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thesisposted on 2017-02-21, 02:44 authored by Edwards, Andrew Grant
The term fetal therapy describes a broad range of therapies that are directed at the fetus with the aim of decreasing perinatal and childhood mortality, and improving quality of life. Current modalities include maternally administered drugs, needle-based interventions, fetoscopic surgery, and open surgery. Maternally administered glucocorticoids, one of the earliest fetal therapies, were shown to decrease respiratory distress syndrome in premature infants in 1972, but it wasn’t until 1999 that they were reported to impact umbilical artery blood flow. Section One examines the relationship between the fetus and placenta, including gender influences, and systematically assesses the impact of betamethasone on the fetoplacental circulation. One of my first findings was an excess of male fetuses with umbilical artery absent or reversed end-diastolic flow (AREDF). In combination with supporting data, this finding suggests that male fetuses might have higher risks of impaired placentation and function, and that perhaps ‘placental origins’ rather than ‘fetal origins’ should be explored to explain sex-ratio differences in mortality rates. In an assessment of flow changes within the fetoplacental unit of fetuses with umbilical artery AREDF after maternal administration of betamethasone I demonstrated that return in umbilical artery end-diastolic flow occurred within 24 hours, and was associated with decreased aorta and middle cerebral resistance suggesting a widespread vasodilatatory effect. I noted that maternal betamethasone administration is also associated with a reduction in fetal limb, body, and breathing movements, biophysical profile score, fetal heart rate variability, and startle response to vibroacoustic stimuli, bringing me to the conclusion that the return of end-diastolic flow in the umbilical artery is not necessarily associated with improved placental function. I also examined the ultrasound methods of estimating fetal weight, finding that the older equations were more accurate in our high-risk population than the newer volume-based equations. Section Two is centered around the treatment of Twin-Twin Transfusion Syndrome (TTTS), and the development of a statewide collaborative service in Victoria to offer fetoscopic laser therapy. I include a detailed literature review, and a separate publication that describes the process of constructing the collaboration and minimising the learning curve, and reports the excellent results achieved by the service in its first 5 years. The bottom line is that the outcomes for the first 49 consecutive cases of advanced (stage 2-4) TTTS were consistent with published Australian and international series, with an overall survival rate of 68% and a one or more survival rate of 86%. Section Three details a new technique for fetal cardiac access that involves the insertion of a cardiac catheter in much the same way that it is performed in children and adults. Utilising a lamb model over a four-year period, my multidisciplinary team including cardiologists and neonatal intensive care physicians and I developed and fine-tuned the needle-based, ultrasound- guided procedure. Without the need for maternal laparotomy, and at mid- gestation, I have been able to access the four chambers of the fetal heart, simulate pulmonary valvuloplasty and valvulotomy, and insert self-expanding stents into the foramen ovale. This capability offers great potential for translation to human care for the in utero treatment of fetal cardiac abnormalities.