The feto-placental unit synthesises a variety of proteins and hormones which are secreted into the maternal circulation and amniotic fluid from early pregnancy. In pregnancies where the fetus has an autosomal trisomy, the normal concentration profiles of these markers in maternal serum and amniotic fluid are disturbed. These marker changes can be used to estimate the risk that a pregnancy is affected by Down's syndrome (or Trisomy 18) and thus allow the parents to make an informed decision regarding prenatal diagnosis by invasive testing. However, the factors which give rise to the varying patterns of marker concentrations in chromosomally abnormal pregnancies are poorly understood. The aim of this project was to investigate the underlying causes of abnormal marker concentrations in Down's syndrome, Trisomy 13, and Trisomy 18 pregnancies. The results of this investigation indicate that in Down's syndrome pregnancies, maternal serum levels of placental products reflect those found in the placenta; intact hCG, FβhCG and SP1 levels were elevated while PAPP-A and placental ALP levels were little changed. This suggests that transport of these proteins from the placenta into the maternal circulation is not affected but there is altered synthesis of hCG subunits and SP1. Hepatic synthesis of AFP does not appear to be altered in Down's syndrome pregnancies, but increased placental and reduced maternal serum levels of AFP point to a possible placental transport defect specific to AFP. Similarly reduced GGT levels in fetal intestine and in corresponding amniotic fluid from Down's syndrome pregnancies suggest that amniotic fluid GGT activity is of fetal intestinal origin since GGT activity was elevated in fetal liver and placental from the same series of Down's syndrome pregnancies.

Informed consent, based on patient autonomy, is seen as necessary if medical interventions are to be seen as legally and ethically acceptable. While 'informed consent' protocols within antenatal care, including prenatal screening regimes are presumed to be robust, emerging research outside of Australia suggests most women do not adequately understand the medical purpose, limitations or potential ethical implications, such as selective termination, of the medical procedures 'consented' to. While the consent given in these situations may well fulfil the minimal legal criteria for informed consent, the required level of knowledge and understanding necessary to meet the ethical standards informed or understood consent often appears not be met. The presumption that legally informed consent equates to morally informed consent inherent within institutional protocols for screening must therefore be questioned, and the ethical integrity of these increasingly routine interventions demand further scrutiny. The purpose of this research was to explore whether the problems identified in research overseas might also exist locally. Underpinned by a phenomenological philosophical approach to understanding the ethical dimensions of clinical practice, the research sought to engage with a small cohort of mothers and practitioners locally. The study adopted a qualitative narrative methodology, analysing individual in-depth interviews using the Listening Guide (Gilligan et al, 2003). The experiences of mothers and health practitioners interviewed exposed a range of institutional, social, personal and philosophical constraints that mirrored the overseas research findings and also illuminated how informed consent may be unintentionally undermined in the clinical setting. A positive outcome of the study was that it provided a locally informed and contextually sensitive basis from which to strengthen existing organisational informed consent protocols and thus support women's ethical decision making. As the process of becoming 'informed' to consent is largely educational, promoting patient learning in the clinical context is an ethical imperative. However, there seems limited awareness at either the clinical or theoretical level of the critical link between patient education and ethically robust medical intervention. Hence a significant contribution of this research was to explore this underdeveloped but practically important link. As the process of gaining informed consent has far reaching applications across a broad spectrum of medical interventions, the contextual and educational insights offered throughout this research may have significant relevance beyond the immediate context of this research.

The overall aim of this thesis was to describe pregnant women's and partners' views and experiences on early prenatal screening with the combined test, with special focus on the two-step information model. Interviews were performed with 15 couples who had taken part in the extended information visit about prenatal screening, describing their perceptions of the information model (I) and ten couples or women of those, for a follow-up interview exploring their decision-making process (II). Seven couples, who had not taken part in the extended information visit, were interviewed describing their views and experiences about prenatal screening (III). A questionnaire was answered by 295 women and by 223 partners about their satisfaction about the decision whether or not to participate in the combined test, and their assessment of whether or not this choice had been difficult (IV). The results showed that different opinions were expressed about the offer of the extended information visit. The separate visit was welcomed by most couples (I). The decision-making process regarding whether to take part in the test or not was described by most couples as a fairly straightforward decision, while for others it was a more complex process that required a great deal of consideration (II). An apprehension of the test, by some of those who had refrained the extended information visit, was that it was an expression of society's involvement in decisions that belong to the expectant parents (III). Ninety-three percent of both women and partners considered the decision about participating in the combined tests as uncomplicated, and well over 90%, of both women and partners were satisfied with their decision (IV). The conclusions in this thesis, are that the decision whether or not to participate in the combined test is multidimensional and influenced by different views. The two-step information model helped the pregnant woman and the partner to make a decision in a fairly straightforward process or a more complex process with mixed feelings.

