Obstetrics and Gynaecology - Theses
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ItemLife after the lab - the short-medium- and long-term outcomes after in vitro fertilisation (IVF) in Victoria( 2022-12)BACKGROUND In-vitro fertilisation (IVF) is an artificial mode of conception. Currently, IVF accounts for approximately 5% of births in Australia and has resulted in more than 8 million births world-wide. From an epidemiology perspective, IVF, like many other perinatal events, is a significant perinatal exposure which may have important long-term sequalae. AIMS This thesis aims to examine specific short-, medium- and long-term outcomes for children conceived by IVF. In doing so, this project was intended to contribute to the growing body of literature looking at outcomes among these children and help fill an existing knowledge gap. RESEARCH QUESTIONS To achieve the project aim, two research questions with were explored. First (project 1), what is the association between IVF using donor gametes and specific adverse outcomes of pregnancy, including hypertensive disorders and fetal growth restriction? Second (project 2), what is the estimated causal effect of IVF conception on school-age developmental and educational outcomes for children, compared with unassisted conception? This second question represents the major project of this thesis. METHODS These research questions were explored separately using contrasting methodologies. In project 1, a retrospective observational study was undertaken to examine the association between IVF using different categories of donated gametes (donated sperm, oocyte, or embryo) and 1) hypertensive disorders of pregnancy and 2) fetal growth restriction (FGR)), compared with IVF-conceived pregnancies using autologous gametes (own egg and partner sperm). The second and major project of this thesis was a state-wide, population-based record linkage study aimed at examining the school-age educational and developmental outcomes for children after IVF conception. IVF cycle data was obtained from the three major IVF providers in Victoria from 2005-2014 to identify a cohort of children conceived via IVF. This dataset was then combined by administrative data linkage with four other separate databases. These datasets, included the 1) Victorian Perinatal Data Collection – to enable identification of spontaneously conceived controls from the same time period and to add birth outcome data for the population, 2) The Australian Early Development Census (AEDC) – a global assessment of childhood development at school entry, 3) the National Assessment Program for Literacy and Numeracy (NAPLAN) – the universal Australian psychometric testing metric, and 4) the birth deaths and marriages registry – which was required to link maternal and child data. Project 2 was approached under the framework of causal inference. This approach stipulates that throughout the study design process, data collection, analysis and interpretation, researchers attempt to curtail bias arising from observational data such that under a set of assumptions, causal effects can be estimated. These methods have been developed since the 1970s but are not commonly used in health research. The application of these methods to the research question of interest in project 2 is a significant focus of this thesis. RESULTS Our findings from project 1 suggest a 2.3-fold increased risk of hypertensive disorders of pregnancy, after adjustments with multivariate regression, in pregnancies conceived via donated oocytes. Sperm donation did not appear to be associated with an increased risk (adjusted odds ratio: 0.94, 95% confidence interval: 0.73 to 1.21). The results from project 2 suggest that there is no causal effect of IVF conception on the risk of being developmentally vulnerable at school entry, as assessed by the AEDC outcome metric (average treatment effect (ATE) risk ratio: 0.97, 95% CI 0.77 to 1.25). Similarly, the findings suggest no causal effect of IVF conception on educational outcomes at age 7-9, with similar overall NAPLAN z-score seen in both IVF conceived children and controls (ATE mean difference: 0.003, 95% CI -0.018 to 0.077). The causal model included adjustment of important covariates including maternal age, education, socioeconomics and parity. DISCUSSION The findings of project 1 confirm that pregnancies with a history of egg donation should be managed as high risk. Previous evidence has suggested that “primi-paternity” (the first pregnancy conceived with a specific partner) increases the risk of hypertensive disorders of pregnancy. Our findings suggest that the concept of primi-paternity is only valid during natural conception. IVF is known to be associated with an increased risk of hypertensive disorders of pregnancy – and our findings did not suggest additional risk using donated sperm. As such, we propose that the products within seminal fluid may contribute to development of maternal immunotolerance and that IVF may subvert this natural process of immunotolerance. The findings in this project provide important reassurance for current and future families of IVF-conceived children. Additionally, this thesis demonstrates that via creation of a population-wide, covariate rich dataset and with considered application of these methods, causal effect can be estimated from observational data to determine the school-age educational and developmental outcomes for children after IVF-assisted conception compared to their peers.
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ItemMaternal ophthalmic ultrasound in the assessment of preeclampsia( 2021)The neurological complications of preeclampsia, including eclampsia and intracerebral haemorrhage, are responsible for most of its maternal morbidity and mortality. Treatments are aimed at preventing these cerebral sequelae, and include antihypertensive agents (to prevent intracranial haemorrhage) and magnesium sulphate (for seizure prophylaxis). It is likely that these agents have a direct effect on the maternal cerebrovasculature, although their precise mechanisms of action remain incompletely understood. Ophthalmic ultrasound makes use of the eye’s direct connection to the brain: the ophthalmic artery, which is similar in size and embryological origin to smaller calibre intracerebral vessels, can undergo Doppler interrogation, while the optic nerve sheath diameter (ONSD) can be measured as a marker of intracranial pressure. This thesis aims to assess the utility of ophthalmic ultrasound in the assessment and prediction of preeclampsia, which hitherto has not been performed in an Australian population. In so doing, sonographic assessment of the optic nerve sheath diameter and Doppler variables of the ophthalmic artery was performed in three discrete cohorts: healthy pregnant women (n = 51), pregnant women with suspected but excluded preeclampsia (n = 50), and women with established preeclampsia receiving treatment with the antihypertensive agent labetalol (n = 20) and the anticonvulsant magnesium sulphate (n = 1). In the cohort of healthy pregnant women, the ocular sonographic variables demonstrated no relationship with maternal mean arterial pressure (MAP), gestational age, or each other. Postpartum analysis identified an apparent increase in cerebrovascular resistance – a novel finding. In the cohort of women with suspected but excluded preeclampsia, ocular sonographic variables were not found to differ between those with transient and gestational hypertension on the day of assessment. In contrast to the first cohort, a positive relationship was identified between maternal MAP and the ophthalmic artery peak ratio, and a negative relationship between MAP and the ophthalmic artery pulsatility index. This novel finding is suggestive of greater cerebrovascular susceptibility to changes in systemic blood pressure in women with hypertensive disorders of pregnancy. These two cohorts were combined to assess the utility of ocular sonographic variables in predicting pregnancy outcome. Univariate analysis identified the ophthalmic artery pulsatility/resistive indices and peak ratio as being significantly different in those who went on to develop a sustained hypertensive disorder, whereas the ONSD performed better in multivariate analysis. This was the first study to examine the utility of the ONSD in predicting preeclampsia. Finally, women with established preeclampsia had lower pulsatility indices and higher peak ratios in the ophthalmic artery, and greater dimensions of the optic nerve sheath, than either healthy pregnant women or those with other hypertensive disorders of pregnancy. In a novel finding, administration of labetalol resulted in a shift in the ONSD and Doppler variables of the ophthalmic artery toward those exhibited by healthy pregnant women, which appeared to be independent of labetalol’s effect on systemic blood pressure. Magnesium sulphate appeared to have a similar effect. These observations may permit more precise and individualised care of women with preeclampsia, and thus a reduction in the neurological burden of this disease.