| dc.description.abstract | Preeclampsia is a multi-system disorder that affects approximately 3-5% of all pregnancies and is one of the leading causes of maternal and neonatal morbidity and mortality globally. At present, there remain many facets of preeclampsia lacking data and comprehensive understanding. This thesis presents a number of studies investigating various aspects of prediction, prevention and long-term sequelae of preeclampsia.
Women with pre-existing diabetes mellitus (DM) form a unique cohort of women with significantly increased risk of developing preeclampsia in pregnancy compared to the general population. Despite this, there is minimal data on serum predictive markers and no data on urinary predictive markers for the development of preeclampsia in this cohort. This thesis explored both urinary and serum predictive markers for preeclampsia throughout pregnancy, in women with pre-existing DM. We described urinary protein excretion as pregnancy progresses in women with pre-existing DM. For total protein excretion measured via spot urine protein-to-creatinine ratio (uPCR), results were in keeping with the literature within the general obstetric population, with increments as pregnancy progressed. However, unlike the general population, in our population of women with pre-existing DM, spot urinary albumin-to-creatinine ratio (uACR) remained stable until late trimester 3. We additionally found that for our population, in each trimester of pregnancy, spot uACR outperformed spot uPCR with respect to its association with the outcome of preeclampsia. Additionally, placental growth factor (PlGF) is known to play a key role in placental angiogenesis in pregnancy - we found that preeclampsia is associated with an anti-angiogenic state, with reduced levels of serum PlGF and increased levels of soluble fms-like protein kinase 1 (sFlt1). We demonstrated correlation between urinary and serum levels of PlGF throughout pregnancy and in contrast to the literature within the general obstetric population, we found that for our women with DM, serum PlGF alone performed as a better predictor of preeclampsia than the serum sFlt1-to-PlGF ratio, at all gestations sampled throughout pregnancy.
Due to their increased preeclampsia risk, there is clear consensus that women with pre-existing DM would benefit from aspirin prophylaxis for preeclampsia risk reduction. These recommendations appear to stem from data obtained in the general population. However, there is evidence suggesting potentially reduced aspirin effectiveness in those with pre-existing DM. We reviewed the current literature of preeclampsia risk reduction with aspirin prophylaxis within women with pre-existing DM. Our systematic review is the first published review exploring the available data around the use of antenatal aspirin for the prevention of preeclampsia specifically in women with pre-existing DM. Our findings revealed a great void of available data surrounding aspirin prophylaxis for preeclampsia risk reduction in this cohort, with results suggesting no difference in preeclampsia outcome with aspirin use, a finding likely a consequence of lack of power due to insufficient data available for our cohort of interest.
Preeclampsia not only poses immediate risk to the mother and neonate during the peripartum period, but it is now understood that it has long-term implications for both the mother and offspring. A wealth of evidence now exists demonstrating women with a history of preeclampsia have increased long term risk of cardiovascular morbidity and mortality. It appears that preeclampsia history may be a gender specific cardiovascular risk factor akin to traditional cardiovascular risk factors such as hypertension or obesity. It is known that those with increased cardiovascular risk are also at increased cardiovascular morbidity and mortality post-surgery. However, no data exists regarding postoperative cardiovascular risk in women with a history of preeclampsia. We aimed to explore this association in the PREECLAMPSIA-VISION study, a sub-study including all female participants with a positive pregnancy history from the original Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) study, a large international prospective cohort study of a representative sample of adults aged 45 years and older who underwent non-cardiac surgery. Our primary outcome was Myocardial Injury after Non-cardiac Surgery (MINS) within 30 days after surgery. We found that a positive preeclampsia history was an independent risk factor for MINS, with 26% relative increase in the hazard of MINS in the first 30 post-operative days when compared to women whose previous pregnancies were not complicated by preeclampsia.
In addition to long-term implications for the woman, epidemiological evidence also supports an association between maternal preeclampsia and long-term neurocognitive function in the offspring. However, the available literature is conflicting and there is often incomplete consideration of confounding factors. We explored this association, taking into account important confounding and mediating factors, via a population-based cohort study using record-linkage of New South Wales birth, hospitalization and education data. Our outcome of measure for neurocognitive function was offspring school performance as assessed by the Grade 3 National Assessment Program–Literacy and Numeracy (NAPLAN), a standardised national test, which assesses children in 5 domains: reading, writing, spelling, grammar and punctuation, and numeracy. Our outcome of interest was a score below the national minimal standard (BNMS) in any of the 5 NAPLAN domains. In children exposed to preeclampsia in utero, crude univariate analysis demonstrated an increased risk of scoring BNMS in all 5 NAPLAN domains compared to children of unaffected pregnancies. Interestingly, once perinatal and child factors were accounted for, these differences were completely attenuated. The perinatal factors had a greater mediating effect than child factors, with gestational age at birth being the primary contributor, accounting for up to 21% of the association between preeclampsia and scoring BNMS.
All the studies presented within this thesis have either direct clinical implication or translational potential to clinical practice and have laid the foundation for further research. We suggest that women with pre-existing DM form a unique high-risk cohort of women with respect to the outcome of preeclampsia, and screening with uACR instead of the current clinically used uPCR would provide improved risk stratification for this cohort. Our results also suggest that the implementation of current clinically used algorithm-based screening, particularly those that include serum sFlt1-to-PlGF ratio may not be appropriate for women with pre-existing DM and screening within this cohort cannot be based on extrapolation of data obtained from the general obstetric population. Additionally, urinary PlGF holds promise for preeclampsia screening within this cohort and possibly the general obstetric population, however more sensitive commercially available kits are required. Further, we suggest caution before extrapolating currently available data for preeclampsia risk reduction with aspirin prophylaxis to women with pre-existing DM. Our PREECLAMPSIA-VISION study underscores the distinct requirement for enhancement in our overall understanding of gender differences in perioperative cardiovascular outcomes and overall long-term cardiovascular risk and suggests benefit in the incorporation of preeclampsia history into current perioperative risk predictive models for female patients. Lastly, to reduce the risk of poorer long-term offspring educational outcomes associated with preeclampsia, we support the implementation of strategies to safely prolong pregnancy and increase gestational age at birth in women whose pregnancies are complicated by preeclampsia. | en_AU |
