My doctoral research begins from the standpoint of pregnant women and mothers living with HIV in Ontario, Canada and explores the concerns that women living with HIV have as they navigate healthcare during pregnancy, childbirth, and early postpartum. Moving beyond a description or abstracted theorization of women’s experiences, I have used institutional ethnography to explicate how women’s concerns are connected to and organized by ruling relations such as the ideological discourses that underpin the work practices of healthcare providers operating within healthcare institutions. This dissertation follows three “threads” that were discovered in the overall institutional ethnographic inquiry, and that form the basis of three manuscripts. The first thread (Chapter Three) focuses on HIV disclosure, which all women who participated in this research expressed as a concern, and uncovers how the issue of HIV disclosure is accounted for in healthcare providers’ work activities. In this analysis, I show how both the women’s and healthcare provider’s concerns about and actions related to HIV disclosure are connected to discourses such as “fear of contagion” and “AIDS hysteria” that continue to permeate public consciousness. The second thread (Chapter Four) focuses on the discourse of “risk” as organizing women’s experiences and healthcare providers’ work, which became visible through medications women were prescribed, the prenatal clinic appointment schedule women were expected to follow, and the medical interventions that were applied to women’s bodies during childbirth and early postpartum. In a third line of inquiry (Chapter Five), I outline how the current organization of “high-risk” maternity care that is delivered by specialists and is located in regional hospitals has particular implications for women’s pregnancy and motherhood experiences, especially for women who live at a distance from these services and/or find it challenging to attend appointments because of employment and familial responsibilities. This analysis shows how the discourses of “risk” and “safety” are differently known and enacted by women and their healthcare providers, and calls into question the classification of pregnancies of women living with HIV as “high-risk.” In following the three threads and tracking the territory of perinatal care for women living with HIV, I illuminate points of disjuncture between women’s and healthcare providers’ ways of knowing HIV in the context of pregnancy and childbirth, and identify possibilities for how healthcare practices can be augmented to respond to the concerns and challenge that women expressed. In the Conclusion chapter, I draw attention to the tensions between the meta-level ideological discourses of “HIV exceptionalism” and “HIV normalization” that run through Chapters Three, Four, and Five, and that are generalized across the HIV and maternity care services that women living with HIV encounter. I end this dissertation with my thoughts regarding implications for the organization of perinatal care for women living with HIV in Ontario. / Dissertation / Doctor of Philosophy (PhD) / In Ontario, the maternity care that women living with HIV receive during pregnancy, childbirth, and early postpartum (also known as the perinatal period) is located in “high-risk” clinical settings within regional, academic teaching hospitals. The organization of such care has important implications for women’s daily lives. This inquiry begins from the personal experiences of pregnant women and mothers living with HIV in Ontario and explores the concerns that women have as they navigate HIV and maternity care during the perinatal period. The inquiry shows how the troubles that women face are produced through institutional conditions and the routine practices of healthcare providers. This dissertation also examines how institutional arrangements related to reducing the risk of HIV to the fetus and infant, and lingering fears about HIV as “contagion,” shape women’s care experiences. Implications for the organization and delivery of perinatal care to women living with HIV is discussed.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed to pregnant women suffering with depression, although the long-term impact of these medications on exposed offspring are poorly understood. Perinatal SSRI exposure alters human offspring's neurodevelopment and increases risk for psychiatric illness in later life. Rodent studies suggest that perinatal SSRI-induced behavioral abnormalities are driven by changes in the serotonin system as well as epigenetic and transcriptomic changes in the developing hippocampus. Studies in humans and experimental animal models shows that perinatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants can lead to abnormal emotional behaviors in adulthood, with a majority of the studies focusing on male offspring behavior. In this dissertation, we assessed whether SSRI-induced neurobiological and behavior changes occur in both sexes and whether these changes emerge in the juvenile period. In addition, we observed gene expression changes in the hippocampus related to metabolism and synaptogenesis. Given that, we hypothesized that the behavioral impacts following SSRI exposure may be driven, in part, by these processes. Juvenile offspring exposed to SSRIs in early life, regardless of sex, displayed increased anxiety-like behavior and altered social play. In adulthood, perinatal SSRI-exposed male and female offspring displayed increased passive coping in the Forced Swim Test but showed no differences in anxiety-like behavior. In addition to emotional behaviors, dams with a history of early-life SSRI exposure exhibited decreased maternal care, including diminished arched-back nursing, reduced licking and grooming of pups, and increased behavioral inconsistency. Alongside these behavioral changes, during infancy, we observed increased metabolic activity in the dentate gyrus of the hippocampus and decreased activity in the basolateral amygdala. During adulthood, the CA and dentate gyrus of the hippocampus in both sexes and the paraventricular nucleus of the hypothalamus in female offspring were more metabolically active in exposed offspring. We also observed differences in inter-correlations of limbic region COX activity in perinatal SSRI exposed and control offspring. Finally, a major gene altered by perinatal SSRI exposure is the G-protein coupled receptor Brain Angiogenesis