 Yr drwsgol yma yn dr Sharlat Weston, sy'n ystod yn y ffynol yma'r phoesol, yn ystod yn y dyfodol y Professor Philip Baker. Sharlat yma yn ymddiadau yma yng ngyfnodd ymlaen, yn ymgrifetigio'r meddwl sy'n 2003 ac yn ymddiadau'r C-H-B yn ym 2005. Sharlat wedyn yn ymddiadau'r trafnig yn ymgrifetigio'r meddwl sy'n gynyddian, yn dweud y ffynol ymlaen yn ymlaen ymddiadau ymddiadau ymddiadau ymlaen ac yn ymddiadau ymddiadau ymddiadau ymddiadau. Mae'r meddwl ymddiadau ymddiadau i gael y Llyfr Gwladiannau Llyfr, i'r ffynol yw drwll ffynol. Sharlat wedyn yn ei ffynol yma ymddiadau a'r ymddiadau'r meddwl sy'n ymddiadau ymddiadau ymddiadau. Gweithio, Frank, yn gweithio. One of my areas of research interest is fetal growth restriction, and this is where during pregnancy the baby doesn't grow to its full genetic potential. This is a really important complication because these babies are much more vulnerable to serious complications around the time of their delivery, including breathing difficulties, brain injury and even death. Ond mynd i'r rhaid o'r dŵr gyda'r fforddau sydd yn ymgyrch gyda'r ddweud o'r ysgolfyniad, yn gwneud yn gyfnod y byd, ac mae'r cyfrifodau sydd yn cael eu cyfrifodau sydd yn cael ei ddweud o'r byd, a'r cyfrifodau a'r bobl yn cael eu bodi amser. Yn llwythau allan o'r ddweud, mae sydd yn cael eu gwaith o'r cyfrifodau sydd yn cael eu gwaith yw yma o'r byddwch chi'n gwneud. ac rwy'n meddwl i'r gweithio ymgyrchau sylwyddiadau rhyw ffordd. Mae yna hefyd yn ei gweithio i ddod i'r oedlau'r lleol. Mae'r gweithio ymgyrch, felly rwy'n meddwl i'r credu dechrau yma ar hyn o'r perffeydd. Yr oedlau yma yma yma yw'r perffeydd yn bwysig o gwelwch. Ac rwy'n meddwl i'r gweithio, ysbryd i'r bwysig yma yw'r mlyneddau Do not undergo the same changes that they do in a normal pregnancy. In a normal healthy pregnancy, the mother's blood vessels become physically larger and they dilate more. This means that large amounts of blood are able to flow through a perfusive placenta. But in many growth-restricted pregnancies, the blood vessels stay narrow and constricted. This means that less blood is able to flow in a perfusive placenta. It's these sorts of differences which have led to the suggestion that substances that can dilate the uterine circulation, may be good treatments for growth restriction, and Syldenafil situates more commonly known as Viagra as one such possible candidate. So, Syldenafil is a potent vasodilator and we all know that it can increase the pelvic blood flow in males, but we hypothesise that when used by pregnant women it will also increase the percental blood flow and result in increased fetal growth. There is now accumulating evidence that Syldenafil can improve fetal growth, but much of the work done to date has been done in mice and rats, and there are two main gaps in our knowledge at the moment. Firstly, evidence of Syldenafil's efficacy at improving growth in large animals is lacking, and in this case it's really important to consider the large animals because mice and rats have very short pregnancies whereas larger animals tend to have pregnancies more similar in length to humans, and if Syldenafil works, and this is a treatment that we want to be able to offer women over a number of weeks, so we need to be able to study it over this timeframe to ensure that it's continued to be beneficial and that there's an absence of harm. We also don't have a clear understanding of the mechanisms through which Syldenafil may improve fetal growth, although we hypothesise that because it's a dilator it's going to dilate the uterine arteries and increase blood flow. Having a clear understanding of the mechanism through which a treatment works is really important because this is what's going to help us to apply or use a treatment most effectively in the clinical situation. Over the next few minutes I'm going to take you through three of my studies where we're trying to answer some of these questions. First of all, we did a large study in mice, and the purpose of this study was to assess the effects of Syldenafil not only on fetal growth but on the dilation in the mother's uterine arteries. We used three strains in mice, the C57, via our control strain, so in the absence of any other intervention these mice have pregnancies which grow normally. Then we used two strains, the enos and the cont, which have growth-restricted babies. In addition we wanted to do something to make sure that the pregnancies that we were studying were as growth-restricted as possible. To do this we put half of the mothers in each strain on a high-fat diet before and during pregnancy because this is something that's known to be detrimental to fetal growth. Then just over halfway through the pregnancy we put mothers, half of the mothers in each group on a syldenafil treatment. This is given by the drinking water and the other half just remained on their standard drinking water. So this treatment lasted for six days and at the end of it we took measurements of the pubs and assessed the mother's uterine artery function. So what did we see? Well as expected the most severely growth-restricted pubs in this study were from the mothers who were on a high-fat diet so this is the weights of their pubs displayed in this graph here. When the