 I think we should start on time. My name is Peter Stone. I'm Professor of Maternal Fetal Medicine in the Department of Obstetrics and Gynaecology, and I just have two housekeeping matters. I'm informed that we're not expecting a fire alarm practice tonight, so if there is a fire alarm, we're supposed to meet outside in the foyer. And please, because we are recording all these sessions, cell phones and all these sessions, all these sessions, all these sessions, all these sessions, cell phones off or on silent, please. Thank you. So it's my very great pleasure to welcome you this evening to our talks in this 50th anniversary series, marking the opening of the Auckland School of Medicine. And actually, we're particularly excited about presenting these talks tonight, which are good news stories about saving or enhancing the lives of our most vulnerable children. Auckland continues to be a world leader in perinatal and placental research. Indeed, we're actually also celebrating that it's 50 years ago that Professor Sir Graham Liggins working in the postgraduate School of Obstetrics and Gynaecology, the forerunner of the Department that our first speaker heads today, Sir Graham Liggins showed the effects of steroids on preterm lung function and he embarked upon one of the most important trials ever done in perinatal medicine to demonstrate steroid efficacy in human lung development and save thousands of preterm babies. Some of you may also be interested to know, particularly those of you that may be somewhat skeptical about committees, that the head of the postgraduate School of Obstetrics and Gynaecology, Professor Bonham, the Senate Advisory Committee tasked with the details of the establishment of the medical school. It had originally been thought that the school would open in 1970. However, the committee worked so well, even faster than the Chancellor Sir Douglas Robb had imagined, that the school was ready to admit its first students in 1968. So we are celebrating 50 memorable years tonight in 2018. Well done, Senate Advisory Committee. So without further ado, I would like to hand over to Sue Brewster, who's the Executive Director of the Auckland Medical Research Foundation to say a few words. Thank you, Sue. You need to forward the slides, Peter. That might be a bit technical. Oh, there you go. If I do that. Oh, does work. Well, good evening everybody, and a very warm welcome to you all. Thank you so much for coming out tonight. A little bit chilly. I think there's been a few traffic events along the way as well, so it's great to see so many of you here. And of course tonight's topic is saving babies, something that you're all interested in and that is dear to our hearts. So Auckland Medical Research Foundation, our purpose is to fund medical research. And of the $71 million of funding that we've awarded to research, a lot of that has gone into funding research into babies and their health. I think you'll see behind me Dr Shirley Tonkin, so there's a newsletter that will be in front of you that says Autumn 2016. It's not because we want to give you outdated newsletters, we'll get rid of them. It's because there's a piece in there that is dedicated to Dr Shirley Tonkin and the work that she's done on the third page inside. So Dr Shirley Tonkin was a remarkable woman, she dedicated her life to saving babies and she was one of three researchers who led to the invention of the foam inserts in babies' car seats, which prevented their heads from falling forward and choking. And that simple device literally has saved thousands and thousands of babies' lives since that point in time. In that piece on Shirley there's a great excerpt in there from Professor Ed Mitchell of University of Auckland and he says about Shirley and her research, Shirley has been one of the most irritating people I ever worked with. She has frequently come up with the right idea but without any data to prove it. Only to be found right after several years of research. So Dr Shirley Tonkin dedicated her life and in 2016 at the age of 94 Shirley passed away but leaving the legacy of saving thousands of thousands of babies' lives and her research lives on. And also she left a gift in her will to the AMRF so that I guess her legacy continues to give to the medical professional and all of the researchers on to do amazing work. Speaking of amazing people and amazing work we've got wonderful presenters here tonight who will talk to us about babies the medical treatments and research connected with that. So thank you very much to our presenters and also tonight please don't forget to fill out your feedback forms which will all be in front of you. Very important to us so we know what you want and what you want to hear about in the future. There will also be a folder like this on the front desk to find out more about Auckland Medical Research Foundation and what we do. Thank you to all of our supporters here tonight. We simply couldn't do what we do without you and I think you'll see out there 100% of your donation goes directly to medical research. All of our administration costs are funded by a very generous benefactor so you can be assured 100% of donation goes directly to where you want it to go. Thank you so much, very warm welcome and I know that you'll enjoy tonight. Thanks. I'd now like to introduce Distinguished Professor Jane Harding who will introduce our speakers. Thank you Jane. Thank you, it's a great honour to be here to chair this evening's lecture series on saving babies lives and improving lifelong health. We have six speakers tonight and we're going to talk about their research contributing to that vision. Each speaker will speak for about 10 minutes and I will introduce each one and we will simply move on after each one because we think six talks is quite a lot for you to listen to. If we have time at the end we will take questions and if we don't will the speakers will be here so come and talk to them after the event. Our first speaker tonight is Professor Leslie McCann. Leslie was the top qualifying student in the fourth intake of this medical school and she's currently head of the Department of Obstetrics and Gynaecology. Her major research interest amongst many and the one she's going to share with us tonight is prevention of stillbirth. An acknowledgement of her research achievements Leslie's recently been awarded the Gluckman Medal for 2018 and she's currently a recognition of research within the faculty. Please welcome Professor Leslie McCann, sleep position a modifier or risk factor for stillbirth. Thank you very much for the introduction, Jane and it's fantastic to see so many many people here in the room and so many young people as well. So on with my talk I'm going to talk to you about stillbirth this evening and that's an area that I spend quite a lot of my research time involved with. So we define stillbirth in New Zealand as the death of an unborn baby at or after 20 weeks but our research focuses on what we call late stillbirth which is the death of an unborn baby at or after 28 weeks and we focus on this group of babies because if these babies are live born we expect them to survive and have a healthy survival and every year in New Zealand approximately 160 New Zealand babies are stillborn after 28 weeks. So if we think about that that's about five empty classrooms that are unfilled with babies who have died before birth but we have got an exciting opportunity because if we can identify modifiable risk factors we have the potential to reduce this tragedy for families and society. So what sort of modifiable risk factors could we think about and it's been known for decades that the position of the mother affects blood supply and early studies and this is a picture from a publication in 1969 this diagram shows that a mother lying on her back the inferior vena cava which is the main vein in the abdomen is compressed by the large pregnant uterus and our anaesthetic colleagues have known about this and when a mother has a caesarean section they tip the table over to the left almost to the extent that it's hard to reach the mum she's tipped over so much and they do that to try and improve the blood supply to the mother and the baby. So in 2006 we started a study called the Auckland stillbirth study where we asked a question amongst others is going to sleep lying on the back a risk factor for late stillbirth and our cases where mothers were stillbirths in the Auckland region and our control group were women who had ongoing pregnancies at a similar stage in pregnancy so what did we find and this research was published in the BMJ and what we found was that women who reported that they went to sleep lying on their back the night before their baby was stillborn had a two and a half fold increase in risk of stillbirth and that risk persisted after we adjusted other common risk factors for stillbirth. Now when we published this there was a lot of discussion and correspondence with the journal and whilst it was thought that these findings were biologically plausible people thought that there was an urgent need to confirm these findings and it was very premature to be making recommendations about optimum going to sleep practices for pregnant women so we rose to the challenge and we conducted this phase of our research so we undertook a New Zealand-wide study we have a