Inhibitor 3 (BAI3). As a G-protein coupled receptor (GPCR), it is an interesting potential therapeutic target, since most recently approved drugs in the central nervous system act on GPCRs. Data present here show that perinatal exposure to the SSRI citalopram increases mRNA expression of Bai3 and related molecules (including its C1ql ligands) in the early postnatal dentate gyrus of male and female offspring. Transient Bai3 mRNA knockdown in perinatal SSRI-exposed dentate gyrus lessened behavioral consequences of perinatal SSRI exposure, leading to increased active stress coping. To determine translational implications of this work, we examined expression of BAI3 and related molecules in hippocampus and prefrontal cortex from patients that suffered with depression or schizophrenia relative to healthy control subjects. We found sex- and region-specific changes in mRNA expression of BAI3 and its ligands C1QL2 and C1QL3 in men and women with a history of psychiatric disorders compared to healthy controls. Together, these results suggest that abnormal BAI3 signaling may contribute to molecular mechanisms and metabolic changes that drive adverse effects of perinatal SSRI exposure and show evidence for alterations of BAI3 signaling in the hippocampus of patients that suffer depression and schizophrenia. Therefore, these data suggest that investigate the Bai3 network may be an exciting route as a potential therapeutic target for depression. / Doctor of Philosophy / Environmental factors during development play an important role in shaping the growth, structure, and function of the brain and as well behavior of an organism. Some of these factors that alter development which can negatively impact behavior include early life exposure to stress, toxins, or drugs. In this dissertation, we will discuss the impact of early life exposure to antidepressants. Many people take selective serotonin reuptake inhibitor (SSRI) antidepressants as a way to treat their depression during pregnancy. It is important to note that is it essential to treat depression during pregnancy, since depression can drastically impact the behavior of the offspring. However, while considering this, it is also critical to understand how exposure to SSRI antidepressants influences behavior of the offspring. SSRI antidepressants work by increasing the neurotransmitter serotonin in the brain and body. Previous work has demonstrated that early life exposure to SSRIs can alter the way the serotonin system develops in the brain and also increases the chance of children to develop emotional disorders (e.g., depression and anxiety). The same is true in rodents, a model organism in research, since we see an increase in depression-related behavior in our rats that are exposed to SSRI antidepressants in early life. Data shown in this dissertation support this claim, as we see altered behavior not only in adult but juvenile male and female rodent offspring. In adults, we found increased depression-related behavior and social deficits (e.g., maternal care). In the juvenile offspring, we saw alterations of social play behaviors and increase in anxiety-related behavior. Given this observation, we were interested in determining what occurs in the brain that alters these emotional and social behavior. To do this, we observed gene changes in the brain following early life SSRI exposure. We found changes in genes related to metabolic activity and communication between neurons (i.e., synaptogenesis). As a follow up to this study, we next wanted to characterize the metabolic and morphological (i.e., structural) changes that as a result of early life SSRI exposure. We found increased activity in several regions of the brain associated with emotion, including the hippocampus, amygdala, and hypothalamus. In addition, we did not find any morphological changes in the hippocampus, although ongoing studies will continue to analyze other brain regions. Lastly, when considering specific pathways whereby early life SSRI exposure can alter emotional and social behavior, we are interested in identifying potential therapeutic targets. One set of proteins (G-coupled protein receptors; GPCRs) are interesting targets to investigate, since most FDA approved medications in the central nervous system target these GPCRs. Interestingly, one GPCR stood out in our gene studies: Bai3. In this dissertation, we present data to show that the Bai3 network is altered in rodents exposed to SSRIs in early life. In addition, we show that manipulating Bai3 in early life can help to improve depression-related behavior. Lastly, to understand if Bai3 could play a role in depression, we assessed human postmortem samples to see if Bai3 alterations occur in the depressed human condition. In this study, we found increased Bai3 levels in human male sample relative to healthy patients. Overall, the work presented here shows that early life SSRI exposure negatively impacts emotional and social behaviors in rodents. Coinciding with these behavior changes, we find differences in gene expression and metabolic activity, thus providing us with a potential mechanism whereby early life SSRI exposure influences behavior. It is possible that by manipulating these aspects of brain function represent fruitful options for therapeutic targets for depression and other mood disorders.

Yes / Poor perinatal mental health, in particular depression, affects at least 10% of new mothers in the UK. Current best practice recommends the use of talking therapies or medication, however, many women choose not to use medication or are deterred from accessing NHS services for example due to immigration status. Those who can access NHS treatment often face a long waiting list to see a clinician or therapist. Untreated perinatal depression impacts on the health and wellbeing of mothers and babies, consequently it is essential that alternative psychosocial interventions delivered by non-clinicians are considered. A systematic review was conducted on seven quantitative studies examining the effect of psychosocial interventions in reducing maternal symptoms of depression. Interventions focused either on physical activity or peer support, measuring depression scores on a validated screening tool. The review concludes that antenatal group peer support may benefit women in the antenatal period and that postnatal peer telephone support may be helpful for primiparous women but further large scale research is required.

