The consequences of complications during calving are currently costing the UK dairy cattle industry approximately £110 for a calving of moderate difficulty and £400 for one that is severe. With incidences of difficult first calvings reaching 24% and 4% for a moderate and severe difficult calving respectively, reducing calving complications would be of great benefit to the UK dairy cattle industry. This PhD evaluates (i) the importance, (ii) the most optimal way, and (iii) the potential consequences of genetically selecting for two main traits associated with calving complications, calving ease (CE) and stillbirth (SB). For this, approximately 50.000 first parity and 300.000 later parity national calving data records were kindly provided by two major milk recording organisations in the UK. The work carried out shows that detrimental effects following a difficult first calving are long-lasting as subsequent performance of both the dam and the calf involved is worsened. Fertility of the dam is negatively affected by a difficult calving resulting in an increased calving interval and decreased ability to conceive. A reduction in milk production of a veterinary assisted dam, compared to a non-assisted dam, was detected in the first part of lactation. Veterinary assisted born calves showed a significantly lower milk yield, compared to farmer assisted calves, throughout their first lactation as adult heifers suggesting that the physiological effects, or causes underlying a difficult birth, are long lived. The study advises that genetic parameters of calving traits are to be estimated with an extended sire multi-trait model (accuracy vs. practicality). On average, direct and maternal heritabilities for calving traits are low. A highly heritable indicator trait such as gestation length (GL) can aid in the estimation of genetic parameters for CE and SB although genetic correlations of these traits with GL are moderate. A significant negative genetic direct-maternal correlation was found for CE in first parity recommending farmers to consider both direct and maternal genetic merit for CE when making a selection decision. CE and SB are highly positively correlated traits. GL is maternally correlated to SB in first parity and directly to CE in later parities, both correlations are positive. Estimated genetic correlations with other important traits in dairy cattle breeding show that CE and GL are both directly and maternally related to important selection traits which need to be taken into account if implementation into breeding indices occurs. Results advise limiting the use of GL to benefit the prediction of parameters for low heritable calving traits rather than selecting on GL itself. Genetic correlations suggest that individuals born easily are genetically prone to high milk yield and have reduced fertility in first lactation. Difficult calving heifers are likely to be associated with being wide and deep and high producing animals with a reduced ability to subsequently conceive. Individuals that are born relatively early are associated with good genetic merit for milk production. And finally, individuals carrying their young longer are genetically associated with being wide and large animals that were born relatively early themselves. Lastly, an extension of the current univariate genomic model to a bivariate model, which allows for a possible genetic direct-maternal covariance, shows that improvement in accuracy of genomic breeding values can be gained from use of a bivariate genomic model for maternal traits such as CE. Further development of the model is however recommended prior to the publication of genomic proofs for CE or any other maternal trait. Genetic selection can serve as a tool in the reduction of difficult calvings. The results of this thesis serve to let this happen in a controlled and sustainable manner.

For every 200 births in the UK, one will end in a stillbirth. Stillbirth is classified as a baby born dead after 24 weeks gestation. Mutations in genes that cause ion channelopathies are known to cause sudden cardiac death in adults and children. Prenatal diagnosis of LQT has been possible for decades, creating a disease spectrum where channelopathies may fatally influence pregnancy. We sequenced 35 candidate genes in 70 unexplained stillbirth cases. Thirty-nine cases harboured a predicted damaging protein missense variant. Two novel and two rare variants were observed in the transient receptor potential melastatin 7 (TRPM7) gene and five rare genetic variants were found in A-kinase anchor protein 9 (AKAP9). The aim of this PhD was to perform functional studies of these variants in TRPM7 and AKAP9. TRPM7 is an ion channel indispensable for mouse cardiogenesis. Two TRPM7 variants (p.G179V and p.T860M) showed significantly reduced current compared to wild-type channels. Conversely, cells expressing p.R494Q TRPM7, had a significant increase in current compared to WT channels, but only in CHO-K1 cells. Western blot analyses failed to detect full length TRPM7 in cells transfected with either p.G179V or p.T860M compared to wild-type expressing cells. Proteosomal inhibition using MG132 produced a small but visible band in p.T860M transfected cells. Expression of TRPM7 in iPSC-derived cardiomyocytes increases during cell maturation, and TRPM7-like current was measured in 20-23 day old cardiomyocytes. AKAP9 is required to couple adrenergic stimulation in the heart with faster cardiac repolarisation. Cells expressing WT AKAP9 alongside the KCNQ1/KCNE1 potassium channel responded to β-adrenergic stimulation, however those transfected with p.A3043T AKAP9 did not respond to treatment with forskolin. Our analyses supports two deleterious variants in TRPM7 and one in AKAP9 in unexplained stillbirth cases. These heterozygous variants could lead to haploinsufficiency and may be a cause of stillbirth.

