Measuring the Placenta: Highlights into the "how" and "when" of gestational complications



too many places but new york university i think is home home base she's a licensed physician and surgeon and she also has a technical degree which explains her interests in a lot of mathematical tools and techniques and she actually does have some roots in North Carolina she went to medical school at Duke University after graduating from Dartmouth and she is a very ill Astraeus in the whole field of pleasant as I don't know what what they took what the exact term medical term is plus ontology yes it is yes no hitting no kidding Wow all right fine oh and she's as i said the currently professor at the medical school at new york university she is also director of early path clinical research consultation services and she is affiliated with many different hospitals in the new york city area and she has a knack at at communicating with technical people and basically which gave her this very prolific and illustrious career in publication and in in all her academic yeah let's wrap it up career it's a pleasure to have you here and she'll be entertaining us about measuring the placenta thank you Oh two things 1i have a knack for communicating with technical people now I have major performance anxiety and 2 i'm going to entertain you to very high bars that i do hope i will try to to meet with a subject that is that most people don't care too much about including obstetricians but the placenta is what was attached to your belly button before you were born and the placenta before you are born serves the function of your lungs serves the function of your gastrointestinal tract serves the function of your kidneys in that you get your oxygen and nutrients exchanged from your mother's bloodstream across the placenta and you get your oxygen through the placenta food comes from the mothers bloodstream into the placenta and then goes to you wastes are excreted from your bloodstream across the placenta into your mother's bloodstream most hormones that are made by the pituitary in the brain and in most of our endocrine system are also produced released if they're not produced releasing factors are made by the placenta it's really a great little structure and as soon as we're born were cut off it and most of the time it's thrown in the garbage but I'm going to try to tell you not only why this is important for a healthy life before birth so that you can start off life reasonably intact but it's becoming increasingly important to understand how and when in pregnancy things happen that can change not only the course of that pregnancy but there's increasing evidence that what happens before birth actually colors the rest of our lives so let's go through that and i love the technology here but I I have to be able to there ok life before birth or intrauterine life is associated if you have problems with this you can imagine that you're at increased risk for dying and and you're right if I touch the screen if it advances morbidity means sickness and mortality means death so dying before birth or having a disease before birth or shortly at the time of birth natal is defined as the first month of life childhood there are a number of risks of problem pregnancies for risks for asthma for cerebral palsy from any neuro developmental cognitive and motor problems in childhood ok and recently over the last 15 years ie less than the total time I've been practicing medicine there's been a new data accumulating that suggests that life before birth actually is associated with health risks at age 40 50 and 60 and that is a little bit hard to necessarily understand how could that happen I mean once you're born don't everywhere all you know all created equal right so we all have a clean slate once we get out of the room out of the womb excuse me out of the room of the womb but basically what this evidence sums up to is that as best as epidemiologists and biostatisticians can try to adjust mathematically you know with with confounding and all of the bio statistical methods as to the best of our ability once we try to correct for or adjust for everything that we do after we're born plus our genes insofar as they're reflected in family history a wide range of adult health risks and this is up to from 50 to 70 is where most of the studies have been done very either directly or indirectly with birth weight so either the higher the birth weight the greater the risk or the lower the birth weight the greater the risk and this is okay and genetics aside eighty percent of birth weight is mediated via placental function bigger people tend to have bigger babies and the placenta is ninety-nine point nine percent baby tissue ninety-nine point nine percent baby so it grows proportionally to you know the genetic capacity of the fetus and almost all of eighty percent four-fifths of birth weight variants apart from your parental size depends on how well or poorly the placenta is able to establish itself now what types of health risks are associated with birth weight are we talking about disorders that affect one in a hundred and fifty thousand people you know very very rare obscure and bizarre ssin here I just hovered my hand over the screen I'm not even touching the arrow you know I have an aura cardiovascular disease we're talking really about very common diseases high blood pressure stroke myocardial infarct which is a fancy term for heart attacks diabetes and related syndromes including obesity and syndrome X which is also called the metabolic syndrome which is a major risk factor for obesity where you carry your all your weight in your tummy and which carries high and independent risks for cardiovascular disease so these two circumstances are actually more closely related than they might appear but then there's also cancers including prostate and breast cancer and I am appointed in of all things a psychiatry department people who know me well have suggested that I should be a patient of not a faculty member in such a department but the CP is an abbreviation for cerebral palsy ADHD attention deficit disorder and autism and schizophrenia now these latter two disorders are strongly genetically influenced the risks of having a second autistic child or an once there is a family history of autism