Yes / Asylum-seeking and refugee women currently residing in Europe face unique challenges in the perinatal period. A range of social support interventions have been developed to address these challenges. However, little is known about which women value and why. A critical interpretive synthesis was undertaken using peer reviewed and grey literature to explore the nature, context and impact of these perinatal social support interventions on the wellbeing of asylum-seeking and refugee women. Four types of interventions were identified which had varying impacts on women’s experiences. The impacts of the interventions were synthesised into five themes: Alleviation of being alone, Safety and trust, Practical knowledge and learning, being cared for and emotional support, and increased confidence in and beyond the intervention. The interventions which were most valued by women were those using a community-based befriending/peer support approach as these provided the most holistic approach to addressing women’s needs.

Yes / Commentary on: Shaw KL, Spry J, Cummins C, et al. Advance care planning in perinatal settings: national survey of implementation using Normalisation Process Theory. Archives of Disease in Childhood - Fetal and Neonatal Edition Published Online First: 14 September 2023. doi: 10.1136/archdischild-2023-325649.

Thesis (MMed)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Background The annual burden of stillbirths is estimated to be more than 3 million deaths globally. Depending on the perinatal classification used, up to two thirds of deaths are reported as unknown.Gardosi, et al (2006) developed the ReCoDe system, which identified the relevant condition at the time of death in utero. The system aims to identify what went wrong in utero, without necessarily indentifying why fetal demise occurred. With comparison to the conventional Wigglesworth classification, the authors were able to reduce the number of unexplained stillbirths from 66.2% to 15.2%. The Perinatal Problem Identification Program (PPIP) is the nationally implemented perinatal classification system in South Africa. The PPIP database recorded approximately 660 000 births from the 1st January 2006 until 31st December 2007. This reflects approximately 40% of all births in health institutions in South Africa during this time period. There were 11742 stillbirths recorded in on the PPIP database for this two year period.Unexplained stillbirths formed 24% of the total perinatal deaths. The Saving Babies Report 2006-2007 has suggested that funding andresearch resources be directed to identifying the causes of deaths in this group. Objective: Our primary objective was to compare the outcomes of the PPIP to the ReCoDe classification system developed by Gardosi, with special attention as to reducing the number of unexplained stillbirths. Methods: We conducted a retrospective descriptive study on the perinatal deaths occurring at or presenting to the Department of Obstetrics and Gynaecology at Tygerberg Hospital, Cape Town, South Africa, for the time period extending from 01 January 2008 to 31 December 2008. A weekly Perinatal Mortality Audit meeting (PNM) is held at Tygerberg Hospital. In attendance at these meetings are General obstetricians, Fetal-maternal specialists, Neonatologists, Pathologists, a Geneticist, Obstetric and Paediatric Registrars. Relevant clinical details are summarised from clinical notes and Perinatal Losses data forms. These forms are specific to Tygerberg Hospital and completed by the attending doctor at first consultation. Placental histology and post-mortem examination would have been performed in certain cases as per the departmental protocol. All perinatal deaths, both stillborn and neonatal deaths weighing more than 499g, are discussed at this forum and consensus then reached on a primary and final cause of death. This information is then entered into the PPIP database, along with any identifiable avoidable factors.The investigators separately reviewed the information available from the Perinatal Losses and the PIPP V2.2 data capture forms and then reclassified each stillbirth according to the ReCoDe hierarchal system Results: We studied the data sheets of 406 stillbirths of babies of whom the deaths had been previously classified according to the PPIP classification. The median maternal age was 25.65 years (range 14 – 45) while the median birth weight was 1127 grams (range 500 – 4100).The vast majority of these stillbirths occurred in singleton pregnancies and are also classified as extremely low birth weight. The three major causes of stillbirth over the study period were antepartum haemorrhage (24.4%), hypertensive disorders (22.4%) and spontaneous preterm labour (11.1%). Within the ReCoDe classification, the leading categories were in the placental group (33.2%), fetal group (21.6%) and the maternal group (20%). The unexplained group (PPIP IUD group), from the index study constitutes 8.1% (33 of 406) of cases, while the number of unclassified stillbirths in the primary ReCoDe classification accounted for 15% (60 of 406) of the total. The main