very talented team in our department who have undertaken some amazing physiological studies which I'm going to talk to you about in a minute and we also surveyed the opinions of pregnant women in South Auckland which is our community which has the highest stillbirth rate in New Zealand. So this slide shows the results from our New Zealand-wide study and what you'll see here is that the risk for mothers who went to sleep lying on their back was almost exactly the same as what we had found in the Auckland study so we confirmed these findings there's now three additional studies that have been published and we're very fortunate that we've now got money to undertake what we call an individual participant data meta-analysis which means that we pull the data, the individual data from all the studies that have been done and we can look to look at those results in a combined study so what did those results show? So you'll see up here that the odds of late stillbirth were very similar to what I have shown you in our individual studies and another a good news story on this slide was that women who reported that they went to sleep lying on their right side had the same risk as women who went to sleep lying on their left side so that means that pregnant women can choose which side they would like to go to sleep on so we've got a fantastic international collaborative research group that also involves consumers and bereaved parent organisations and there'll be a lot of research that comes out of this IPD going forward so having made these clinical findings we now set to to try to understand the physiology behind it and this work has been led by Professor Peter Stone in collaboration with other members from our department and from the Department of Physiology so Peter recruited 30 healthy pregnant women and looked at the behaviour of their babies when they were lying on their back their left side and their right side and monitored the fetal heart through the mother's abdomen and what they found was that low activity behaviour in the baby and we call that state 1F we can see a picture of it here in the picture and that was much more common when mothers were positioned on their back and in contrast the high fetal activity state which we call state 4F was very uncommon when the mother was lying on her back so this suggests that lying on the back is associated with lower oxygen behaviour in the baby even in a healthy pregnancy now this work has been extended and it was led by an amazing medical student last year who has undertaken some magnetic resonance imaging studies during pregnancy so Amy Humphries led this work so he is a mother in late pregnancy in the MRI scanner lying on her left side and here's her spine and here's the baby and this blue circle is the main vein in the abdomen that we call the vena cava and when the mother turns over onto her back there's almost complete obliteration of that vena cava and there's also a reduction in the diameter of the aorta so to summarise quite a lot of studies in one slide we believe we have a pretty good understanding now about the physiology that's associated with maternal position and the effects that we're seeing in our clinical studies so the pregnant uterus compresses the major vein called the vena cava there's a reduction in the blood going back to the heart and a reduction in the output of blood from the heart there's a reduction in the blood flow from the aorta which is the main artery this leads to reduced blood supply in the placenta and low oxygen levels in the baby and whilst a healthy baby can cope with a reduction in oxygen levels a baby that is vulnerable or compromised may not be able to do the same so the next step for us was okay well it's all well and good now we've got these consistent clinical findings we understand them but can women change their going to sleep position and the answer is yes they can and they already have so when we recruited women to the Auckland stillbirth study 43% of women reported they went to sleep on their left side by the time we did our New Zealand-wide study that had gone up to 68% because at that time we thought that left was best and in our survey of women in South Auckland 85% of women said they could change their going to sleep position if that was better for their baby so we have been through a cycle of research from hypothesis generation confirming the findings further clinical studies understanding the physiology we've done a survey of women and now we're at a very exciting stage of having launched a public awareness campaign and some of you may have seen some of this information already and this is called the sleep on side while babies inside the sleep campaign and this work has been done in collaboration with a large number of professional groups parents groups stillbirth organisations and we've had complete buy-in and complete agreement between all of the stakeholders involved which is not always that easy to achieve and we've had an amazing research team and incredible support from cure kids who has been behind this project from the outset so we launched this in alignment with our national stillbirth conference at the end of June and we have produced information leaflets for pregnant women and you may have one of those in front of you take it away if you know somebody who's late in pregnancy information leaflets for health professionals and we've got a video that I will share with you in just a minute so the messages that we want to share these messages have been produced by our stakeholders going to sleep on your side halves the risk of stillbirth compared to going to sleep on your back start every sleep on your side including daytime naps it doesn't matter which side they're both good and it's common to wake up on your back so don't worry about that just roll back onto your side and we suggest that health professionals discuss this at 24 to 26 weeks of pregnancy our next steps are to share this sleep position information we're going to translate our pamphlets into other widely used languages we're going to evaluate the views of consumers and health professionals about our campaign and we're going to resurvey pregnant women to see what impact we've had on changing further changes in sleep position and of course there's ongoing data about stillbirth rates so this is a little video that we have produced which I would just like to get the mouse just to share with you because we think that's a pretty cool resource new research shows that sleeping on your side in the last three months of pregnancy helps prevent stillbirth it's usual to change position while asleep the important thing to remember is to start on your side if you wake up on your back just roll back onto your side going to sleep on your side from 28 weeks of pregnancy means you're helping to keep your baby healthy for more information go to sleeponside.org.nz final slide is just to acknowledge the funders who have supported this work in particular cure kids who has been there right from the outset and supported the whole journey from the initial hypothesis generation through to the public awareness campaign and we couldn't have done this work without them so we've had funding from Australia as well for our IPD particular thank you to the participants it's incredible that women who have experienced a stillbirth are prepared to share their stories for the for the advantage of other women and we're incredibly grateful for that and we've also got a fantastic research team multidisciplinary from several departments within this faculty and multi-professionals so it's a pleasure to work as part of this combined team so thank you for your attention our next speaker Associate Professor Katie Groom is the Associate Professor of Maternal and Perinatal Health and the Hugo Charitable Trust Fellow at the Liggins Institute she's a subspecialist in Maternal Fetal Medicine at National Women's Health in Auckland City Hospital she's passionate about improving health outcomes for mothers and babies through effective clinical trials research and in this role she has been the chair of the Australian New Zealand Maternal Perinatal Australasian Collaborative Trials Network and she currently chairs the National Executive of the newly established New Zealand-wide on-track network for better health for mothers and babies Katie is currently leading the New Zealand and Australia Strider trial part of an international consortium exploring a potential therapy for fetal growth restriction and tonight she's going to tell us about developing therapies for this important problem Thanks very much Jane and thank you everyone so much for coming out to listen to us tonight so I'm going to talk a little bit about developing a specific therapy for fetal growth restriction and share with you a little bit of the journey that I've been on for the last six or seven years which one may have been quite familiar to some of you seeing it in the media in recent weeks but before I start I'm going to introduce you to Archie so as Jane mentioned I'm a maternal fetal medicine specialist so in my clinical job we see people referred to us when problems arise in their pregnancy so Archie obviously came along with his mum because he was still in utero at the time to meet me when he was 24 weeks pregnant his mum was 24 weeks pregnant and the reason that they