is as high as ten to twenty percent whereas the risk in the population as a whole is less than one percent however in both autism and skits freni ax despite this genetic predilection there seems to be something built into the families the children who tend to manifest either of those two conditions tend to be the ones who were lighter born preterm have their cord wrapped around their neck a couple of times etc so people who had some type of complication during pregnancy now cardiovascular disease and diabetes with cardiovascular disease your risks of dying at age 50 of a heart attack are bigger are less if you're 10 pounds then if you're 9 pounds less if you're 9 pounds and if you're eight pounds etc works right across the birth the entire normal birth weight spectrum so it's not just like the little itty bitty babies in the intensive care unit are causing all of these problems these are circumstances and the idea of programming your biology before birth is something that would apply to everybody in this room regardless of your your mother's pregnancy history with diabetes and related syndromes again certainly there's a genetic component to diabetes but the idea is that your risk of diabetes goes up as birth weight goes down and why would that be why would a skinny baby have a greater risk of developing diabetes the idea is that if in before birth you are attached to a placenta that is not working right so that you are chronically hungry for nutrients your physiology start setting up receptors and thresholds and sensitivities so that you really are able to hang on and maximally utilize every single calorie and you don't spend a calorie unless you absolutely require it has to happen as soon as you're cut off the placenta and everybody wants to fatten up that skinny little kid because otherwise they don't look like a good mother and they eat and eat and eat they end up putting on weight and then their biology is still set to optimally manage every calorie so the idea that diets don't work for me can actually be physiologically just it could actually be true for people and one of the things that of some interest is that there are risks that are associated with certain ethnicities for example African Americans have very high rates of hypertension diabetes obesity etc African Americans also have a very high rate of infant mortality and morbidity about fifty percent higher than other ethnic groups in the country matched for City matched for neighborhood as best we can you know what have you and most of that increased poor newborn health is related to babies being born too small so you can see that there's there's the potential with this type of circumstance that if a mother has a baby that's small that child will grow up to be a sicker adult may have more pregnancy complications themselves and this is it's what's called the transgenerational passage of diseases a problem happening in the grandmother may not be fully manifest as early onset disease until a granddaughter as the effects of passing the predilection passing the problem through a couple of generations becomes fully manifest now for example with cancers breast cancer in particular the bigger you are all other things being equal including your genetics the greater the risk of breast cancer and that's thought to be related to having an optimal placenta and an optimal endocrine and growth factor environment so that there's some programming to the primitive the embryological mammary tissue so that it's more geared up to be responsive to something that wants it to grow so it is has a greater chance of its growth becoming uncontrollable if something else happens to it later so that's a little bit more than i intended to spend but i think this stuff is really neat and the animal models of all of these diseases suggest that it's not just size that matters and of course my standard joke and you've heard it before is that of course i would not want to think that being small was something that would be intrinsically bad okay so the animal model suggests that it is not some is that it's not that if you're born at five pounds you have a smaller heart with fewer cells in it so that at age 50 or 60 you have a greater chance of it wearing out it is not just size it is something about either the network of vasculature that you develop something about this physiology etc so it is not just sighs so that makes me happy fishin I mean the mother's nutrition has a lot to do with also the baby's physical at least the appearance in terms of size and that's true of the things that influence you know there's maternal age socioeconomic status parody and what that means is how many babies you've had second babies tend to be bigger than first babies gender boys tend to be bigger than girls and then maternal pre-pregnancy weight which is related to height and then pregnancy weight gain and again when you put on the weight in pregnancy also is important whether its first second or third trimester the thing is is that birth weight though is is actually quite resistant you can't modify it very easily with vitamin or nutrient supplements they tried to a study in Harlem in the 60s of providing people with more protein and and what have you and they weren't able to budge birth weight more than half an ounce you know by improving diet of you know inner-city low-income folks and so so yes these large things do influence birth weight but things like just nutritional status per se it is less important than you might expect yes sir give an ideal gestation conditions minority people can't improve birth weight um even given ID if you the studies suggest that even if you have to medical school you know a black classmate of mine at Duke you know who had the same socio-economic status had the same neighborhood who had the same diet who had the same everything and the same family history of other things that person would have a 50-percent greater chance of greater risk of infant mortality than I ok that and and so you it's not anything that you can point to any one person this is a population characteristic but overall that population adjusted for all other things has a very stubborn increase in infant mortality that initially for example I went back and got a master's in biostatistics at Columbia and one of the things