiling of 2nd trimester AF (and, although based on less studies, maternal urine) for the development of new complementary prenatal diagnosis methods, namely for FM and PTD.

Objective: Expanding the original scope of the study, which was to explore the decision-making process of pregnant women in the uptake of invasive diagnostic tests - amniocentesis and Chorionic Villus Sampling (CVS) – and taking into account the latest emergence of a Noninvasive Prenatal Testing, NIPT, the primary goal of this study was to explore factors that influence women’s decision to have an invasive, a non-invasive or no further testing at all. Design and sample: The Prenatal Decision Making Questionnaire (PDMQ) developed for the purposes of this study. Following a pilot test and factor analysis, it was distributed to a population of pregnant women (N=421) prior to them receiving their combined screening results. The total sample was divided into three sub-groups according to their risk status (low-intermediate-high) for the analysis. Results. Logistic regression analysis using the R version 3.0.3 revealed that none of the PDMQ factors had a significant impact on women’s decision to have an invasive test (CVS), whereas the following three factors had a significant impact on the decision to have a non-invasive test (NIPT): negative attitude to doctors and an internal locus of control were associated with the uptake of NIPT, whereas a negative attitude to medicine was associated with rejection of NIPT When risk status was included in the model it was found that uptake of NIPT was predicted by the presence of some level of risk for T21 or T13/T18. On the contrary, uptake of CVS was only predicted by an increased risk for T21. Conclusion(s): Women’s decision making process in prenatal diagnosis is affected by several factors with personalised risk being one of the key determinants. The findings of this study can be used by healthcare professionals in providing the appropriate support and information and facilitating an informed decision during this stage of pregnancy.

OBJECTIVE: One major problem in counselling couples with a prenatal diagnosis of a correctable fetal anomaly is the ability to exclude associated malformations that may modify the prognosis. Our aim was to assess the precision of fetal sonography in identifying isolated malformations. METHODS: We retrospectively reviewed the prenatal and postnatal records of our center for cases with a prenatal diagnosis of an isolated fetal anomaly in the period 2002-2007. RESULTS: The antenatal diagnosis of an isolated malformation was made in 284 cases. In one of this cases the anomaly disappeared in utero. Of the remaining cases, the prenatal diagnosis was confirmed after birth in 251 (88.7%). In 8 fetuses (7 with a suspected coarctation of the aorta, 1 with ventricular septal defect) the prenatal diagnosis was not confirmed. In 24 fetuses (8.5%) additional malformations were detected at postnatal or post-mortem. In 16 of these cases the anomalies were mild or would not have changed the prognosis. In 8 cases (2.8%) severe anomalies were present (1 hypoplasia of the corpus callosum with ventriculomegaly, 1 tracheal agenesis, 3 cases with multiple anomalies, 1 Opitz Syndrome, 1 with CHARGE Syndrome, 1 COFS Syndrome). Two of these infants died. CONCLUSIONS: the prenatal diagnosis of an isolated fetal anomaly is highly reliable. However, the probability that additional malformations will go undetected albeit small remains tangible. In our experience, it was 2.8%.

The primary aim of this thesis was to outline an approach for the prenatal diagnosis of β-thalassaemia in the Asian Indian population by DNA analysis. A polymerase chain reaction (PCR) based, nonradioactive and rapid technique, allele specific PCR, was successfully developed for the detection of β-thalassaemia mutations. A large sample of 656 unrelated carriers from seven different regions of the Indian subcontinent was studied by allele specific PCR and DNA sequence analysis. Sixteen different β-thalassaemia mutations were identified, two of which were new mutations. Of these five common mutations accounted for 91.7% of β-thalassaemia alleles. The β-globin gene haplotypes of 419 β-Th and 196 β-A chromosomes were constructed. On analysis of which it was inferred that β-thalassaemia mutations occurred relatively recently on existing chromosomal backgrounds and then they experienced positive selection. A strong but not invariant haplotype-mutation linkage was observed. A regional variation in the distribution of β-thalassaemia mutations was found. a-Globin gene mapping studies identifed the single a-globin gene deletion in 24 out of 51 unrelated Asian Indians who were suspected to have a-thalassaemia. It is likely that the remaining carriers have nondeletional a-thalassaemia determinants. To perform preimplantation diagnosis of β-thalassaemia, by analysis of a 10-30 cell embryonic biopsy, a PCR protocol was developed. Using two rounds of PCR with nested primers, successful amplification of a 597 bp fragment of the β-globin gene was achieved from as few as two embryonic cells. The problem of false positive amplification was encountered which appeared to be resolved by UV transillumination of the pre-amplification PCR mix. By allele specific PCR with nested primers it was possible to identify the presence or absence of five β-thalassaemia mutations from 10 pg of template DNA (equivalent to approximately two diploid cells). Thalassaemia control in India is a complex issue; the financial, social and demographic factors involved were considered and recommendations made.