came along to see me was because Archie was much smaller for how far on he was in the pregnancy and these charts here show that all the parameters of growth were well below what would be the expected norm for this gestational age so I immediately made a diagnosis of fetal growth restriction but this could be caused by a number of different things so my job was to think about what that might be so we went on to look at a number of blood flow patterns both into the placenta from the placenta to the baby and within the baby there was a problem with how the placenta was functioning and the reason that Archie was smaller than expected was due to a condition called utroplacental insufficiency so what does that mean for Archie and his mum well unfortunately there wasn't any magic treatment that we could offer we currently have no proven therapies to aid fetal growth while the baby is still inside the womb unfortunately all we can do is watch mothers very closely watch babies very closely and then time the best time to deliver because the options that we've got are to continue on in that hypoxic environment with reduced nutrient supply reduced oxygen and risk that risk of stillbirth that Leslie's talked about or the alternative option when this has occurred really early in pregnancy is to get on and deliver the baby but we know then that adds further risk to these babies who are already very vulnerable and that's not just an immediate preterm risk while the babies are in the niku life long risk to their health so it's not the ideal situation and it would be much nicer if we could offer a therapy now obviously having said that we think this is related to utroplacental insufficiency and potentially uterine blood flow a perfect opportunity seems to be can we increase uterine blood flow and there's a number of potential candidates but I'm going to talk about Sildenafil which is better known as Viagra and a lot of the work is first was developed by Phil Baker here at the Liginsford for a couple of years until I think 2015 and this has been work that he's been doing for the last 20 years so Sildenafil is a drug that helps to dilate blood vessels it's particularly developed for its effect on the cardiovascular and pulmonary vascular but it also affects the pelvis so there's potential that giving it to mums may help the blood vessels to dilate this is a study taking from some myometrial samples taken after a caesarean section that shows if you apply Sildenafil in the laboratory to these blood vessels they do dilate so again giving us an opportunity that maybe it's a good thing to do and over the last 10 to 15 years there's been a huge number of animal studies looking at the potential of Sildenafil Jo Stanley worked here at the Liginsford a number of years and she's done a lot of work in the mouse model and Charlotte Oyston did her PhD with us looking at the sheet model and the vast majority of these studies do suggest that Sildenafil by increasing the potential vascular reducing the resistance of blood flow to the baby and in fact particularly in the sheep and the mouse model increasing the growth of the baby so can we use it in humans is it a safe thing to do well actually in my job for women who've got a really severe pulmonary vascular condition we already use it in pregnancy it's a small number of women but it hasn't raised safety concerns and it's actually now used quite routinely in the neonatal unit called persistent pulmonary hypertension of the newborn which is a recognised complication of preterm birth so Phil Baker while he was working in Canada worked with Peter von Daedelsen and under a specific ethical clause within their practice they were able to offer women the opportunity to have Sildenafil and 10 women who had very very small babies at about that same point as when Archie was small elected to take the therapy and they compared that to 17 women who chose not to take the therapy but were happy for their information to be shared and this is what they saw when they looked at how well the babies were growing inside the uterus and you can see there clearly that it looks like the babies that mothers have received Sildenafil grew more and this is by measuring their abdominal circumference and actual fact it also looked like these babies did slightly better they were more likely to survive and more likely to survive discharge from hospital feeling well so what happens next when you've got this information what happens next was a number of clinicians all around the world thought let's get on and start using this drug and they published case reports the Daily Mirror thought it was of interest but really having had results from 10 cases it's not the way forward what we need is well designed clinical trials to answer the question and Leslie myself and a few others got involved in a consortium back in 2011 with a plan that we would do a single trial across the world but logistically we realised that that wasn't going to work for us so we had planned trials across five different countries and we made a plan in advance to do a study as Leslie said about individual participant data analysis by putting all of our data together but running our trials separately so we'd all publish our results individually but we'd have this opportunity with shared resources to combine our data at the end of it and we'd have sufficient information to find out whether the drug helped to improve survival free of major morbidity so Strida New Zealand we were very fortunate we were the first trial across the consortium to be funded and we're very grateful to the Health Research Council of New Zealand for that we're the first to receive ethics approval but it did take us a little bit longer to recruit patients and therefore were grateful to Cure Kids for the additional funding and Gravidor and Nurture who funded some stub studies and we were also very fortunate 13 maternal fetal medicines so high risk obstetric units across Australia and New Zealand agreed to participate in the study we recruited women between 22 weeks and 30 weeks if their babies were incredibly small so the criteria to enter the study the babies need to be at a really significant risk of a poor outcome and then women were randomly assigned to receive a bottle of tablets that were either sildenafil or an identical placebo and neither us, the women or the clinicians caring for the patients knew who was taking which drug and we asked our clinicians to watch the patients really closely and make their usual decisions on when they should deliver the baby and for our study we looked at the rate of growth so were there more babies who grew quicker after having the treatment who took sildenafil compared with placebo so it was just yes or no did your baby grow more but we collected a huge another amount of information which we worked with the other groups to define so we could compare our outcomes we calculated in advance that we would need 122 women to be able to see an increase in the proportion who had an increased growth from 50 to 80% and that was very similar to those graphs I showed you from the observational data now it took us 3 years to find 122 women who met the criteria and were willing to be randomised now that doesn't sound like very many but as I say these were really really high risk pregnancies and there's not many women that are affected to this degree they were severe growth restriction these babies were recruited at 24 weeks they were less than 500g when they were recruited and that abdominal circumference centile was below the first centile so what did we find well we didn't find there was an increase in the proportion of women who had babies with an increased growth that's a pretty crude measure but even if we look at that abdominal circumference Z score which is a way for us to measure that we can see that there was really no effect on fetal growth but what about other outcomes now we did find consistent with what we thought we might find that for a short period of time syldenofil did improve the blood supply to the uterus so in the first 48 hours we saw a drop in the resistance of blood flow to the uterus but interestingly when we looked at that over a period of time it was not a sustained effect when we looked at the outcomes for the babies live birth risk of having a major problem risk of surviving or chance of surviving to hospital discharge all of them seem to go in the right direction in suggesting that there was possible benefit for these infants even if it wasn't affecting how they grow then it may be having another effect so looking there the survival to hospital discharge free of major morbidity was 67% in those on syldenofil compared with only 56% in those on placebo so that odds ratio approaching 2 suggests that if we saw this same effect in a much larger group of babies it really would be something that was quite important so what's the future from here well we need to know whether or not if there has been any positive effect if it's sustained through childhood and we're very grateful to all of those funders who have funded a childhood outcome study and all the families of the Strider Trial have agreed to come back when their children are two to three years of age for a fairly detailed assessment particularly focus around neurodevelopment we started our first follow-up in March 2017 and I