that i did in the summer was I did an internship at the Public Health Department in New York City and 15 years ago they thought that the increased morbidity and mortality and african-americans was due to poor access to health care ok so they put in this enormous drive to make sure that everybody who wanted to go to a doctor could get to a doctor as soon as was humanly possible 15 years later they look at their numbers and the rates of early-onset prenatal care you know before 12 weeks how many people see a doctor same across the ethnicities all of the infant mortality rates are lower than they were 15 years ago but still african-americans are fifty percent higher than the other ethnic groups so i SAT through a meeting where it was suggested that the quality of the health care must be different and the providers in new york city must be intrinsically racist you know I don't know but you know I you know these are alternative explanations you know and i think that understanding this better takes it out of philosophical arguments and let's let's figure out what the heck the x oh jeez you know is there a biology then let's just deal with that now how do we measure placentas and this is an artist rendition of an umbilical cord and this is the placental disk and placenta I forget if it's Latin or Greek it must be Greek means little cake okay pathologists is supposed to be really renowned for disgusting food analogies I try to keep mine to a minimum but how do we measure them basically the same way we've done since nineteen sixty one in 1961 a former Luftwaffe ace who is the great-grandfather of placental pathology in this country Kurt burner ski wrote a protocol and that's exactly what we're doing now and in fact the government is thinking of is in the process of committing four billion dollars to a project called the National Children's Study if you put that in Google you can find out about this where they're going to follow a hundred and twenty thousand pregnant women to delivery and follow the expected 100,000 live born babies to age 21 to better understand these fetal origins of health risks and many of my colleagues are thinking that we should do it exactly the same way we did it in 1961 but you know luckily i'm working with some people and we're going to try to implement some of the new measures that i'm going to talk about with you today but we're going to change that right so why do we need better measures and let's see if i can make this there oops this this is probably not going to animate too well on this but if you measure something poorly right say you measure the placenta poorly and what you want to understand is how maternal smoking affects this is Sigma birth weight variants in birth weight just as an example could be childhood IQ could be anything at all if you measure the placenta poorly then you're going to have an attenuated relationship between the maternal factor and the placenta because this is going to be fuzzy and amorphous and then what's going to happen is that it will appear statistically that the maternal factor effects birth weight directly you know and bypasses the placenta totally however if you measure placenta better then what happens you might be able to find that the Oh the true relationship in here was not this but that the mother affects the placenta and by affecting the placenta affects the baby so if this is not the case but this is say it's smoking say it's an environmental exposure to arsenic and I worked in Chattanooga where eighty percent of the placentas in a three-month period in Chattanooga Tennessee had detectable levels of arsenic because of groundwater contamination and pollution in general from factories this allows you to approach possibly intervening and dealing with things in a completely different fashion maternal stress any type of factor so what we're trying to do is understand the biology it is really important not to measure our intermediate step poorly we need to measure the placenta as well as we measure birth weight as well as we measure maternal smoking what have you it has to be well measured or else we're going to get a false finding why is this whole problem important well if we can measure placentas well and take measurements of the placenta at delivery what we can do is understand when in pregnancy a developmental trajectory started to go awry for example I'm looking at all of you now and I've never met most of you before right now and I certainly wasn't looking at you at five or six weeks when you were in the womb but we know that your neural tubes you know that you initially your brain is like a flat piece of paper and it turns into a tube and zips down the middle and seals at both end and becomes your brain on one end and your spine on the other pretty amazing stuff this is this is I do what I do because I just love embryology but I know that that happened to all of you and early on we have a little flipper and at a particular with in about 12 hours all of us at the same time in our gestation cells started to die along one two three four lines in that flipper and that's why we have five fingers so I know that you had all of these developmental steps happen even though I wasn't watching you at the same at the time that it was happening and the placenta also is the accumulation of a series of growth and developmental trajectories and if we can measure it carefully enough that's when we're going to get into when y is when important because the earlier the stress the greater the risk of fetal effect for example if you do something that kills one cell at eight weeks that if it had lived would have given five hundred cells by term killing one cell at eight weeks is a lot worse than killing one cell at 40 weeks because you lose those 500 cells ok so the earlier the stress the greater the risk of fetal effect if we could understand how severe that deviation from growth trajectory would be again the more severe the stress the greater the risk of fetal effect a gentle stress is something that you can habituate to I used to say that this was like being married that after 15 years you'd say you know I never thought I would tolerate this kind of not but you know it's a slippery slope you know I mean all of a sudden Here I am you know but if something happened that was very abrupt