reasons for this difference is that ReCoDe does not incorporate preterm labour as a cause, and uses customised growth charts for identifying fetal growth restriction. Conclusion: PPIP remains the gold standard in Perinatal Audit in South Africa.We would recommend that ReCoDe be evaluated prospectively, alongside the established PPIP system, to better compare their performance outcomes. The development of customized fetal growth potential charts relevant to the local population should be explored. The Perinatal Losses data capture form should be revised to be more comprehensive and relevant. / AFRIKAANSE OPSOMMING: Agtergrond Die jaarlikse las van doodgeboortes word geskat op meer as 3 miljoen sterftes wêreldwyd. Afhangende van die perinataleklassifikasiesisteem wat gebruik word, tot twee derdes van sterftes is aangemeld as onbekend. Gardosi, et al (2006) het die ReCoDesisteemontwikkel, wat die betrokke toestand in die tyd van die dood in utero geïdentifiseer. Die sisteem het ten doel om te identifiseer wat verkeerd geloop het in utero, sonder om noodwendig te indentifiseer waarom fetaledood plaasgevind het. Invergelyking met die konvensionele Wigglesworth klassifikasie, was die skrywers in staat om die getal van die onverklaarbare dood geboortes van 66,2% tot 15,2% te verminder. Die Perinataleprobleemidentifikasie Program (PPIP) is die nasionaalgeïmplementeerperinataleklassifikasiesisteemin Suid-Afrika. Die PPIP databasis aangeteken ongeveer 660 000 geboortes van die 1ste Januarie 2006 tot 31 Desember 2007. Dit weerspieël ongeveer 40% van alle geboortes in die gesondheids-instellings in Suid-Afrika gedurende hierdie tydperk. Daar was 11.742 doodgeboortes aangeteken in op die PPIP databasis vir hierdie twee jaartydperk. Onverklaarbaredoodgeboortesvorm 24% van die totaleperinatalesterftes. Die Saving Babies Verslag 2006-2007 het voorgestel dat befondsing en navorsing gerig word aan die identifisering van die oorsake van sterftes in hierdie groep. Doelstelling: Ons primêre doel was om die uitkomste van die PPIP te vergelyk met die ReCoDeklassifikasiesisteem wat deur Gardosiontwikkelis , met spesiale aandag aan die vermindering van die aantal van onverklaarbaredoodgeboortes. Metodes: Ons het'n retrospektiewebeskrywendestudie uitgevoer op die perinatalesterftes wat aangemeld het by die noodeenheid van die Departement Obstetrie en Ginekologie aanTygerberg Hospitaal, Kaapstad, Suid-Afrika, vir die tydperk wat strek vanaf 01 Januarie 2008 tot 31 Desember 2008. 'n Weeklikse Perinatale Mortaliteit Ouditvergadering (PNM) word gehou by Tygerberg Hospitaal. In die bywoning van hierdie vergaderings is Algemene Verloskundiges, Fetale-moederskant Spesialiste, Neonatoloë, Patoloë, 'n Genetikus, Obstetriese en Pediatriese Klienieseassistente. Relevante kliniese inligting is uit die kliniese notas en perinataleverliesedatavorms opgesom. Hierdie vorms is spesifiek na die Tygerberg-hospitaal en deur die dokter by die eerstekonsultasie voltooi. Plasentale histologie en post-mortem ondersoek sou voltooi gewees het in sekere gevalle soos per die departementeleprotokol. Alle perinatalesterftes, beide doodgebore en neonatalesterftes wat meer as 499g, word bespreek op hierdie forum en konsensus bereik oor 'n primêre en finale oorsaak van die dood. Hierdie inligting word dan in die PPIP databasis, saam met 'n identifiseerbare voorkombare faktore. Die navorsers afsonderlik die inligting beskikbaar van die perinataleverliese en die PIPP v2.2 datavasleggingsvorms en dan herklassifiseer elke stilgeboorte volgens die ReCoDehiërargiesestelsel. Results: Ons bestudeer die data velle van 406 doodgeboortes van babas van wie die sterftes voorheen volgens die PPIP klassifikasie geklassifiseer is. Die mediaanmoeder se ouderdom was 25,65jaar (range 14? 45?) Terwyl die mediaangeboortegewig was 1127 gram (reeks 500? 4100). Die oorgrote meerderheid van hierdie doodgeboortes plaasgevind in Singleton swangerskappe en word ookgeklassifiseer as &'n baie lae geboortegewig. Die drie grootste oorsake van doodgeboorte oor die studietydperk was antepartum bloeding (24,4%), die hipertensiewesiektes (22,4%) en &'n voortydsekraam (11,1%). Binne die ReCoDeSistematiek, die voorstekategorieë in die plasentalegroep (33,2%), die fetalegroep (21,6%) en die moedergroep (20%). Die onverklaarbaregroep (PPIP IUD groep), van die indeksstudie behels 8,1% (33 van 406) van gevalle, terwyl die aantal van ongeklassifiseerde doodgeboortes in die primêre ReCoDeSistematiek verantwoordelik vir 15% (60 406) van die totaal. Die belangrikste redes vir die verskil is dat ReCoDenieneemvoortydsekraam as &'n oorsaak, en gebruike aangepasgroeikaarte vir die identifisering van fetalegroeibeperking. Gevolgtrekking: PPIP bly die gouestandaard in Perinataleoudit in Suid-Afrika. Ons sal aanbeveel dat ReCoDe vooruitwerkend geëvalueer word, saam met die gevestigde PPIP stelsel, om beter te vergelyk hulprestasieuitkomste. Die ontwikkeling van persoonlikefetalegroeipotensiaalkaarte met betrekking tot die plaaslike bevolking moet ondersoek word. Die perinataleverliese data capture vorm moet hersien word om meer omvattende en relevant te wees.