Typescript. / Digitized by Kansas Correctional Industries

Background Unexplained stillbirth is the largest contributor to perinatal death, accounting for one third of stillbirths. Although prognostic information is limited, there is no increase in perinatal death rates in subsequent pregnancies after an unexplained stillbirth. However, those pregnancies have increased rates of preterm birth, low birthweight, induced labour, instrumental and caesarean delivery, 'fetal distress,' and postpartum haemorrhage. These outcomes might be iatrogenic, caused by obstetric intervention. Aims 1. To examine obstetricians' and womens' wishes for management in pregnancies subsequent to an unexplained stillbirth, and whether these might contribute to an increase in rates of intervention. 2. To examine whether socio-demographic factors, or how women perceive that an unexplained stillbirth was managed, influence how women want their next pregnancy managed. 3. To assess whether management of unexplained stillbirth differs according to model of care, or country where the event occurred. Methods 1. An anonymous postal survey of all Australian obstetricians to determine recommended management of the next pregnancy after an unexplained stillbirth. 2. An Internet-based survey of women after an unexplained stillbirth, seeking details about their wishes for subsequent pregnancy management. Results 1. Obstetricians' survey Early pregnancy managements were little different from standard care of low-risk pregnancy. Increased 'fetal surveillance' (by ultrasound, cardiotocography, and formal fetal movement charting) in late pregnancy was recommended by most respondents. Induction of labour would be offered by 93% of respondents, as early as 37 weeks by one third. More than one third of obstetricians would offer elective caesarean delivery, with 13% offering this before 38 weeks. 2. Womens'survey 93% of respondents wanted 'testing' over and above normal pregnancy care in their next pregnancy. 81% of respondents wanted early delivery, and 26% wanted a caesarean delivery, irrespective of obstetric indications. These wishes were not influenced by socio-demographic factors, management of the index stillbirth (with the exception of having had a caesarean delivery), or advice received about management of the next pregnancy (with the exception of being advised to have an early or caesarean delivery). Conclusions Both obstetricians and the women they care for wanted increased fetal surveillance and early delivery, but not necessarily elective caesarean section. These practices have the potential to increase the rate of intervention, with consequent adverse maternal and neonatal outcomes.

Thesis (M.S.W.)--University of Wyoming, 2008. / Title from PDF title page (viewed on Nov. 12, 2009). Includes bibliographical references (p. 51-57).

This study aimed to address how fathers made sense of their experience of losing their baby due to stillbirth after receiving one-to-one counselling/therapy. An Interpretative Phenomenological Analysis was used to explore the unique lived experience of each father. Eight semi-structured interviews were carried out with fathers of a stillborn baby who had experienced some form of one-to-one counselling/therapy in the aftermath of their loss. The research found that fathers developed an embodied relationship and continued to experience an ongoing relationship with their stillborn child. The fathers were changed by their experience of having a stillborn baby in fundamental and complex ways. The fathers also re-addressed aspects of their ‘masculine selves’ in response to this profound loss. It was meaningful for the fathers when their relationship with their stillborn child was validated and legitimised in their one-to-one counselling/therapy. Moreover, some fathers were able to address the confusion and ambiguity around the nature of their loss and their experience as men. The fathers expressed the unique ways they were transformed by their experience emotionally, psychologically, and existentially. Some fathers could begin to make sense of this and find meaning in their experience when it was recognised in their individual therapy. Finally, a critique of the limitations of the research process and methodology was provided and suggestions for further research were offered.