can say that we have 100% follow-up of the babies that have so far been approached and offered appointments of course we've got a few more assessment and a few more that will become ready for assessment but we've even managed to track a baby down to Scotland and the UK Strider team have been to assess that baby for us so our primary outcome will be survival free of neurosensory impairment at 2.5 years of age but what about the Strider consortium because we've already planned that we could put all our information together will that be sufficient so we've already registered our individual participant data meta-analysis but also the other studies are looking at the children at the age of two to three so we'll have the opportunity to look there this is where we're at so unfortunately for particular justical reasons Ireland after a very long battle with their ethics and their governance made a decision not to proceed with the study the UK despite starting after us outshon us and finished recruiting before us the Canadian Trial has recruited 21 women and the Netherlands have now recruited 216 but there will be no more recruits to the Dutch study and this is what I alluded to at the beginning because you may have all seen the stories in the media that spread like wildfire across the globe and I think this is because of it being Viagra it wasn't Viagra it was the generic preparation but in planned interim analysis of the Dutch study after 184 participants suggested that it was potentially causing harm of course that was of interest to us and to our media and so you know we fronted up and talked about our study but what the interim analysis has shown was that there were more cases of persistent pulmonary hypertension that condition that we said Sildenafil is the treatment for in neonates and there was a non-significant trend to more neonatal deaths and for that reason and that the study was unable to be able to complete to show a difference in the primary outcome based on the analysis at the midpoint of the decision to stop their trial and the Canadians put their trial on hold now I can tell you that the Strider UK trial has completed and published their results they saw no effect on fetal growth but they saw also no effect on neonatal death and no increase in this lung condition our results were presented and present this year and is currently under review for publication and again we have seen no evidence of harm we've only had two cases of pulmonary hypertension one on drug and one on placebo so where to from here well it's certainly been a journey for me it's been a journey for our team and it's been a journey for the IPD but we are still in the situation where we don't know what's happened the Dutch study are going back and they're having blinded reviewers of all of their cases as yet this is not fully validated and we're not certain of it we have made a decision to review all of the New Zealand cases as yet we haven't identified any additional cases under our criteria and we're pretty confident with our results with regards to that so we need to think about what's the difference in these results but also to go ahead and do the individual participant data meta-analysis it's really important if we find out that the drug cause is harm of course but we may be in a bit of a quandary because I estimate that what we will find is that any difference is nonsignificant and we may not be any further forward with the potential of sildenafil but I think it's going to be quite tricky to take that any further but don't worry there's plenty of other potential therapies so sildenafil sits up there just here but this is just even thinking about uterine blood flow and all of these therapies are currently under investigation most of them not yet at the clinical trials phase but lots of ongoing work so what I'd like to end with is just to tell you a little bit about Archie and I'm pleased to say it's a good news story for Archie Archie was actually Strider baby number two so he was right at the beginning of the Strider trial and his family were delighted to participate in the study he received six weeks of therapy but he did get very sick at 30 weeks and earlier one Saturday morning we delivered him by caesarean section and he was born weighing just under 800g he's almost four years old now and he's managed to gain a little brother and he's meeting milestones and doing extremely well and very happy to have been part of the Strider trial so I'm going to end by acknowledging a huge number of people but most importantly the mothers and the babies and the families who took the step to be engaged in a clinical trial of a therapy that was new in pregnancy we had an amazing team working here in Auckland but of course a huge number of collaborators across Australia and New Zealand around the world and of course a huge number of funders to achieve all of this thank you very much our next speaker is Professor Alistair Gunn who is a pediatrician and a scientist who conducted groundbreaking basic research into the ways of applying compromised fetus in labour he was also working on the mechanisms and treatment of asphyxial brain injury he was the first to show that delayed cooling could improve outcomes after babies had been exposed to low oxygen levels he worked on how late that could start how long it needed to continue and practical ways of choosing which babies who might benefit his research has helped establish therapeutic cooling as the first ever technique to reduce brain injury in babies exposed to low oxygen levels in the time of birth and Alistair is going to talk to us tonight about saving babies' brains thank you very much tonight I'm basically going to tell you a little bit about a great New Zealand success story so pretty much all of the foundation work that led to therapeutic hypothermia was carried out in New Zealand there's no intellectual credit I can taste him to say because this is an idea that was first proposed more than 3,000 years ago has been repeatedly suggested ever since there you see a baby being called you can see the little cooling cap underneath a little shield to stop the infrared light from overheating the head there's one of the great ugly secrets of labour labour is intrinsically an experience of low oxygen levels a hypoxic experience so if we look at at blood flow and contractions there's a contraction there's a fall in blood flow to the uterus if you see a fallen heart rate that means that blood flow to the uterus has fallen by more than 50% if you see a deep desoliation it means it's been reduced by more than 90% so is that a problem? well the thing to remember is that babies are built to live on Mount Everest so here we there's the baby giving us a thumbs up this is my typical PO2 is about 20mm of mercury compared with roughly 4-5 times that in adults I consume twice as much oxygen as an adult but in fact I have an oxygen surplus so babies have both a reserve and major adaptations let them survive labour perfectly happily in fact if they don't go through labour they adapt less well after birth that labour that repeats its hypoxia does help stimulate it revs up the endocrine system it gets them ready to be born so here we see the super baby flying out afterwards now of course not everybody well 0.2% I mean those numbers pretty precisely 2% will hit the wall so what happens then? well one of the fundamental things is that just because there's been an excessive amount of hypoxia it doesn't mean that the baby's brain has turned to mush at the time quite the contrary so this is just an example of an experiment with the brain waves you can see they go up and down that's the baby showing sleep state cycling before birth this is impedance which was developed by a colleague of mine Chris Williams primarily exactly the same as the way we measure fat at the local corner store and you can see during a period of low oxygen brain swelling has increased because the cells have all depolarised oxygen is restored and the brain waves don't immediately return to normal and there's a a few hours later about 8 hours later there's a period of overactivity of the brain waves followed by a secondary swelling a secondary failure of the oxide metabolism of the cells and evolving changes so what's happening is hyperactivity you can't really tell from the outside but if you look closely that's what it looks like a repeated stereotypic large depolarisation of the brain those are seizures so you have a period of prolonged seizures here and as the seizures resolve you can see there's actually very little brain wave activity left and here you see the brain swelling gradually recovering at the same time and if you look at the brain after here you see severe damage you see a severe loss of brain cells of various types but what's interesting about this it's all exciting stuff happening here the seizure, the brain swelling and so forth the interesting thing is there's a period where nothing much is happening where actually brain activity is suppressed and we have shown that it's being actively suppressed by release of your protective hormones and where the brain swelling has gone down nearly to normal so that's a very intriguing thing and you see exactly the same thing in babies who've been affected by low oxygen that they recover initially they stabilise and then hours later they