Mestrado em Métodos biomoléculares
A aplicação da metabonómica na pesquisa de novos biomarcadores de doenças tem ganho um interesse crescente na investigação e desenvolvimento, tanto ao nível do processamento analítico como do tratamento de dados. Nomeadamente, a análise metabonómica usando espectroscopia de Ressonância Magnética Nuclear (NMR) fornece uma grande quantidade de dados de uma forma rápida e não invasiva sobre a composição de amostras complexas como o plasma sanguíneo. Uma vez que as doenças pré-natais têm um elevado impacto no metabolismo materno e fetal, sendo responsáveis por várias complicações durante e depois da gravidez, esta estratégia foi aplicada ao estudo destas doenças através da análise de sangue de senhoras grávidas (colhido entre 15-24 semanas de gestação), com o objectivo de investigar possíveis metabolitos marcadores ou com poder de previsão para a diabetes gestacional e malformações fetais. Num primeiro passo, foram estudados os perfis metabólicos em RMN dos controlos (n=20) e gravidezes com diagnóstico ou suspeita de malformações fetais (n=11) e pré-diabetes gestacional (com posterior diagnóstico clínico entre 22-34 semanas de gestação). A análise multivariada (análise de componentes principais, PCA; análise discriminante pelo método de mínimos quadrados parcias, (PLS-DA) e duas versões deste último, interval PLS-DA e ortogonal PLS-DA (OPLS-DA)) foram aplicados com o objectivo de pesquisar por correlações de solidez estatística entre a composição do plasma e a ocorrência das doenças em estudo. Os resultados mostraram que as amostras controlo e doença podem ser diferenciadas com base no seu perfil metabólico, nomeadamente mostrando níveis mais elevados de compostos que contêm colina em mulheres que desenvolveram diabetes gestacional mais tarde na gravidez. Adicionalmente, níveis mais elevados de piruvato, manose e compostos que contêm colina, e níveis mais baixos de vários aminoácidos e acetato foram encontrados nas gravidezes afectadas por malformações fetais. Numa segunda etapa do trabalho, as mesmas amostras foram analisadas por espectroscopia de Infravermelho com Transformadas de Fourier (FTIR), um método mais barato e acessível para eventual uso clínico. O perfil dos espectros de FTIR também revelou algumas diferenças entre controlos e doenças, no entanto a sua interpretação específica torna-se difícil devido à grande sobreposição de bandas característica de espectros de infravermelho. Estes resultados mostraram que a análise metabonómica de plasma de mulheres grávidas por RMN e FTIR pode ser uma ferramenta poderosa para obter informação bioquímica sobre a saúde pré-natal e encontrar possíveis novos marcadores com potencial para prever doenças, particularmente no caso do diabetes gestacional. ABSTRACT: The use of Metabonomics to search for new disease biomarkers has gained increasing interest in the research community and continuous developments, both at the analytical and data processing levels have boosted this area into new quests in biomarker research. Namely, Nuclear Magnetic Resonance (NMR)-metabonomics provides a large amount of compositional data on complex samples such as blood plasma, in a rapid and non-invasive manner. Since prenatal diseases have a high impact on both maternal and fetal metabolisms, being responsible for a range of complications both during and after pregnancy, this strategy was hereby applied to the study of prenatal diseases, through the analysis of blood (collected at 15-24 gestational weeks), in order to probe for possible marker/predictor metabolites for gestational diabetes and fetal malformations. In the first stage of this work, the plasma metabolic profiles of controls (n=20) and pregnancies affected by diagnosed or suspected fetal malformations (n=11) and pre-gestational diabetes (with posterior clinical diagnosis at 22-34 gestational weeks) were evaluated by NMR spectroscopy. Multivariate analysis (principal component analysis, PCA; partial least squares discriminant analysis, PLS-DA and two extended versions of the latter, interval PLS-DA (iPLS-DA) and orthogonal PLS-DA (OPLS-DA) were applied in order to search for consistent statistical correlations between plasma composition and the occurrence of the diseases. It was found that controls and diseased subjects could be differentiated with basis on their plasma profile, namely showing higher levels of choline-containing compounds in pregestational diabetic women. In addition, higher contents of pyruvate, mannose and choline-containing compounds and lower contents of several amino acids and acetate were found in pregnancies affected by fetal malformations. In a second stage of the work, the same samples were analysed by Fourier Transform Infrared (FTIR) spectroscopy, a cheaper and more-accessible method, more suited to straightforward clinical use. The FTIR spectral profiles also revealed some differences between controls and diseased subjects, the interpretation of which posing a harder challenge than that of NMR. These results have shown that NMR and FTIR metabonomics of pregnant women blood plasma may be a powerful tool to gain insight into prenatal diseases and find possible new markers with potential predictive value, particularly in the case of gestational diabetes.