Os trabalhos que visam estudar as relações entre a saúde materna e a saúde perinatal são de um modo geral parciais e também restritos à mortalidade perinatal. Visando conhecer melhor esta relação, o presente estudo se propôs a acompanhar 160 mulheres no ciclo gravídico-puerperal desde o parto até a criança completar 7 dias de vida. As principais variáveis foram idade materna, paridade, idade gestacional, estado nutricional e morbidade materna, peso ao nascer do recém-nascido, morbimortalidade do concepto, assistência pré-natal, trabalho de parto e parto. Após a análise dos dados pôde-se observar que a população estudada apresentou uma mortalidade perinatal de 67,9 por cento nascimentos, taxa bastante elevada, sugerindo, no caso, um alto risco de mortes no período. Em relação ao baixo peso ao nascer este foi de aproximadamente 11 por cento . Quanto à assistência pré-natal, 13,3 por cento das gestantes não fizeram este controle, tendo as crianças destas mulheres apresentado uma maior incidência de prematuridade, baixo peso ao nascer e mortes no período perinatal (eventos negativos) do que as que o controlaram. Das gestantes estudadas, 15,33 por cento tinham idade de 19 anos e menos e 10,22 por cento 35 anos e mais. As mulheres com 35 anos e mais apresentaram maior número de patologias durante a gestação; a paridade também foi elevada e suas crianças apresentaram mais eventos negativos que as demais. Além da alta mortalidade perinatal a morbidade neste período também foi elevada, uma vez que cerca de 73 por cento das crianças que sobreviveram apresentaram problemas na 1ª semana de vida, sendo que nestas 90 por cento dos problemas apareceram ainda durante a permanência do recém-nascido no hospital e nas 10 por cento restantes o problema surgiu no domicílio. As condições sócio-econômicas desta população mostraram uma importante variável de risco de morbimortalidade perinatal bem como de morbidade materna, pois observou-se uma estreita relação entre o status sócio-econômico e os problemas de saúde apresentados por esta população. O peso ao nascer do concepto também se associou a variáveis tanto orgânicas como sócio-econômicas, podendo ser indicado como um elemento importante no estudo do risco de saúde do recém-nascido. Finalmente a assistência ao trabalho de parto como ao parto se apresentou como sendo um determinante de traumatismo de nascimento que se somou às demais variáveis de risco, expondo o recém-nascido a um risco ainda mais elevado de morbimortalidade perinatal. / Researches which have studied the relationships between maternal and perinatal health are, as a rule, incomplete and restricted to questions of perinatal mortality. This present study sought to follow the pregnancy-infancy cycle of 160 women through from the delivery to the end of the first week of life. The principal variables studied were maternal age, parity, gestational age, maternal nutritional state and morbidity, birthweight, morbidity and mortality of the child, antenatal care, labour and delivery. After an analysis of the data it was discovered that the population studied presented the very high perinatal mortality rate of 61.9 per thousand births, which suggests a high level of risk in this period for this population. As for low birth-weigh, this was of the order of approximately 11 per cent . 13.3 per cent of the pregnant women did not receive antenatal care and their children presented a higher incidence of prematurity, low birth-weight and deaths in the perinatal period (negative events) than those who had received such care. Of the pregnant women studied 15.33 per cent were of 19 years of age or less and 10.22 per cent were of 35 or more. Those women of 35 or more presented a greater number of diseases during pregnancy, parity also was higher and their children presented more negative events than those born to the lower age groups. Beyond the high perinatal mortality the morbidity in this period was also high as 73 per cent of the surviving children presented problems in their first week of life, 90 per cent of these appearing while the child was still in hospital, the remaining 10 per cent arising later in the home. The socio-economic conditions of the population were seen to be an important variable for risk of perinatal morbidity and mortality, as also of maternal morbidity, because a close relationship between social strata and the health problems presented by this population was observed. The birthweight of the child (still or live-born) was also associated with both organic and socio-economic variables and was thus shown to be an important element in the study of the health-risks to the new-born. Finally, assistance during labour and at delivery was shown to be determinative of the incidence of traumatism at the birth which, added to the other high-risk variables, lead to the attribution of an even higher risk of perinatal morbidity and mortality to the new-born.