hey that would you know then you would notice it and physiologically you would have a a change in homeostasis possibly so if there's a severe effect you might have altered homeostasis compared to a milder effect which you might be able to accommodate for without really any type of biochemical changes and again the greater the fetal affect the greater the potential for long-term modulation it may be that some of the measurements that we we come up with may say that the developmental trajectory was not just modified at one point in time but that it was modified at several points in time if this is a normal developmental trajectory that maybe somebody would and that would be one hit and then the developmental trajectory would come up but maybe for some people you know that there are multiple hits that bring them down from baseline and this may be very different physiologically than someone who's either programmed to be small okay for chronically stressed from the beginning small from the beginning so these types of information when severity and single single hits versus multiple multiple hits all could give us information that would help us understand the fetal environment better and be able to get some biology so again if what we're trying to do now is understand the nature of shape variability and also branching why I'm here is because your group and working with jamila has given us the possibility that we may be able to develop metrics that would help us quantitate and and and apply standards to branching variability and again with the idea of understanding better intrauterine life now what are the types of measures I was told that saying that there's a gross examination is really not a very you know the colloquial use of the word gross you know is disgusting right it's gross and placentas are really bloody and that's when I started dressing out of second-hand stores when practically everything you know whatever you know but it is it's a naked eye examination okay looking at the whole placenta and the whole placenta is base is what we're going to be focusing on here then there's also microscopic pathology and microscopic pathology here's a naked eye placenta and you have an umbilical cord insertion here and you can see that this is a little bit of an irregular you're going to be seeing this placenta a lot but this is a naked I photograph of a placenta and then we can I don't know why that erased and I don't know I'm being impatient aren't I okay there was some slices into actually that you can carry you can use your your mouse okay when you take this you can you slice it and you look at the thickness okay and the thickness is actually where the maternal blood this is the part of the placenta that's attached to the uterine wall so the mother's blood vessels are coming up and feeding into the placental tissue here and this is actually where nutrients exchange is taking place in this dimension then what we do is we take a small square out of it and make a glass slide that we can take and put under the microscope and review as well so so thanks for the tip okay what I'd like to talk about of the measure type the current way it's done the limitations of how it's done currently and a little bit about our work and moving from structure to function and I'm probably going to speak progressively faster as the minutes pass this is hole measures okay naked eye measures and the current way that we measure the placenta is a single length width and depth so we take the larger diameter and we take a smaller diameter and there is actually no standard that requires those be at a perpendicular I tend to and then you measure the depth of the placenta and the more normal a placenta is the more uniform the perimeter the more uniform the thickness and basically these standard measures were pretty darn good placentas that are from healthy normal uterine environments however this placenta I told you'd see it against this placenta is obviously very irregular and this placenta clearly has issues with how it was growing you know in the womb there's a lot of variability there what do you do you do take the maximum do you take the minimum do you average the two do you know do you take a majority percent how would you get one number that would characterize this placenta now the placenta normally starts off with an umbilical cord pretty much smack dab in the center all of our belly buttons are pretty much in the same place right and this is my Latin I love embryology but when we're a flat piece of paper our butt is down here our spine is here our brain then our mouth and then our heart and our belly buttons are the result of us folding top to bottom so that its heart mouth and brain and then side to side so the belly buttons are windows to the plains of cleavage of folding intersect and so early on the placenta also has that type of structure and its belly button is where most of the major big blood vessels are coming out and if you are going to be this is going to come into something that we're going to talk about at the end if you are going to be devising an organ to transfer oxygen and nutrients what would be the optimal design well it would be probably radial right you know and it would be equal length of trips right and you'd have if these are the nutrient supply areas like the farmlands every nutrient supply area would not be too terribly far from a blood vessel etc so there's an optimum transport component to this that would dictate that these placentas be reasonably uniform in thickness and reasonably uniform as far as a growth about the umbilical cord and its perimeter however these placentas obviously were changed you know these are not round to oval the umbilical cord is not in the center the umbilical cord is actually over here and if early on the placenta was centered about the umbilical cord well early on maybe half of this placenta got killed women often not uncommon Lee have first trimester bleeding maybe there was an event that killed a portion of the placenta to result in the umbilical cord being marooned at one extreme edge of the tissue and again just like this implies something about the intrauterine environment the placenta will Arbor eyes this is all branching growth here what makes the placenta thick is a series of dichotomous