Healthy pregnancy requires a tightly regulated materno-fetal dialogue for processes such as embryo implantation, endometrial decidualisation (in the mouse), placentation and maternal adaptation to occur. Disruption of placental development as well as maternal adaptation can lead to fetal intrauterine growth restriction (IUGR) which increases the risk of late miscarriage/stillbirth (e.g. 53% of preterm stillbirth and 26% of term stillbirth are found to be IUGR). Furthermore, IUGR is a risk factor for neurodevelopmental conditions in childhood and for a spectrum of related adult health disorders such as cardiovascular disease and type II diabetes, often termed metabolic syndrome. Despite these pregnancy disorders being common (e.g. 1 in 200 pregnancies results in stillbirth in the UK) the molecular lesion(s) underlying their pathophysiology are poorly understood and in particular those with placental and/or maternal aetiologies most frequently remain unexplained. Here we investigate the hypothesis that poly(A)-binding protein 4 (PABP4) is required for healthy pregnancy in mice. PABP4 is an RNA-binding protein and a member of the PABP family which are central regulators of mRNA translation and stability. Using all four permutations of wild-type and knock-out crosses, we find that maternal PABP4-deficiency results in a reduced litter size and IUGR. The number of implantations at e8.5 were not reduced in Pabp4-/- females, implying that the reduced litter size was not a consequence of decreased ovulation, fertilisation or implantation frequency. Further longitudinal analysis (at e13.5, e15.5 and e18.5) reveals that fetal death primarily occurred between e18.5 and birth, suggesting these mice may provide a unique opportunity to inform on the maternal causes of stillbirth. The onset of IUGR, which was found to be symmetrical in nature, was established by e15.5 preceding the majority of fetal death. During pregnancy, a materno-fetal dialogue directs and responds to changes in gene expression to give rise to the placenta and adapt the maternal physiology. Defects in these processes may result in reduced growth and/or fetal death and were examined in Pabp4-/- mice to shed light on the mechanistic basis of these related phenotypes. Fetal to placental (F:P) weight ratio, whose changes can be indicative of placental insufficiency or placental adaptation in an attempt to aid fetal growth, was found to be increased in Pabp4-/- dams at e15.5 and e18.5 due to the presence of IUGR fetuses with placentas of normal weight. Consistent with this observation, placental volume was unchanged at e18.5. Total placental weight and volume alone fails to discriminate potential differences in the individual placental zones which include the labyrinth zone, where materno-fetal gas and nutrient exchange occur; the junctional zone, which has endocrine functions including those that promote maternal adaptation; and the decidua basalis, derived from the maternal endometrium and is the site of trophoblast invasion and maternal vascular remodelling in early pregnancy. Therefore, volumetric analysis of these zones and the maternal blood spaces, which transcend the decidua basalis and junctional zone, was undertaken. This showed no change in the maternal blood spaces or the labyrinth, the latter being the zone whose size is most frequently altered in IUGR. Critically however, the size of the maternally-derived decidua basalis was increased with a concurrent decrease in the size of the junctional zone. These morphological changes may play a causative role either through directly affecting placental function and/or by the reduced junctional zone failing to promote appropriate maternal adaptation. Alternatively, they may reflect compensatory adaptations to a primary defect elsewhere in the mother. Complementing these morphological studies, functional studies were undertaken: remodelling of maternal vasculature and the resistance index of vessels delivering blood to the fetus were assessed; as was delivery of nutrients to the fetus (measured by fetal glucose); and systemic maternal adaptations (maternal hormonal profile, circulating glucose levels and organ weights). Uterine, umbilical and decidual spiral arteries were examined, but displayed no apparent differences suggestive of normal blood supply to the fetus. However fetal blood glucose was reduced suggesting a reduced delivery of nutrients important for fetal growth. This was not due to lower circulating maternal blood glucose levels, and mRNA levels of the placental glucose transporters Glut-1 and Glut-3 were not reduced but upregulated, suggestive of an attempt to compensate for reduced fetal glucose. Furthermore, upregulation of at least one system A amino acid transporter mRNA, Snat-2, was observed. The maternal physiological state of PABP4-deficient dams showed deviations in some organ weights (e.g. spleen weight is reduced at e13.5 and e15.5) and the levels of some circulating hormones (e.g. estradiol is deceased whereas progesterone is increased at e18.5). However, future work will be required to determine which, if any, of these changes are primary defects rather than downstream consequences and to identify which mis-regulated mRNAs/pathways within in the materno-fetal dialogue underlie the phenotype. Taken together, my results suggest that the regulation of mRNA translation/stability by PABP4 is critical to achieving the correct pattern of gene expression within the materno-fetal dialogue to enable appropriate placentation and maternal adaptation. Furthermore, my results suggest that Pabp4-/- mice provide a unique opportunity to further understand the maternal causes of a spectrum of related pregnancy complications including IUGR, late miscarriage and stillbirth.