Thesis advisor: June Horowitz / Parents who simultaneously grieve the loss of one twin and nurture the surviving twin experience a paradox of grief and joy. The acute grief of losing a twin coincides with a critical time in the development of the parental role and relationship with the surviving twin. Very few researchers have addressed the unique parenting situation in which one twin infant dies. The aim of this qualitative descriptive study was to describe the experience of parents who lose one twin in utero, at birth, or in the neonatal period. The study question was "What is the parenting experience of mothers and fathers who simultaneously face the grief of the loss of one twin while nurturing the surviving twin during infancy?" Nine parents, recruited via a support group, were interviewed. Systematic content analysis, emphasizing in-vivo coding (participant's own words), was conducted until data saturation was reached. A comprehensive description of the experience of raising a surviving twin was constructed. Four descriptive themes were identified: (1) Living with ambiguity: the irony of raising a lone twin, belonging and not belonging, and at least there is one; (2) Communicating the family journey: telling or not telling, deciding who needs to know, and how many children; (3) Parenting with wonder and worry: doubt and hyper-vigilance, unanswered questions, and the living twin as a unique person; and (4) Life is different now: loss of innocence, honoring both twins, making and keeping relationships, work-life challenges, and accepting that it doesn't go away. Issues raised by parents included the ambiguity and irony of losing one twin, no one understands, multiple losses, and living with this loss. The description of this experience gives insight to the dynamics and burden of this loss. Data from this study can inform pediatric nurses about the issues, concerns, and needs of parents who sustain this kind of loss. Therapeutic interventions based by the tenets of family-centered nursing care can be developed by understanding the long-term effects of grief on parenting. / Thesis (PhD) — Boston College, 2012. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.

O presente estudo visou avaliar efeitos da I. carnea e de seus princípios ativos sobre a imunidade natural de ratos e, os efeitos de sua administração durante a gestação ou lactação às mães e os possíveis efeitos imunotóxicos sobre os filhotes quando adultos. Nas o resíduo da planta (RAF) foi diluído na água de bebida nas doses-alvo de 3,0 e 15,0g/kg de folhas secas da planta, durante 14 e 21 dias e por via oral, por gavage, na dose de 15,0g/kg, durante 14 dias, para avaliação da atividade de macrófagos (MO) peritoneais e das inflamações crônica e aguda, induzidas pelo BCG e pela carragenina, respectivamente. Os princípios ativos (suainsonina e calisteginas B1, B2, B3 e C1) foram administrados isoladamente em ratas, nas mesmas concentrações presentes em 15,0g/kg do RAF, durante 14 dias, para então avaliar a atividade macrofágica. Em ratas prenhes ou lactantes empregaram-se as doses de 1,0; 3,0; 7,0 e 15,0g/kg do RAF, por gavage. Ainda no estudo perinatal, foram realizados o cross-fostering para observação da passagem transplacentária da suainsonina, a amniocentese e a coleta de leite para quantificação deste alcalóide. As proles foram avaliadas até os 70 dias de vida, para avaliação da atividade macrofágica e das inflamações crônica e aguda. Foram realizados ensaios de imunotoxicidade, (peso relativo de órgãos linfóides, resposta imune humoral e celular), em ratos jovens e adultos, tratados durante 14 dias. No final da experimentação foram coletados diferentes órgãos para o estudo histopatológico. Em relação à imunidade das ratas adultas houve aumento da fagocitose e da produção de peróxido de hidrogênio de MO, maior processo inflamatório crônico e supressão da resposta inflamatória aguda, apenas nas ratas tratadas com baixas doses do RAF. Dos alcalóides da I.carnea, apenas a suainsonina mostrou-se tóxica. Em relação às ninhadas de mães tratadas durante a gestação ou lactação, verificou-se menor peso ao nascimento e menor peso ao desmame, respectivamente. O emprego do cross-fostering evidenciou a passagem da suainsonina pela placenta, confirmada pela quantificação deste alcalóide no líquido amniótico. A suainsonina também foi quantificada no leite. Em relação à imunidade natural da prole de ratas tratadas durante a gestação ou lactação, não se observou alterações nos parâmetros avaliados, porém filhotes de ratas tratadas com a planta durante a lactação e desafiados com o BCG quando adultos, desenvolveram artrite. Nos ensaios imunotóxicos, ratos jovens apresentaram involução tímica, os adultos esplenomegalia e menor celularidade de medula óssea, e em todos os animais, aumento no título de anticorpos. Dos órgãos coletados, apenas o SNC não apresentou as degenerações vacuolares características da toxicose por I.carnea. Concluindo, baixas doses do RAF promovem aumento da atividade de MO. Dos alcalóides da planta, apenas a suainsonina mostrou-se tóxica. A suainsonina passa a barreira placentária, ocasionando ninhadas menores e com menor peso e, também é excretada no leite, ocasionando lesões degenerativas vacuolares, bem como alterações no desenvolvimento tímico, o que possivelmente resultou em autoimunidade quando do desafio imune na idade adulta. Finalmente, em ratos, mesmo em altas