start to cease so this is not an artefact of laboratory medicine so the question is what's happening in here next clue comes from the fact that in fact sick babies get cold after birth we spend a lot of time and effort keeping them warm this is a very traditional picture I think from France I don't know what the hat is for but yes so incubating babies if you like the question though is should we once you start looking there are lots of clues that say that in fact temperature is probably very important so this is a classic one that grounding victims will resuscitate after birth here's myself and my younger daughter of much younger age at risk of testing that experimentally so what happens if you allow that natural cooling to occur the answer is all sorts of interesting things so remember this picture shows the brain swelling here we have the period of low oxygen brain swelling happens it partially recovers when you start cooling here 2 hours later you can pretty much completely prevent that secondary brain swelling so as soon as we saw that we knew something fundamental was happening if you look at the cell survival here we see severe loss if the brain temperature is kept quote normal unquote but if you start cooling it an hour and a half actually very dramatic protection much more than I certainly I ever expected delay to 5.5 hours partial protection but if you wait until 8.5 hours and the seizures have started which is when clinicians would really like to wait you get nothing this is a time dependent delay but a useful window opportunity 5.5 hours is a practical time to realise that something has gone wrong to assess baby to talk to mum and dad to get permission to try doing something new and unexpected so that was very practical information the second practical thing was that in fact you don't need that much cooling we're talking roughly 3.5 to 5 degrees for mild cooling so this is just showing the relationship there's a normal temperature fall and brain temperature and there's a threshold around about 34 degrees this has been replicated in lots of other studies so we're talking mild cooling we're not talking about cardiac surgery so given all of that the next question is it safe I was taught by my mother was this nice lady here that a low temperature after birth was essentially killing the baby that there was a tight correlation between the fall and temperature after birth and mortality on any complication you cared to look at so I persuaded her that we should really do a trial a simple safety trial so this was the very first ever safety trial of induced cooling after 3,000 years of thinking about it with a proper randomisation and it said yes it is completely safe that in turn with experimental evidence for efficacy the clinical human evidence that it was safe to a proper randomised trial here's a proper commercially developed water cooler we used a modified Fisher-Pickel cooler because we had Kiwis and there was a trial in New Zealand US, Britain and Canada this is a this complicated figure is called a forest plot and I think you can see why it's always branch and twiggy here's the cool cap trial which was us and then a whole lot of other trials because basically people didn't believe things that happened in New Zealand which was a good thing the fact that it may hurt your feelings but because they basically repeated the studies we were able to say right all of these studies in different countries from competing institutions found exactly the same benefit I mean that's an amazingly homogenous result and the overall conclusion is more babies survive with no disability wait don't do that to me so for every six babies one extra baby will survive and it's completely normal so we're improving both survival and preventing disability it's not perfect we have a not being significantly affected but one in six I compare that with treating lipids for heart attacks it's an effect size of what 250 there's a lot of people being treated with lipid lowering drugs and that's normal but you can also look okay what about the poor babies who have cerebral palsy a severe motor disability usually hypertonic with difficulty releasing and you can see in total 30% of the babies in our study had cerebral palsy being reduced by about 40% here's our competing study for the National Institutes of Health showing exactly the same effect so even the severe outcomes are being prevented the challenge now is to find ways of building on that success and I hate to admit it for a long time I have been the king of negative studies for some time now but finding difficulty improving hypothermia as such our initial settings seem to be perfect but everybody is pretty convinced that cocktails and ice adding beneficial therapies on top of hypothermia will eventually help make it better so here we've gone this is a genuine picture from the 1898 of a baby being resuscitated in cold water but never going anywhere to the definitive trials in New Zealand Thank you Professor Ed Mitchell was born in Iran to British parents and trained in London and subsequently worked in the UK in Zambia and in New Zealand indeed he came to New Zealand in 1977 did his paediatric training here in Auckland and in due course became Cure Kids Professor of Child Health Research at the University of Auckland from 2001 to 2015 and he's now a part-time professorial research fellow his work on the epidemiology of sudden infant death earned to amongst other things a doctorate a doctor of science from the University of London and he's going to talk to us tonight on preventing sudden infant death past, present and future Ed Thanks Jane In this very brief period of time is where we were in the 1980s talk about the New Zealand cot death study talk about the prevention program which subsequently was called the back to sleep the reduction in mortality and about our current safe sleep program but first I need to just sort of talk about terminology when I started working in this area in the mid 1980s we referred to this as cot death then we started using the scientific term sudden infant death syndrome and now we're using the term suidi or as the Americans say suid and that means sudden unexpected infant death in America sudden unexpected death in infancy here in the rest of the world I also admitted to say that the Americans didn't call it cot death they called it crib death anyway in the 1980s this statement SIDS is unpredictable unpreventable unexplainable tragedy was being said all the time but this was the first reference I could actually find on it and there's so many times that statement is made so when we were looking at this in the mid 1980s SIDS as you can see here in New Zealand was much higher than other countries whereas the non SIDS rate was actually very similar running around about 2 per thousand so our total mortality from all causes and we're using the post neonatal period which is from 28 days through to the first birthday is much higher in New Zealand or was much higher in New Zealand than any other country and in fact was actually twice as high as that was present in the Netherlands what's more that the post neonatal mortality rate that's the top line had not changed over 20 years whereas other age groups in children had actually improved but that crucial first year of life there was really minimal improvement apart from in the neonatal causes from the work of the neonatologists and better obstetrics looking at national data there was a really good description of SIDS cases we knew that it was more likely to occur in males it was more likely to affect low birth weight babies or babies that were born pre-term infants of young mothers there was a big winter peak and disadvantaged communities and particularly Maori were overrepresented and it's got a very characteristic age group age distribution and this is data that this pattern of being sparing the first month of life and then an increase and then two to three months being the highest rate by six months of age 85% of the deaths have already occurred from this cause and even now and all around the world that age distribution exists and it's still somewhat unexplained so in the mid 1980s we thought well we needed to do a study and try and identify what the risk factors for SIDS were and what was the emphasis on infant care practices why was our rates higher in New Zealand than in other comparable countries like Australia and the UK and the Netherlands so we wondered whether we were doing things differently to other countries so we did a case control study so we compared cases with control infants the cases were all ones that were certified as dying from SIDS and in the middle age group that's 28 days through to the first birthday we ran it for three years and in that time there were 485 deaths and our interviewers did a fantastic job interview in these families and managed to get 81% we compared them with living babies that were representative of all births and we interviewed them at a time to produce SIDS and we selected 1800 randomly sampled babies and we interviewed 88% so this was a big study that 400 485 deaths actually only came from 80% of the country those yellow areas we just didn't have the resources to get to all the other smaller centres and we had an opportunity to acknowledge all the other my colleagues that helped make this study a success