This research examines the many different ethical issues that emerge in the health care setting with regards to prenatal diagnostic testing. Identifying the areas of clinical practice and religious counselling in need of improvements, particularly physician-client communication, is important to ensure that competent pregnant women make informed, considered choices about prenatal testing. This paper investigates the many factors that contribute to pregnant women's decision-making processes surrounding the acceptance or refusal of the maternal serum alpha-fetoprotein screen, ultrasonography, amniocentesis, chorionic villus sampling, and preimplantation diagnosis. Integrating scholarship in bioethics, religious studies, and the anthropological and sociological study of medicine, this dissertation offers a comparative analysis of religious attitudes toward prenatal diagnostic testing, describes the complexities of practical decision-making by pregnant women faced with genuine ethical dilemmas, and provides an analysis of ethical issues related to prenatal testing. This research will be of interest to scholars in religious studies and bioethics, prenatal genetic counsellors and obstetricians involved in the provision of prenatal diagnostic testing services, and specialists in women's health and reproductive decisionmaking.

There has been an increase in rates of chromosomal abnormalities in newborns as a result of reproductive aging. For the past decades, a lot of effort has been placed on identifying pregnancies at risk of genetic defects. Conventional prenatal genetic diagnosis is achieved by invasive procedures that have been associated with an increased risk of pregnancy loss. This has led the researchers to explore the use of non-/minimally invasive techniques for prenatal diagnosis. Trophoblasts are known to be shed from regressing chorionic villi into the lower uterine pole of pregnant women during the first trimester. These cells are trapped within cervical mucus, which can be retrieved with a cytobrush. By using human leukocyte antigen G (HLA-G) and cytokeratin-7 (CK7) as trophoblast markers, this study aims to investigate the possibility of isolating individual fetal trophoblast from transcervical samples for genetic diagnosis. 195 healthy pregnant women requesting for legal termination of pregnancy (TOP) were recruited in this study. Transcervical cells were collected from them with the use of a cytobrush before TOP. HLA-G+ or CK7+ cells were then isolated by a combination of mucolytic action, fluorescent immunohistochemistry, and micromanipulation. The origin of these cells was subsequently investigated by either fluorescent in situ hybridization (FISH) or allelic profiling by quantitative fluorescent polymerase chain reaction (QF-PCR) based on chromosome 16, chromosome X, amelogenin gene and sex determining region Y (SRY) gene. This study first demonstrated the presence of fetal cells in transcervical samples based on the detection of chromosome Y signal by ordinary PCR. Cells expressing HLA-G and CK7 were also identified among transcervical cells. Immunopositive cells were isolated by micromanipulation under fluorescent microscopy. One isolated cell expressing CK7 was shown to inherit paternal allele at a locus on chromosome 16, suggesting the possible fetal origin of this cell. However, this study was still hampered by a number of technical factors. Further optimization of the protocol is required before transcervical trophoblasts can be retrieved in a reliable manner.
published_or_final_version
Obstetrics and Gynaecology
Master
Master of Philosophy