branches okay and it will branch where the blood flow is lush and gentle and it will not branch where the blood flow is maybe too harsh and damages the tiny developing tissues or what have you where the uterine lining is not good it won't develop so basically at some level you could consider these two dimensions if you could understand them you could and and and I always still sound like I'm faking it when I use math terms because I have one of the worst cases of math anxiety you'll ever meet but the inverse solution to this shape would be the intrauterine environment okay because the intrauterine environment modulates this dimension and also modulates this if you could solve for the two of them you would be able to describe the intrauterine environment that created this and deformed it you might have multiple solutions to this and multiple solutions to this but my hope it would be is that if we put the two together that you might end up with with a much smaller family of solutions that would account for both of them and then those solutions would differ possibly by the time of onset of the stress the severity of the stress the multiplicity of the stress and the reason that I walk around and still go to hospitals and see placentas is that there are a lot of obstetricians who want me to help them understand when they deal with somebody who has a complication at 14 or 16 or 18 or 20 weeks they want to know how that baby turned out so what we can do is if I have a series of hypotheses that are the come you know the unique group of solutions that both solve this and this at the same time that generates a set of hypotheses that then I can start looking at people throughout pregnancy and start seeing which one actually is you know do they all happen in some people or is there one solution that really is the most common one that we see in humans you know what one pattern of severity multiplicity and timing or you know art is is one of those solutions work for one set of people maybe it would work for people who had pointed who had low socioeconomic status that there would be one pattern of pathology that would be more common there maybe there would be no distinguishing features may be only one one solution would would would really be but that's the kind of work that we're looking to do now the other problem with measures is something again the main reason that we're here and talking to jamilah this is a branching organ and here's the umbilical cord insertion on these two placentas and I think you can appreciate that here there's blood vessels and blood vessels and blood vessel there are lots and lots of blood vessels and they're doing a lot of branching you know they there's this is a very complicated chorionic plate surface and I can say that it's more complicated than this one which only has really three main branches okay and goes for long stretches on the placental surface without branching this is very different we don't have a metric for saying how much different this is than this but certainly from the point of view if this was a railroad you know if this was a railroad system as far as efficiency and cost these would be very very different functioning struck functioning entities okay why do you generate this what are the circumstances that caused this to be generated then what is the impact of having a more costly system on the baby because remember how does this whole system work I love to draw you have a baby and you have the baby has a heartbeat and about half of every heartbeat goes down the cord to the placenta fifty percent of every heartbeat okay so there is no the heart pumps the blood down and there is no pump there's no heart in the placenta so basically it's the force of the heart that gets it all the way down into the capillary bed where blood moves very very slowly right it moves faster and big blood vessels very slowly in capillaries how the heck does it get a head of steam to go all the way back up the umbilical cord it's still the pressure of the baby's heart with the pulsations in the umbilical cord what the baby gets out of every heartbeat cycle basically is the amount of nutrients transferred minus the cardiovascular work okay so if you have an inefficient system this number will go up and presumably the fetal benefit from every cardiac cycle would go down and this would modify birth weight remember birth weight is what is being used in all of these studies as a proxy for intrauterine health because these studies that were done on 50 60 70 year olds they did them on people who were born in the teens and 20s and they found places for example in England Herefords year where is Herefords year I don't know it's a little place where midwives wrote down the birth weights and there were enough people still living there 50 years later where they could go back and say you were this much weight when you were born and they could match it up and look at the disease so this is just a proxy for intrauterine health yes the winner of the events of the babies born to these placentas or are these just detached from the babies kind of observations okay this was heartening in him no this is part of a cohort that was collected down the road university of north carolina they had a contract to recruit people at age 18 weeks before it was known how they were going to end up and they measured them and ask them questions and took samples and followed the pregnancy and then when they delivered whenever they delivered the placentas were shipped to me actually to my home my family used to love the boxes of placentas they rarely leaked you know but but in any case and you know this is a study ID number I know the birth weights on all of these and I'm going to show you some of the Simon and I have been working with this data set and you know Jamila will be working with that as well our hope might be that if we can find things that are predictive and useful that this population could then be written up for federal funding to follow these children into early childhood there's 1,200 people in this cohort that's not probably enough people to study autism but it would be some enough to study blood pressure childhood growth trajectories you know it would be enough to study a number of different things not rare just disorders but a number of things