one of the key factors and certainly was the one that was most striking to me and it was interesting that we started the talk talking about Shirley Tonkin she was telling me all along that it was sleep position was the problem because she was interviewing families and identifying these babies at the front we actually looked rather than just relying on the position found we also looked at the position last place to sleep and in this time 32% of babies were sleeping on their front but 64% of the cases were placed to sleep on their front and this increases the risk six fold to sleep on their back this was the first study that showed that side sleeping position was a risk and I'll come back to that three other factors that were found smoking increased the risk by 41% look at the smoking rates 31% back in the mid 80s or late 80s not breastfeeding and bed sharing interest in becoming back to that bed sharing 10% of babies 24% in other words a quarter of the babies were dying in bed with a parent this information influenced the Department of Health now the Ministry of Health to launch a prevention campaign and this was some of the brochures and material that they produced and this is the very first pamphlet very first poster that they produced and what we actually see underneath the figure is place baby on side or back to sleep because it was the first study we were unsure about what we should be recommending apart from not going to sleep on the tummy that message subsequently changed to back or side and then eventually to back only two other comments about this picture if you look at that baby the right arm right underneath the baby and that baby will land on its face so that's not very good but I did like the no smoking sign that was on the blanket I thought that was a neat touch we launched the campaign in February 1991 but what you can see here is actually mortality had dropped quite considerably the year before because we'd spent so much time talking about it people were actually changing their behaviours in the year before the grey area is the SIDS mortality and you can see that where we were running at 4 per thousand by 1992 it was only a fraction over 2 per thousand and the white is the post neonatal mortality from all causes showing a similar drop which shows that this isn't just an artifact of calling it something else this is real in 2019 people there from the UK and I sat down and back of the envelope stuff tried to calculate how many babies this simple intervention had saved and we calculated then that 3,000 lives had been saved in New Zealand 17,000 in England and Wales and 40,000 in the US so this is an effect bigger than immunisation finishing with bed sharing as I showed you 24% of babies were dying in bed with a parent that risk was identified in other studies the risk is actually much higher if the mother smoked in pregnancy we think that's because the baby was damaged by the smoking and doesn't respond well since the reduction of deaths from prone sleeping position bed sharing now accounts for over 50% of all our sudden unexpected deaths the problem is advice not to bed share has been somewhat controversial in promoting bed sharing for improving breast feeding rates the big advance we had here was Dr David Tiffany Leach who developed the wahakura in the bottom one which is a woven basket which allows the baby to be taken to bed with the parents but in their own safe sleeping area the problem with the wahakura is it actually needs a skilled weaver to actually make it otherwise the sides are floppy and when the mother or father leans against it it collapses the next big advance was the pepi pod which was developed by Stephanie Cowan in Christchurch and this is a plastic box it's not as attractive as the wahakura but it can certainly be produced a lot more quickly and easily and what we've seen and we reported this a couple of years ago is that the mortality rate and that's the middle line over the whole country has actually dropped by 30% since 2010 through to 2015 but what you see there the top line is our Maori rate whereas the rate had been pretty constant just over 4% there was a substantial drop which has been maintained in the Maori community and of course the wahakura and pepi pod and co-sleeping is very important in that group and has been really effective so we've heard off by saying SIDS is unpreventable unpredictable and unexplainable tragedy the only we've basically shown that it's preventable in the mid 1980s we had 250 deaths a year in New Zealand by 2010 it was 70 currently it's 45 and we estimate we can get down to 6 to 7 if the advice is followed is it a the only part of the statement I accept is it's a tragedy and that's because sudden infant death is preventable and avoidable thank you Associate Professor Justin O'Sullivan is the Associate Director for Research at the Liggins Institute his research centres on understanding genome biology and his goal is to interpret the relationships between what is DNA codes that is the genotype and what we actually see that is the phenotype his group specialises in integrating novel techniques to answer biologically important questions including what is the physical structure of the genome within the cell and what is the genetic structure of the genome within an environment tonight Justin is going to talk to us about the microbiome and the lifelong effects of preterm birth thanks very much and thanks to the AMRF for sponsoring this event it's always difficult to come in and talk about these things you know because the work that we do it's not me so there's a lot more to us than you see and I think this is true for all of us so the work I'm going to talk to you about tonight is actually work that's done by predominantly the grip you see here it's led by myself and Wayne Cutfield in the corner there and predominantly done by and was funded by these people so there's a lot more to us than you see our guts are really quite beautiful environments doesn't seem like it but if you actually get in there and have a look around they're actually quite nice places they have good nutrients they don't have much oxygen but they're quite attractive spaces to live in so inside your guts there are trillions of microbes and in fact the microbes that are in your guts actually are equivalent in number to the number of cells that you have that are actually of human origin so you're roughly 50% microbe and 50% what you think you are yourself so you're a walking ecosystem wandering around breathing and eating basically you're feeding these microbes but the microbes themselves don't just sit there and live there happily they actually communicate with you so for a long time we've thought along the lines of Cox postulates which is that things infect us they cause disease and sickness for these microbes that live in you and on you are really important with respect to your health, your wellbeing your longevity and the way you develop so just like a city your foundations are laid early so in this map it's a map of Auckland City it's a pretty recent one but in fact this map hasn't changed a lot since Auckland City was founded well there's motorways being put in predominantly it's very very similar so the foundations for the structure are laid very early on in the development of a city and just like that for you and your microbes are laid very early on as well so that if we actually look at microbes what we see is that when you're born and you come through the birth canal you get a good dose of microbes from the mum a lot of those microbes though and in fact in your gut already as an infant or as a baby as you're being born you already have some microbial material which you got while you're actually in the womb itself so the womb is not the sterile environment sometimes that we think but as you come out you get this nice dose of microbes and it differs if you're born by C-section obviously you get a different sort of dose of microbes there but over the first year of your life you go through a period where your guts change from being sort of an aerobic environment to being an anaerobic environment because when you're first born you're quite aerobic as that happens in the microbial community and it changes and it modifies itself and so there's a period of your life over the first year where you have quite a lot of change in the microbes that are present in your stomach but after a while that settles down and about the age of two to three when you're weaned effectively your microbes stabilise and the population stabilises so that you have effectively what you should have for a long period of your adult life if you get diseases a picture is for type 1 diabetes so people that have become type 1 diabetic and non-diabetics what you see is that there's a divergence here in the microbe population and that divergence correlates with the onset of the type 1 diabetes in these individuals and similar things happen for different disorders so we know that the microbial population you have in your guts and the diversity of it is linked to your BMI or your weight and to other factors associated with your health so we know that that happens in a very short period of time so what happens over individuals' lifetime so we did a study with Billy Apple he did an exhibition in 1970 which was called Excretery Wipings so it doesn't take