This project considers how disability studies and rhetorical studies—specifically the area of medical rhetoric—might usefully inform one another. In particular, this project examines prenatal testing for Down syndrome as a rhetorical situation that initiates and circulates many different discourses about Down syndrome. Chapter One begins by examining a frequently cited statistic in critiques of prenatal testing—the estimated pregnancy termination rate after a prenatal diagnosis of Down syndrome. It explores the validity of this statistic and uses this discussion to suggest that the effects of prenatal testing on social understandings of Down syndrome are complex and largely unknown. Chapter Two argues that intellectual disabilities, like Down syndrome, are underrepresented in disability studies literature and that their absence can be partially attributed to models of disability used in the field. Chapter Three argues that rhetorical analysis provides a means of examining how Down syndrome is discursively constructed. Chapter Four describes the events of prenatal testing for Down syndrome and analyzes the events as a rhetorical situation. In addition, it reviews feminist, disability, and cultural critiques of prenatal testing demonstrating the strengths of each strand of scholarship and suggesting where rhetorical analysis might provide new information. Chapters Five and Six provide analysis of two commentaries on the rhetorical situation of prenatal testing—genetic counseling discourse and parent discourse. These chapters find that ideal genetic counseling discourse offers pregnant women some opportunities to resist medicalization but also exhibits tension between what counselors say they do and what their rhetorical practice affords, especially regarding disability. In addition, analysis shows that users of prenatal testing are concerned with several factors of decision-making that are either not emphasized or ignored entirely in genetic counseling discourse. This project concludes that although different discourses about Down syndrome are available, elements of the prenatal testing situation make it easier for participants to draw on some discourses rather than others. Furthermore, it appears that certain events in the prenatal testing situation—such as the offer of amniocentesis—operate rhetorically in tacit ways, obscuring the relationship between the choice to undergo genetic screening and perceived meanings of Down syndrome. / Ph. D.

Hensikt: Hensikten med studien er å fordype kunnskapen om hvordan gravide kvinner opplever en tidlig ultralydundersøkelse med risikovurdering for kromosomavvik, og hvordan de resonnerer omkring resultatet. Nytteverdien blir å løfte frem denne kunnskapen, og ta den med i den videre debatten omkring dette tema. Metode: Det ble gjort en kvalitativ intervjuundersøkelse med ti gravide kvinner som skulle få utført en risikovurdering for kromosomavvik. Kvinnene ble intervjuet både før og etter undersøkelsen. Grounded theory ble benyttet som analysemetode. Resultater: I studien ble det ble generert en kjernekategori; Jeg vil ha valget, men ikke ta det, og fem hovedkategorier: Eksistensielle valg, Trygghetsfølelse, Engstelse, Skyldfølelse og Veiledning / Ivaretakelse. Kjernekategorien beskriver kvinnenes konflikt mellom å ville ha muligheten til denne undersøkelsen, og samtidig ha vanskeligheter med å ta de påfølgende valgene. Noen av faktorene som gjorde valgene så vanskelige var engstelse, tap av kontroll / mestring, tilknytning til fosteret, skyldfølelse og sosialt press. Siden kvinnene ønsket selvstendige valg uten påvirkning fra andre, følte de også en større ansvarlighet for de valg som ble tatt. Forståelsen av den kalkulerte risikoen varierte mellom kvinnene, og de benyttet ulike metoder for å lette vurderingen og valget. Gravide kvinner har et stort informasjonsbehov når det gjelder prenatal diagnostikk, og de ønsker en lett tilgjengelighet til spesialisthelsetjenesten. For å få tid til refleksjon over egne verdier og holdninger, er det viktig at informasjonen blir gitt på et så tidlig tidspunkt i svangerskapet som mulig. Konklusjon: Studien viser kompleksiteten av følelser som gravide kvinner kan oppleve i forbindelse med en tidlig ultralydundersøkelse og risikovurdering for kromosomavvik. Disse stressrelaterte følelsene kan sammen med beslutninger på komplisert risikoinformasjon, og på et sterkt ansvarlig og moralsk område vanskeliggjøre beslutningsprosessen. En bedre informasjonsformidling og kontakt med helsevesenet er nødvendig for at kvinnene skal ta informerte valg, som er i tråd med deres verdier og holdninger. / Purpose: This qualitative study aimed to increase understanding of how pregnant women experience early ultrasound examination that includes risk assessment for chromosomal anomalies. Moreover, this study examined how such women rationalize test results. Method: I conducted pre- and post-examination interviews of ten pregnant women undergoing risk assessment for chromosomal anomolies, and used grounded theory to analyze the results. Results: The study generated a core category (I want a choice, but I don’t want to decide) and five main categories (existential choices, feeling of safety, anxiety, guilt, and counselling and care). Factors contributing to choice difficulty included anxiety, loss of control or coping, emotional connection to the fetus, feelings of guilt, and social pressures. The core category describes the conflict between choice and decision. Since the women sought independent choices without external influence, they also felt greater responsibility. The women’s understanding of actual risk varied, and they used different logic and methods to evaluate risk and reach a decision. Conclusion: Pregnant women need for prenatal diagnostic information and want easy access to specialty services. This study shows the complex feelings pregnant women experience regarding early ultrasound examination that includes risk assessment for chromosomal defects. Stress, non-transparent information about actual and perceived risks, and personal moral judgments further complicate the decision-making process. Therefore, improved distribution of information and frequent contact with health professionals will help women to make informed choices in accordance with their values and beliefs. / <p>ISBN 978-91-5-85721-47-4</p>