okay and here again is our nice normal placenta with all the branches and here's the umbilical cord and basically if I were going to trace around where the blood vessels are on this placenta that's where they are there's only one artery and one vein and that's it and the placenta what is this placenta out here doing you know how is it structured how what would be the cost of having a lot of major highways only in one spot you know relative what is the cost so again I can say that these two are not the same but how much not the same is this one worse than that one you know I don't know so metrics we need methods so and again chorionic vasculature how long the blood vessels are reflects the number of mitosis or cell divisions right and if you're healthy your cells can divide well and if one of the things that can make you not healthy my blackberry hasn't rung all day but it's ringing ringing now it is something about the welfare and the well-being of the intrauterine environment and then vascular branching specific genes control branching of vasculature but the same gene families that control branching in the placenta also control branching in fetal organs such as the lung the pancreas the kidney and of course neurons with their dendritic arborization which is essential for neuronal connectivity and all of our complex neurological function is due to the branching density of dendrites so the other thing is measures are not taken in relationship to each other we have a larger in a smaller diameter and then people measure where the umbilical cord is to the closest margin and what pathologists generally describe things the reason that you have a description on a pathology report is because that the doctor wants to try to communicate what they receive and basically you you can't form a mental picture of what these placentas look like from these from these descriptions so they're they're taken completely as independent measures and not taken as being measures of the same structure that might reflect a shared biological health or pathology so four better measures what we did is we took photographs of these placentas blew them up put them on kurta graphics tablets and marked them at at least one centimeter intervals around the curta graphics tablet and perimeter and related geometrics there's a number of different ways that you can look at ruffling and and irregularity of the perimeter accounted for just thirty six percent of birth weight variants that doesn't that's that's a little bit more than a third but actually if you just threw the whole placenta on the scale it it accounts for about a third of birth weight variants just the weight you see we have a lot of birth weight bearings that we need to explain so basically just this perimeter was as useful in explaining birth weight as the entire mass of the placenta so we actually think that we're probably going to get three quarter we're going to probably get close to that eighty percent when we put all of these things together now chorionic vasculature this is Simon's a hand mask tool using Adobe Photoshop we still have to we've done a lot better with taking these structures out initially what we had thought about doing was you know overlaying a spiral grid and doing a stereological estimate as to how many times the blood vessels crossed the grid and that would give us an estimate but now with better image processing and the help of you know friends we're able to extract this we still have ain't got no metrics to describe what what is normal here obviously there's more branching here there's very little branching this structure here there looks like there's holes in this you know where they just didn't cover the structure well so we don't have any metrics for those but we're better at extracting the information so now we're ready for metrics to be generated and then in terms of things being related to each other the next thing we did was we took the perimeters and remember i said earlier that you can sort of see where these blood vessels disappear and what we did was we just marked where every blood vessel went away okay and then we ended up with an area and achieved area a vascular area and the umbilical cord insertion okay so now let's take all of these things and and try to look at them in relationship to each other when we looked at this when I did this my hypothesis was that vascular area over area was going to influence birth weight that if these blood vessels didn't go out very far and this placenta you know didn't have a you know uh a high resist high capacitance low resistance distribution system a big blood vessel nearby then this was going to be inefficient and that these babies were going to do worse if this area was this area ratio was off so that was my hypothesis the way we approached it is from this drawing we can actually get three areas one the perimeter which I've talked about already the second of vascular area and then the third area that we can get is actually the area of the circle with the same the ideal placenta the placenta that would be circular that had the achieved placental area okay and each of those would have a centroid a weighted center of of the shape and we looked at ratios and then we looked at these centroids and actually what we found out was if this is you know that ideal and this is the actual area this is the ideal circle this is the actual area and this is the vascular area what we found is that the air that the ratio of these two areas was not predictive of birth weight but how misaligned these guys were actually influenced birth weight a total of about a third of a pound and as I said that doesn't sound like an awful lot but when you think that taking prenatal vitamins to not taking prenatal vitamins to giving people extra protein when they have adequate calories that does barely a half an ounce to announce these are actually relatively large amounts so this type of misalignment implies that there is something about the growth of these structures the greater that they are off kilter what was the word that you you used a word that I was going to trust that they are that they are not concentric that they don't overly each other that the umbilical cord is off if this is the true umbilical cord that would be in the ideal circle the distance between