too much explanation to understand what there was and so this display of Billy's it got censored and shut down which also for some people may not seem that unusual but it was censored and shut down and Billy kept his material and he kept it archived and so a couple of years ago Billy rocked on and he said I've got this material can you do anything with it so we extracted it and when we extracted it what we actually saw was that over Billy's lifetime since he was a young man and you went through to now being an older man over his lifetime 50% of his microbiome has been stable which means that when it's established and lasts a long period of time it's stable there's a bit of fluctuation in it but it's pretty stable that carries on right through into your later life as Billy is now about 80 so we know there are changes over a lifetime those changes can be thought of as predominantly maybe cosmetic type changes like the subway artery and cycle routes that are being put into Auckland Central City but it's really a city's industry that contributes to its identity and so in this instance we have Auckland on the left here and I was looking for boats but this is what I could find so it makes a lot of kayaks and different things here because we live by the sea other cities make maybe cars and things and these cars contribute and the factories that make them contribute to their identities they contribute to the people that are there if this is a case and you lay the foundations early then that means that what happens at birth should affect you later on in life out here and we know that preterm birth is a very very severe stress on infants and it affects people you go through a period where you're getting parentarial feeding you're being kept in an incubator you're on antibiotics a whole lot of things happen so what we did is we asked the question whether or not what happens to you here affects the microbiome when you're way out here when you're childhood at about eight years of age when we looked what we found was that we expected to see differences just like this we thought term children will be like this but in fact what we found was that the microbiomes were the same they looked the same we couldn't tell differences between the preterm microbiome or the term microbiome and this was kind of weird we didn't expect that but we know that like house prices microbiomes go through cycles of activity and right now of course our house prices are doing something like this but you know that's okay but the microbiome does the same thing so if the foundation is there but perhaps there are different organisms that are active in fact when we looked in the microbiomes of the preterm and term children and we actually looked to see which bacteria were working what we found was that even though they have the same populations of bacteria the bacteria that were active in the preterm children here contains some members of this family called colon cellar while the ones that were in the term family had a whole lot of active alastippies and this is really interesting because the colon cellars have been linked to serum cholesterol levels hepatic triacyl sorry tags less glycogen and glucose metabolism so changes in metabolism alastippies by contrast have been linked to protein rich diets which is kind of weird because in fact when we looked at the diets between our populations they weren't different so something else is going on so if the active members of the population are different then other products are making the same well one would argue that they shouldn't be and in fact if we look at the microbiome we should see something like this that the products being made in the preterm kids here they have a lot more of certain things and in fact when we looked we found that they did we found that the preterm children were making a lot of arginine heaps of arginine green bars out here and so the arginine that they're making is interesting because arginine is a conditionally essential amino acid it's also something that we know that preterm children can't make when they're born and so they get a lot of supplementation for arginine the genes that they require to produce arginine are not turned on fully in preterm children when they're first born and so this is a really interesting thing that 8 years on after these children have left hospital they have still got microbes that are making a lot of arginine histidine biosynthesis histidine was also different in fact the microbes in the preterm children while the microbes that were present in the term children here were actually degrading histidine which is really cool so there's a big difference in these two things arginine and histidine there are also differences in a number of other products and when we look at the variation in those products and we look at the correlation with different samples well we see here that the microbes here in the feces for the preterms there was a correlation between the structure of the microbial population the active ones were minor acids whereas in terms it was a lot less fecal volatiles a lot here again so microbes from the preterms correlated with the fecal volatiles we were seeing but a lot less for the terms when we look here at the plasma amino acids though we saw this that the plasma amino acids so in their blood, their peripheral blood the microbes didn't correlate with any concentrations for the preterm but they did for the term and here the plasma volatiles again correlated with a lot less fecal volatiles and microbial correlations in the preterm then they were in a term and this really is indicative of this happening that the guts in the preterm children if we were to interpret this data really should be leaking they shouldn't be able to maintain concentrations across them and in fact what we did is we looked at some indicators of this and there's good reasons to think this because arginine as well and the production of lots of arginine in your stomachs is nitric oxide causes inflammation which is linked to gut leakage a lot of reasons to think this when we look and we actually look at products the actual product we look at is calprotectin and calprotectin levels indicate gut inflammation and leakage and what we see are that the preterm children here on the left have much higher levels in fact there are individuals way up here off the chart that are actually in the realms of having Crohn's disorder in this particular population by contrast the terms are much more condensed much lower levels of calprotectin so their guts were inflamed and leaky the children born preterm also had reduced insulin sensitivity which is really interesting it correlated very well with the production of some of the amino acids that we were seeing correlated with the short chain fatty acids and various other things that we were seeing oops and these individuals so our current hypothesis is that the early life events programme are changing the foundation flora which is in these microbes and the structure of the population but it's about what the microbes are actually doing as these children eat, breathe and live and whether or not these differences influence or contribute to the changes in insulin sensitivity remains unclear to us but we're trying to figure out ways to move forward and understand if we can interfere with this process so when you think about the microbes in your stomachs okay it's not about us and them it's not about labelling them so that there are things that you should fear and you should embrace them hopefully they're not that big again there's more to us and you see and these are the people who did it and these are the current people in my group at the moment, thank you very much Distinguished Professor Jane Harding is currently a researcher in the Life Path Research Group in our University's Lingans Institute Jane did her basic medical training here in the University of Auckland and then the Doctor of Philosophy in Oxford in Britain and then a postdoctoral Fogarty Fellowship at the University of California in San Francisco she's undertaken teaching and research in this University for much of her career her ongoing research concerns the role of nutrition and growth factors in the regulation of growth before and after birth and the long-term consequences of treatments given around the time of birth and the regulation and significance of neonatal hypoglycemia that's low blood sugar levels she's a pediatrician and she's practised as a specialist neonatologist caring for newborn babies at National Women's Hospital and has just recently stepped down from her role as the Deputy Vice-Chancellor Research in the University where she had overall responsibility for the University's research activities she was awarded the Howard Williams Medal by the Royal Australasian College of Physicians in 2014 for her outstanding contribution to pediatrics and child health and in 2016 she was awarded the Bevan Medal by the Health Research Council of New Zealand for excellence in translational health research so Jane, it's my pleasure to introduce you Thank you, Peter. Low blood glucose hypoglycemia is a really common problem. We estimate that it's affecting more than 10,000 babies a year-born in New Zealand and it's probably the only really common and readily preventable cause of brain damage in newborn babies and that's