mothers we treated with syldenafil there was a significant increase in the weights of their pubs and we also saw a significant increase in the length of these pubs and their girth. When we looked at the mother's uterine arteries we assessed the way that these arteries responded to both constricting agents and dieting agents and what we expected to see is when the mothers have been treated with syldenafil that the constriction curve would move to the right or the dietation curve would move to the left but in fact there was no difference and what this suggested to us was that the increase in growth that we'd observed was happening independently of changes in the mother's uterine artery dietation. So in our next study we took quite a different approach and here we use pregnant sheep. In the first group we embolised the uterine arteries of their sheep while they were pregnant to induce growth restriction in the lamb and what this involves is injecting tiny microscopic beads into the uterine bloodstream. These travelled downstream and blocked the small blood vessels at the supply of the placenta and caused placental damage. After this process was complete we randomised half the sheep to treatment with syldenafil infusion for three weeks and the other half of the group were treated with a water infusion, a vehicle infusion. In the third group we didn't do any embolisation, we didn't give any treatment, we just left these to grow normally so these were our controls. Here the embolisation as expected caused a dramatic reduction in the lamb weight and the placental weight in these pregnancies. When the use had been treated with syldenafil there was a small but positive effect on the lamb's weight and this was in the region of 200 grams and we saw a larger positive effect on the placental weight. We looked at the uterine arteries as we did for the mice and again no difference in the way that these arteries either constricted or dilated. Where we did see differences were changes in the blood flow from the lamb to the placenta. So just as in human pregnancy we were able to do ultrasound measurements of blood flow in these sheep and we measured the umbilical cord blood flow. What this tells us about is resistance of blood flow through the placenta and in normal healthy pregnancy in both use and in women we see a reduction in resistance to blood flow as the pregnancy advances. This is exactly what we saw in our control group. However when there is placental disease such as in the case of fetal growth restriction as a pregnancy progresses we get a plateau and an increase in resistance to flow and this is what we saw in our embolised group. However if the mothers had been treated with syldenafil there was a fallen resistance intermediate to the other two groups and this suggested that syldenafil was somehow reducing placental resistance. So in combination with the mice work both our studies have shown an increase in fetal growth of syldenafil but in both cases the changes have not been due to changes in a mother's uterine artery dilatation. Instead our work suggests that perhaps syldenafil causes changes in placental growth or even placental structure. So finally what are that in humans? Well the first ever randomized study of syldenafil as a treatment for growth restriction in human pregnancy started right here in Auckland and this is a Strider New Zealand Australia study which is led by Dr Katie Groom who is a maternal fetal medicine specialist at Auckland Hospital. This study randomizes women with the most severely growth restrictive pregnancies to syldenafil or a placebo and for the women who are delivering at Auckland Hospital we're collecting a uterine biopsy if they have a caesarean section and a placental biopsy and what we're doing is studying the same blood vessels that we've studied in the mice and the sheep to see if these same changes are present. So the study is fully blinded and recruitment is still underway so I don't have any data to show you on this tonight but recruitment is due to finish early next year so it's a very exciting time for us and hopefully this time next year we'll have something very interesting to show. So just to wrap up the different animal studies have their different strengths and we've been able to harness these strengths and use them in conjunction with research done in human subjects to investigate a potential new therapy for fetal growth restriction. Our work certainly supports syldenafil as a treatment for growth restriction but suggests that the changes in growth are not due to uterine artery dilatation but may be mediated by changes in placental growth. The studies confirming these findings in human pregnancy are ongoing as further studies of placenters collected from both the mice and the sheep and the studies I've talked about to really try and tease out what is going on in these tissues to cause these changes in fetal growth. And I'd finally like to finish by acknowledging all the support these projects have received the supervisory support from Phillip Baker, Frank Bloomfield, Katie Groom and Joanna Stanley and to acknowledge the different funding bodies in particular the Mercia Barnes Trust, Graveda and the Lottery Health Research. Thank you and welcome any questions.