Emerging data support a link between sleep disordered breathing (SDB) and adverse pregnancy outcomes, particularly preeclampsia. Furthermore, SDB, which is characterized by intermittent nocturnal hypoxia- reoxygenation as well as sleep disruption, results in endothelial dysfunction and metabolic dysregulation, the same biological pathways that have been associated with adverse pregnancy outcomes. Obesity is a well- known risk factor for both adverse pregnancy outcomes and SDB, and has been associated with the same aforementioned biological aberrations. Therefore, obesity complicates the definition of a causal relationship between SDB and pregnancy outcomes. While some classic cardiovascular risk factors (prehypertension) are certainly relevant in pregnancy, there are also well-established risk factors that are unique to pregnancy (uterine vascular stiffness, placental angiogenic factors). The interplay between SDB, obesity and these unique cardiovascular risk factors remains undefined, and this proposal aims to address this knowledge gap. Without this data, our ability to understand how we can mitigate these risks through the use of therapeutic interventions for SDB, such as CPAP (continuous positive airway pressure), is compromised. To further address this knowledge gap, we will make use of the placenta's ability to accumulate evidence of damage over time and provide a record of maternal vascular health throughout gestation. Numerous placental lesions deriving from maternal vascular disease have been identified and can be readily detected on placental pathology. These lesions can provide a measure of the severity of hypoxic stress experienced by the fetus during gestation. Our central hypothesis is that SDB is an effect modifier that increases maternal cardiovascular risk and placental hypoxic injury in obese pregnant women, and that CPAP treatment during pregnancy will result in an improved cardiovascular risk and placental profile. To test this hypothesis we will identify a cohort of obese women both with and without SDB. We will examine SDB's impact on maternal vascular stiffness (uterine artery Doppler), angiogenesis (pregnancy specific angiogenic factors e.g., sFLT-1) and metabolism (insulin resistance) across pregnancy (Aim 1). We will perform a randomized controlled trial of autotitrating- CPAP verses sham-CPAP in pregnancy to examine the impact of CPAP treatment during pregnancy on cardiovascular risk (Aim 2) and we will explore the interplay between SDB, CPAP and evidence of maternal vascular disease and chronic fetal hypoxia by evaluating the placental profile of obese women with and without SDB (Aim 3).
To determine whether efforts and resources should be allocated to systematically screening for, and treating, sleep disordered breathing (SDB) in pregnancy, there is a clear need to objectively evaluate the impact of SDB on maternal cardiovascular and fetal health, focusing on how it acts as an effect modifier in obese women. Moreover, we must concomitantly determine whether continuous positive airway pressure (CPAP) treatment of SDB during pregnancy can improve or reverse early cardiovascular and placental changes implicated in the development of serious pregnancy morbidity. This proposal will result in data with significant clinical implications by addressing these critical knowledge gaps.
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