doses, não ocorre lesão vacuolar no SNC. / The aim of this study was to evaluate the toxic effect of I. Carnea and its toxins on the immune system of rats, and to evaluate its effects on mothers and offspring when administered to dams during gestation or lactation. An alkaloid-rich plant extract (RAF) was added to drinking water to obtain doses equivalent to 3.0 and 15.0g/kg of dry leaves for 14 and 21 days, and a dose of 15.0 g/kg by gavage for 14 days. Macrophage activity (MO), and chronic and acute inflammation induced by BCG and carragenine, respectively, were evaluated. Each toxin in I. carnea (i.e., swainsonine and calystegines B1, B2, B3 and C1) was administered by gavage to female rats, in similar concentrations as contained in 15.0g/kg of RAF during 14 days to evaluate MO. The RAF was dosed by gavage in pregnant or nursing rats at 1.0, 3.0, 7.0 and 15.0g/kg. Cross-fostering was used to evaluate placental passage of swainsonine; swainsonine concentration was determined in amniotic fluid and in milk. On postpartum day 70 the litters were evaluated for MO and chronic and acute inflammation. Immunotoxic responses were evaluated in young and adult rats treated with RAF for 14 days. Tissue samples were then harvested for histopathology. The immune function of adult rats was enhanced by lower doses of the RAF. Phagocytosis and hydrogen peroxide production were improved, and there was enhancement of chronic immunity, but suppression of acute inflammatory responses. Among the I.carnea alkaloids, only swainsonine showed toxicity. The litters of dams treated with swainsonine during gestation or lactation showed a reduction in body weight at birth and after lactation, respectively. Swainsonine clearly passed through the placenta, and was found in amniotic fluid, and in milk. There were no effects on the immunity of litters from mothers treated during gestation or lactation. However, pups from mothers dosed with swainsonine during lactation had an increased occurrence of arthritis. Further, young rats showed thymus atrophy, whereas adults developed splenomegaly and reduced bone marrow cellularity. Finally, animals of all ages showed enhanced antibody titers. Only CNS tissue did not have the characteristic vacuolar degeneration typical of I. Carnea toxicosis. In conclusion, low doses of RAF enhanced MO activity. Among the I. Carnea alkaloids, only swainsonine showed toxicity. Swainsonine passed the placental barrier, resulting in smaller litters with diminished birth weights. Swainsonine was also excreted in milk, resulting in vacuolar lesions in pups, as well as thymus atrophy, which could cause autoimmunity in adulthood. Finally, even with higher doses, CNS tissue in rats is resistant to the toxic effects of swainsonine.

O glifosato é um herbicida utilizado na agricultura para o controle de plantas daninhas. No Brasil o glifosato é comercializado com vários nomes, dentre eles Roundup®; esses produtos são acrescidos de ingredientes ditos inertes que permitem a penetração do glifosato através da membrana plasmática da planta, potencializando a sua ação, além de propiciar maior estabilidade e potencial de bioacumulação. Considerando que a presença de certas substâncias químicas em formulações comerciais de glifosato pode aumentar sua toxicidade e que há carência de estudos sobre a toxicologia do desenvolvimento com essas formulações, o presente estudo investigou os efeitos da exposição perinatal de ratos ao Roundup®, a fim de avaliar o comportamento e neuroquímica cerebral materna, bem como o desenvolvimento físico e neurocomportamental da prole, desde o nascimento até a idade adulta. Para tanto, ratas prenhes receberam 50, 100 e 150 mg/kg do 15° dia de gestação até o 7° dia da lactação. Os resultados mostraram que o glifosato- Roundup® não alterou o peso materno durante os períodos de exposição ao herbicida e tampouco o consumo de água e ração das ratas, sugerindo ausência de toxicidade materna. Por outro lado, observou-se que o número de filhotes vivos de todos os grupos de ratas expostas ao herbicida foi menor do que aquele das fêmeas do grupo controle. Nas ratas expostas ao glifosato-Roundup® observou-se redução de atividade geral no campo aberto na maior dose, prejuízo no comportamento materno (CM) e no comportamento materno agressivo (CMA), bem como no hipotálamo aumento da atividade do sistema dopaminérgico e redução da atividade do sistema serotoninérgico, enquanto no hipocampo e estriato houve diminuição da atividade do sistema dopaminérgico. Esses achados sugerem que o aumento da atividade do sistema dopaminérgico hipotalâmico, por reduzir a liberação de prolactina, um hormônio essencial para a expressão do CM, prejudicou a manifestação desse comportamento. No mesmo sentido, a serotonina e dopamina por modularem os efeitos da ocitocina, um peptídeo importante no controle e na eliciação do CM e CMA, podem ter contribuído para os presentes achados. Quanto ao estudo dos parâmetros de desenvolvimento físico e neurocomportamental da prole, não foram modificados pela administração do herbicida. No presente trabalho foi avaliada também a atividade geral da prole na infância e na idade adulta, mostrando que as alterações foram pontuais tanto na prole masculina como na feminina, não caracterizando alterações motoras ou emocionais. Quanto ao comportamento de brincar de luta, a administração do glifosato-Roundup® reduziu apenas o pinning tanto