because glucose is the major fuel for the brain and of course babies have relatively big brains so if your glucose levels are low your brain has a problem. Why on earth do babies get low glucose levels? Well, very broadly speaking this is in term babies in the first few hours and days after birth and you can see that at the time of birth babies have high-ish glucose levels that's because they get a constant supply of glucose across the placenta from the mum when mother's glucose goes up then the babies goes up and mother's goes up with the stress of labour and delivery and so the babies goes up and then somebody comes along and cuts the cord. So now the baby has a problem and the glucose levels fall because they still need glucose for their brains and it takes them a few hours you can see the low point is around 1 or 2 hours of age it takes them a few hours to get themselves sorted out start making glucose of their own start feeding and sort out their glucose levels and they come up to normal adult levels until about day 3 or thereabouts but because we don't know which babies are going to have low glucose levels and we can't tell from looking at them we end up doing blood tests to look for glucose levels in the babies who are known to be at high risk of low levels who are those, they're the big babies the small babies the babies whose mothers have diabetes and the babies who are pre-term and are sick for any other reason and that turns out to be if you add all those together nearly a third of all babies fit into one or other of those categories so we're doing lots of blood tests on lots of babies to try and detect this problem and prevent brain damage so when we started working on this problem a few years ago we asked every neonatal unit in Australia and New Zealand we said how do you treat babies with low blood glucose levels and we used this this is just two of many scenarios we showed them, we said these babies, one's a pre-term baby at 34 weeks the other's a term infant of a diabetic baby this baby's two hours old and it's got a low glucose level of two how would you treat it and when you get that many different answers you know that none of them know what they're doing so it's very clear at this time that we really weren't sure what the best treatment was for low glucose levels and we thought well surely we could do better than that and we set about doing what we called the sugar babies study this is Deborah Harris's work in Waikato and we said could we use this 40% dextrose gel it's a simple sugar gel would it work better than just feeding these babies to reverse low glucose levels in the first 48 hours after birth and the short answer is it works really really well in the green bars you see the babies who got the placebo gel and in the white bars you see the babies who got the sugar gel it gets rubbed inside the baby's cheek and you can see that treatment failure which was defined as not getting your glucose up after two doses of gel decreased from 24% to 14% being admitted to the intensive care unit for treatment of low glucose levels and it was done down by a similar amount the thing we were really worried about is what it would do to breastfeeding because we know that giving babies stuff other than breast milk is inclined to inhibit breastfeeding so it was a great relief when we asked how these babies were feeding two weeks later that the rate of formula feeding was much reduced in babies who'd got dextrose gel I presume because they didn't go to intensive care which means they got to stay with their mothers and got to breastfeed so dextrose gel looked like it was a great treatment it's very inexpensive, it's non-invasive it's easy to give you can use it almost anywhere this was published in 2013 and for once the medical profession actually latched on to this and changed practice really quickly because usually it takes years and years and years and years to change practice and this is just in the first three years after that study was published this is just an example five different places reporting all of them reporting that the babies were less likely to be admitted for intensive care and those who reported it said that breastfeeding was improved so it's a very exciting example of how when a treatment is simple and easy to use and seems to people to make sense that they do start using it and it's very reassuring for us there's not yet been another trial and previous speakers have talked about the importance of multiple trials well there hasn't yet been another trial everybody's just using it but they are all reporting the same effect we went on to do a cost analysis and this is Matt Glasgow who's doing his PhD on health economics and amazingly enough it even saves money saves about a thousand dollars per baby that would equate about eight million dollars a year in New Zealand we think if all those babies were treated mostly because it keeps them out of intensive care a critical thing that we still don't really understand is which of those babies who we are treating would have had brain damage how low does the glucose have to be for how long for those babies to have brain damage do we really need to test all of these babies and treat them all or would some of them be okay and we thought well surely we could answer that question and we hypothesised that development of children is related to this variety, duration and frequency of low glucose levels when they were babies and the reason the different ages are crossed out is we saw them at two and then we said oops better see them again at four oops better see them again at nine this is 614 children born at risk of hypoglycemia in the Waikato have grown up and travelled all over the world but we're still finding them what did we find well when they were two there was no relationship that we could find between the low glucose levels and their development and I didn't know whether to be disappointed about that because that wasn't the hypothesis or to be really pleased and say well we treat them all and they're fine but it wasn't quite that simple because when we saw them at four in fact they had a two to four fold increased risk of problems with visual motor function that's understanding what you see and coordinating between your eyes and your motor system and executive function which is your capacity to short term memory, learn rules follow instructions, pay attention those two things together are very strong predictors of how children do at school so our prediction at four years that these children are going to have a problem at school so we're seeing them now at nine years and I'll tell you in another year or two whether they do have problems at school the worrying thing was that that increased risk was there even if they only had one low glucose level and if it is true that there's a bad problem after only one low glucose level then all the best treatment in the world is not going to help us and about the same time as we were finding this finding something quite similar they had looked at babies they tested all babies in the hospital we only tested babies at risk they tested all the babies in the hospital and looked at whether they were proficient which means at grade level in fourth grade when they were about 10 and the odds of being proficient were about halved in babies who had a single low glucose level so we've moved on from treatment to say should we be doing something about trying to prevent low sugar levels and if dextrose gel works so well to prevent low sugar levels could we use it to prevent this problem and usually when I go to work and say I've had this bright idea guys everybody go hides and groans and tries to keep out of my way because the first question was well is there a dose of gel that could prevent low glucose levels what dose are you going to use Jane I don't know better do the first study and figure out if there is a dose that will prevent low glucose levels the answer is there is we used 415 babies and we do have a dose of gel that does reduce the incidence of low glucose levels but who cares well only matter won't it if we can do something important like keep them with their mothers so we're currently doing the H-pod study hypoglycemia with our old dextrose we're giving preventative dextrose gel to babies and the outcome of that trial is going to be do babies stay with their mothers and stay out of intensive care we're recruiting 2,129 babies which is quite a lot but we're about two thirds of the way there and we hope to finish by next year but of course okay to be great to keep them out of intensive care but what really matters is what happens to their brains so we're also looking at them at 2 and I expect we'll have to look at them when they're older but at the moment we're looking at them when they're 2 and the first results are quite promising so I don't do all the stuff by myself there's a big team doing it and lots of people he'll help support our research and I will stop at that point and thank you all for your attendance tonight a little flyer for the next public lecture put it in your diaries you are welcome to come and talk to the speakers we won't take questions because everybody's been sitting on hard seats for a long time please do come in and talk to us if you have questions thank you for coming for this evening and thanks to the AMRF for your support