the true umbilical cord insertion site and the weighted center of the area the distance between the umbilical cord insertion site and the centroid of the vascular area that all of these being misaligned makes a placenta that this is all adjusted for placental wait so for the same placental wait the greater the misalignment the smaller the baby ok so we're interested in capturing these surface branches we're also interested in capturing the branching of the three-dimensional placenta as well but you know what have you so placental thicknesses I've mentioned is where actually nutrient exchange occurs and this is a high magnification of part of the state this the mom red blood cells would be here these are the placental villi these are the cells that turn the pregnancy test positive these make HCG which is what's measured in the pregnancy test and these are the baby's blood vessels and you can see that there's a very narrow distance between the baby and the mother so that diffusion works very very efficiently to transfer okay so that's how all of this works so the work that we still need to do is figure out what are the metrics and then what are the parameters that can be quantified by those metrics for our chorionic vessels now that we're able to extract them and all of the work that we've done so far has been stuck on the 2d but if we can take this thickness and consider it as a height function and add it in again I think you know whether we solve these two equations similar differently and then look for the equations that solve you know we look for the intersection of the two or if we simultaneously solve for them and integrate it would be with a a height function type of thing that's what we're looking for to explain the complexity of the shape of the placenta and the shape of the placenta is basically the shape of the branching structure that developed throughout term now we're trying again we're interested in anatomy because Anatomy has a function and in the placentas case there is only one reason why you have a placenta which is to make as much baby as you can so what we're looking to do is to derive anatomical measures that imply functional functionality so here we're going to talk a little bit work that we're trying to move forward on to move from shape to a cost function and jaw I don't know his last name okay apologies I have good friends in Beijing and I never get named order correct and I apologize he's at UCSD yes and he's been working on leaves and if you give him the shape of a leaf and where the stem inserts he can tell you what is the optimal transport function what is the optimal distribution of you know veins in the leaf to cover that shape and from a placental point of view surprise surprise the optimum transport distribution network is a circle that looks a little bit more like this with a centrally inserted umbilical cord and the efficiency of this structure is around six seven so far the only thing that he's worked with is the part of that graph that I showed you that that the plots the plots of the perimeter so we've given him the shape of the placenta and the umbilical cord insertion and what he does is he calculates the optimum distribution system for that shape given the umbilical cord insertion and what he can do is say how much this shape and court insertion result what what is the cost of having this shape and cord insertion given an ideal an optimal vascular transport system okay he hasn't looked at the vessels because we can't give him the vessels to look at yet because we have no metric so what he's looked at here now is this is the efficiency of the transport system and this is a projected birth weight based on some calculations that he has done and basically the the babies that are the that are larger than our estimated have optimal efficiency okay that this is this isn't the way I would show this data I would take the observed birth weight observed birth weight and divide it by the estimated birth weight and show that difference but basically he's finding a very high correlation between his measures of a fish efficiency just based on just based on these two point two data points the perimeter and the cord he's finding a high correlation of that efficiency being correlated with a bigger baby than you would otherwise predict given the size of the placenta and you know obviously we can do a lot more now on ours up right it's um 130 United question about that efficiency a lot and how it exceeded 1 okay you're talking about these outliers I would assume that the maximum efficient arrow good rate that four that's a cost that's cost function does it cost so maximum efficiency is that circle and the way he calculates it it comes out to be about point six seven deal and everything else is none right and what these placentas are for example is instead of a nice round placenta a placenta that has a lobe here and a lobe here and the umbilical cord is inserted here okay that's extremely inefficient and very costly okay that's actually primate placentas are by lobed baboons chimps monkeys are multi lobate but human placentas are our single lobes okay what is our I have five minutes questions um should i skip two questions or should I let's just I'm not going to talk about this we're doing some segmentation issues that are trying to help us distinguish better our bottom line is that microscopic review of these slides is very complicated and what we're looking to do with image segmentation is improved reliability have more aspects of a process like bacterial infection than just counting pus cells which is what's done now and instead of having things be semi quantitative some none some more and a whole hell of a lot which is basically what a zero to three scoring system is which is what was recommended by the Society for pediatric pathology to generate continuous quantitative scales because the disease processes that we're dealing with before birth that are associated with poor outcome are actually physiological continuous variables and under the microscope nobody has even tried to categorize placental architecture and I'm going to skip this and it's it is pretty neat I I think that you know I I obviously love what I do and let's structure and function the last thing this was from I Pam as well I was dealt