de ratos machos como de fêmeas, sem alterar outros parâmetros deste comportamento. A duração e frequência do pinning são consideradas como parâmetros que expressam o início do comportamento social do rato. Desta forma, nestes animais não foram estabelecidos os padrões de comportamento social durante o desenvolvimento, porém aqueles relacionados com o comportamento de luta e sexual foram preservados. Na idade adulta, não foram observadas alterações na interação social de ratos e ratas expostos ao herbicida, ou seja, não promoveu efeitos em longo prazo no comportamento social. Quanto aos achados de neuroquímica cerebral da prole adulta exposta ao herbicida, foram encontradas alterações nos diferentes sistemas de neurotransmissão, contudo a ausência de alterações relevantes na atividade geral e na interação social das proles masculina e feminina adultas, não foi possível especular sobre o envolvimento desses sistemas de neurotransmissão com esses comportamentos. Esses achados em conjunto, mostraram que a exposição perinatal a diferentes doses de glifosato- Roundup® promoveu prejuízo no comportamento materno, os quais foram associados aos sistemas de neurotrnasmissão cerebrais, e na prole, embora não tenham sido observados efeitos no desenvolvimento físico e neurocomportamental, ocorreram alterações comportamentais na infância que se estenderam até a idade adulta. / Glyphosate is a herbicide used in agriculture to control weeds. In Brazil glyphosate is marketed under several names, including Roundup ®. Ingredients considered inert are added to these products in order to allow the penetration of glyphosate across the plasma membrane of the plant, increasing its action, as well as providing greater stability and bioaccumulation potential. Considering that the presence of certain chemicals in commercial formulations of glyphosate may increase its toxicity and that there are insufficient data on the toxicology of development using these formulations, the present study investigated the effects of perinatal exposure of rats to Roundup®, to assess behavior and maternal brain neurochemistry, as well as physical and neurobehavioral development of the offspring from birth to adulthood. To this end, pregnant rats received 50, 100 and 150 mg/kg from the 15th gestation day to the 7th lactation day. The results showed that glyphosate-Roundup® did not alter maternal weight during neither periods of exposure to the herbicide nor the consumption of water and feed the rats, suggesting the absence of maternal toxicity. On the other hand, it was observed that the number of living offspring of all groups of rats exposed to herbicide was smaller than that of the female control group. In rats exposed to glyphosate-Roundup® it was possible to observe a reduction in general activity in the open field at the highest dose, impairment in maternal behavior (CM) and maternal aggressive behavior (CMA), as well as in the hypothalamus there was an increase in the dopaminergic system activity and a reduction of the serotonergic system activity, whereas the hippocampus and striatum showed decreased activity of the dopaminergic system. These findings suggest that the increased activity of the hypothalamic dopaminergic system by reducing the release of prolactin, an essential hormone for the expression of CM, damaged the manifestation of this behavior. Similarly, serotonin and dopamine, which modulate the effects of oxytocin, an important peptide in the control and elicitation of the CM and CMA, may have contributed to the present findings. Regarding the study of the parameters of physical and neurobehavioral offsprings development, no modification was caused by the administration of the herbicide. The present study also evaluated the overall activity of the offspring in childhood and adulthood, showing that the changes were punctual in both male and female offspring in not characterizing motor or emotional changes. Regarding the behavior of play fighting, the presence of glyphosate-Roundup® reduced only the pinning from both male and female rats, without changing other parameters of this behavior. The duration and frequency of pinning are considered parameters which express the beginning of the social behavior of the rats. Thus, during the development of these animals, the patterns of social behavior have not been established, but those related to fighting and sex behavior were preserved. In adulthood, no changes were observed in the social interaction of male and female rats exposed to the herbicide, i. e., it did not promote long-term effects on social behavior. In the present study, considering the findings of brain neurochemistry of adult offspring exposed to the herbicide, it was possible to observe in the hypothalamus an increase in dopamine turnover in both male and female adult offspring and an increased turnover of serotonin only in male offspring. In the hippocampus, the most relevant findings were increased turnover of serotonin in males and in females the opposite effect. In the striatum an increased turnover of serotonin was found in both males and females, and dopamine only in females. Taking these data together and considering the absence of material changes in general activity measured in the open field and social interaction of male and female adult offspring, it is not possible to speculate about the relation of these neurotransmitter systems with these behaviors.