Thesis (MSD(Play therapy))--University of Pretoria, 2006. / Abstract in English and Afrikaans. Includes bibliographical references. Available on the Internet via the World Wide Web.

Statistics Canada data indicates that between 2002 and 2006, the late stillbirth incidence (at or beyond 28 weeks gestation) was 3.0/1000 and 4.0/1000 among Canadian and Saskatchewan births respectively. This difference questions the characteristics and associations of late losses in our province; this work aims to assess late Saskatchewan stillbirths in regard to incidence, causes, characteristics, and area-level factors.<p> Accessing Vital Statistics cases (1987 to 2007, n=1119), descriptive statistics and incidence were examined utilizing Chi-square testing and Poisson regression. Associations between variables were evaluated by log-linear models. Area-level factors relating to incidence within census divisions were explored using Poisson regression.<p> Although some variation existed by time and region, women were most often less than 35 years, of moderate parity, non-Aboriginal, had no previous stillbirths, and were not carrying multiple fetuses. Approximately half of the losses were preterm and half were inadequately grown. Incidence per 1000 births differed significantly for Saskatchewan (3.86) and Canada (3.43) with only Canada declining. Several division values were also higher than Saskatoons Division 11. Associations were seen between characteristics; most notably the combination of Aboriginality, increased maternal age, and large-for-gestational-age appeared over-represented compared to live births. Regions with higher proportions of Aboriginal preschoolers or land area with herbicide application had higher incidence (RR = 1.53 and 1.55, p-value less than 0.001). Further work is required to understand Saskatchewans lack of decline, what can be done about areas where incidence is increased, the significance of the associated characteristics as actual risk factors, and how Aboriginality and herbicide influence risk at the individual level.

Statistics Canada data indicates that between 2002 and 2006, the late stillbirth incidence (at or beyond 28 weeks gestation) was 3.0/1000 and 4.0/1000 among Canadian and Saskatchewan births respectively. This difference questions the characteristics and associations of late losses in our province; this work aims to assess late Saskatchewan stillbirths in regard to incidence, causes, characteristics, and area-level factors.<p> Accessing Vital Statistics cases (1987 to 2007, n=1119), descriptive statistics and incidence were examined utilizing Chi-square testing and Poisson regression. Associations between variables were evaluated by log-linear models. Area-level factors relating to incidence within census divisions were explored using Poisson regression.<p> Although some variation existed by time and region, women were most often less than 35 years, of moderate parity, non-Aboriginal, had no previous stillbirths, and were not carrying multiple fetuses. Approximately half of the losses were preterm and half were inadequately grown. Incidence per 1000 births differed significantly for Saskatchewan (3.86) and Canada (3.43) with only Canada declining. Several division values were also higher than Saskatoons Division 11. Associations were seen between characteristics; most notably the combination of Aboriginality, increased maternal age, and large-for-gestational-age appeared over-represented compared to live births. Regions with higher proportions of Aboriginal preschoolers or land area with herbicide application had higher incidence (RR = 1.53 and 1.55, p-value less than 0.001). Further work is required to understand Saskatchewans lack of decline, what can be done about areas where incidence is increased, the significance of the associated characteristics as actual risk factors, and how Aboriginality and herbicide influence risk at the individual level.