Statement of problem: We have shown that the C677T 5,10 methylenetetrahydrofolate reductase (MTHFR) variant is associated with elevated maternal serum α-fetoprotein (MSAFP), the most common screening test for neural tube defects (NTD). Therefore, past contradictory studies of NTDs and C677T MTHFR may have been biased because of changes in case populations after prenatal diagnosis and termination of pregnancy. Further, an unexplained elevation of MSAFP is known to increase the risk for later pregnancy complications. Is the C677T MTHFR variant a predisposing genetic variant for both NTDs and later complications of pregnancy? Methods: A retrospective study of women with pregnancies resulting in NTD outcome and women with unexplained elevations of MSAFP was undertaken. Women and their partners were genotyped for the C677T MTHFR allele. Couples with a pregnancy resulting in a NTD outcome were compared to couples whose pregnancy outcome did not involve. Couples with unexplained elevations of MSAFP who did and did not have later complications of pregnancy were also compared. Allele frequencies for all groups were then compared against the previously established Manitoba population allele frequency (based on 977 consecutive newborn metabolic screening bloodspots). A review of all studies of NTDs and association with the C677T MTHFR variant was undertaken to determine if the association between the variant and MSAFP is a source of bias. NTD incidence was examined before and after folic acid food fortification introduced in Canada in 1999. Results: There is an increase in the allele frequency of the C677T MTHFR variant in parents with an unexplained elevated MSAFP followed by later complications of pregnancy. The C677T MTHFR variant is also a contributing genetic factor to NTDs worldwide. The incidence of NTDs in Manitoba has decreased by 37% since food fortification with folic acid was introduced. Conclusions: The C677T MTHFR variant is a contributing genetic factor to both later complications of pregnancy after an unexplained elevation of MSAFP and to NTDs. This variant is folate sensitive and folic acid fortification has reduced the incidence of NTDs. / February 2005

Statement of problem: We have shown that the C677T 5,10 methylenetetrahydrofolate reductase (MTHFR) variant is associated with elevated maternal serum α-fetoprotein (MSAFP), the most common screening test for neural tube defects (NTD). Therefore, past contradictory studies of NTDs and C677T MTHFR may have been biased because of changes in case populations after prenatal diagnosis and termination of pregnancy. Further, an unexplained elevation of MSAFP is known to increase the risk for later pregnancy complications. Is the C677T MTHFR variant a predisposing genetic variant for both NTDs and later complications of pregnancy? Methods: A retrospective study of women with pregnancies resulting in NTD outcome and women with unexplained elevations of MSAFP was undertaken. Women and their partners were genotyped for the C677T MTHFR allele. Couples with a pregnancy resulting in a NTD outcome were compared to couples whose pregnancy outcome did not involve. Couples with unexplained elevations of MSAFP who did and did not have later complications of pregnancy were also compared. Allele frequencies for all groups were then compared against the previously established Manitoba population allele frequency (based on 977 consecutive newborn metabolic screening bloodspots). A review of all studies of NTDs and association with the C677T MTHFR variant was undertaken to determine if the association between the variant and MSAFP is a source of bias. NTD incidence was examined before and after folic acid food fortification introduced in Canada in 1999. Results: There is an increase in the allele frequency of the C677T MTHFR variant in parents with an unexplained elevated MSAFP followed by later complications of pregnancy. The C677T MTHFR variant is also a contributing genetic factor to NTDs worldwide. The incidence of NTDs in Manitoba has decreased by 37% since food fortification with folic acid was introduced. Conclusions: The C677T MTHFR variant is a contributing genetic factor to both later complications of pregnancy after an unexplained elevation of MSAFP and to NTDs. This variant is folate sensitive and folic acid fortification has reduced the incidence of NTDs.

Statement of problem: We have shown that the C677T 5,10 methylenetetrahydrofolate reductase (MTHFR) variant is associated with elevated maternal serum α-fetoprotein (MSAFP), the most common screening test for neural tube defects (NTD). Therefore, past contradictory studies of NTDs and C677T MTHFR may have been biased because of changes in case populations after prenatal diagnosis and termination of pregnancy. Further, an unexplained elevation of MSAFP is known to increase the risk for later pregnancy complications. Is the C677T MTHFR variant a predisposing genetic variant for both NTDs and later complications of pregnancy? Methods: A retrospective study of women with pregnancies resulting in NTD outcome and women with unexplained elevations of MSAFP was undertaken. Women and their partners were genotyped for the C677T MTHFR allele. Couples with a pregnancy resulting in a NTD outcome were compared to couples whose pregnancy outcome did not involve. Couples with unexplained elevations of MSAFP who did and did not have later complications of pregnancy were also compared. Allele frequencies for all groups were then compared against the previously established Manitoba population allele frequency (based on 977 consecutive newborn metabolic screening bloodspots). A review of all studies of NTDs and association with the C677T MTHFR variant was undertaken to determine if the association between the variant and MSAFP is a source of bias. NTD incidence was examined before and after folic acid food fortification introduced in Canada in 1999. Results: There is an increase in the allele frequency of the C677T MTHFR variant in parents with an unexplained elevated MSAFP followed by later complications of pregnancy. The C677T MTHFR variant is also a contributing genetic factor to NTDs worldwide. The incidence of NTDs in Manitoba has decreased by 37% since food fortification with folic acid was introduced. Conclusions: The C677T MTHFR variant is a contributing genetic factor to both later complications of pregnancy after an unexplained elevation of MSAFP and to NTDs. This variant is folate sensitive and folic acid fortification has reduced the incidence of NTDs.

Pregnancy alcohol consumption has been linked to poor birth outcomes and long-term developmental problems. Despite this, a significant number of women drink during pregnancy. Although most prenatal care providers are asking women about alcohol use, validated screening tools are infrequently employed. Research has demonstrated that currently available screening methods and intervention techniques are effective in identifying and reducing pregnancy drinking. Implementing universal screening and appropriate intervention for pregnancy alcohol use should be a priority for prenatal care providers, as these efforts could substantially improve pregnancy, birth, and longer term developmental outcomes for those affected.

No / Although Streptococcus agalactiae, the group B Streptococcus, is a leading cause of invasive neonatal disease worldwide the molecular basis of its virulence is still poorly understood. To investigate the role of lipoproteins in the physiology and interaction of this pathogen with host cells, we generated a mutant S. agalactiae strain (A909DeltaLgt) deficient in the Lgt enzyme and thus unable to lipidate lipoprotein precursors (pro-lipoproteins). The loss of pro-lipoprotein lipidation did not affect the viability of S. agalactiae or its growth in several different media, including cation-depleted media. The processing of two well-characterized lipoproteins, but not a non-lipoprotein, was clearly shown to be aberrant in A909DeltaLgt. The mutant strain was shown to be more sensitive to oxidative stress in vitro although the molecular basis of this increased sensitivity was not apparent. The inactivation of Lgt also resulted in changes to the bacterial cell envelope, as demonstrated by reduced retention of both the group B carbohydrate and the polysaccharide capsule and a statistically significant reduction (P=0.0079) in A909DeltaLgt adherence to human endothelial cells of fetal origin. These data confirm that failure to process lipoproteins correctly has pleiotropic effects that may be of significance to S. agalactiae colonization and pathogenesis.