with my math anxiety at the Institute of pure and applied mathematics at UCLA for three months between April and June and Dennis core bank off and Bernard SAP eval at the Polytechnic in in France are looking at how lungs function and for them this is the lung at rest and at rest we're breathing relatively gently we're not having a great deal of force bringing things in and out and there is not an au nuh form oxygen level at all parts of the functional unit of the lung however it exercise and you start you know when your chest starts to heat and what have you there is a uniform so this is exercise and to be able to go from this to this is your pulmonary functional reserve that's what allows you to exercise and they looked at this from the point of view of conductance to reach the surface with the conductance to cross it and if the reach versus cross if reaching is greater than crossing the service you works uniformly if it's the reverse then there's diffusion screening and they calculated something of of diffusion versus conduction and called it lambda and they found that if they took a histology section through the lung and just traced the outlines that the length of this line was proportional to this lambda now we can do this very easily with the slides that we have and tracing the perimeters of the villi and histology and what we are thinking is that what's that in in in the placenta the normal circumstance is exercise the mother puts twenty percent of every heartbeat into the space around the placental villi the baby puts half of every heartbeat down into the placenta this is an exercise situation but in diseases maybe you have overgrowth so that you can hardly see where there would be space for the mother's blood to flow around this structure because there's so much of it this is a diabetic placenta so is there baffling and a limitation is it harder maybe for some of these blood vessels to see nutrients because there's too much placenta and and there is screening and a less efficient placenta for unit size by contrast this is a placenta from a lady who became severely hypertensive and the only cure for her was to take the baby and the placenta out and Hippocrates recognized this disorder called it preeclampsia because if you didn't get the baby out then she often seized and died and and the placenta out and the treatment for this condition in the time of Hippocrates was delivery of the baby in the placenta and guess what the treatment is now delivery of the baby in the placenta okay but this is what the placenta can look like here and here again you have weight I mean we're all the villi aware of all the flowers gone where have all the Ville like so why are there not more villi here then these are really big spaces there are gaps here and the villi that are here are really really teeny weeny okay so again a disease in which you have abnormal function and diffusion screening even within a placental functional unit these are what the villi look like and you could trace their perimeters you know like this but then within the villi the blood vessels tend to be relatively large and occupy the majority of the cross-sectional area in disease states like preeclampsia you have tiny blood vessels and not very many of them and instead of them being located right out here so that there's good diffusion they're bare it's almost like they've been beaten up and now they're protecting their blood vessels by keeping them deeper down because if they're at the surface they would have been damaged and popped and here is again a diabetic placenta that has way too many blood vessels and some of them are out at the perimeter but why should the baby want to have to pump blood through all of these blood vessels that are so far away from the maternal blood stream that there's unlikely going to be any type of nutrient and gaseous exchange under normal circumstances okay so these are the types of things that we're looking at we like their metric because this this is extremely simple metric that we think we might be able to reliably capture and that might give us some sense as to structure and function and then the group that once we have these metrics what am I going to do am I going to try to get a birth cohort and then wait for 21 years until they grow up and what have you I I will be 72 I don't know I think I want to retire by then but in any case they have a group in England that collected 12,000 placentas and for 17 years they've been sitting in formaldehyde in bristol UK and their executive committee gave permission for us to apply the metrics and apply our techniques to their studies to their placentas where they have followed these kids they followed their growth they followed their blood sugar they followed their white blood cell counts they followed their body mass index they followed their cognitive and motor development and this is where we're going to be applying these metrics to so that hopefully within my professional career will get a little bit more understanding of this now I know so our vital organs depend on branching the placenta is the only one of those vital organs that we can actually take apart and our working hypothesis is that deviations from normal patterns of branching will explain health risks associated with complicated pregnancies and what we really need is is a way to but we need a metric system this is a completely open area this has not been approached at all in any way shape or form and again our goal is to not only understand how placentas grow and develop but to potentially be able to use that to at the time of birth triage children for risks that might allow them to have access to earlier interventions and optimize their their lifelong outcomes okay thank you okay i want to give the chance to the remote site participants to ask any questions if any i guess today normally we should be able to see them over there today David okay wait I cleared out the room no I see because he went over that's all all right um anybody all right okay if there are no questions they're motorcyclists get back questions here yes I would like to ask you if in the future dude imagine a rating system just like they do on newborn babies of course or even to the baby would they give us a kind of a capture school for the placenta as well yes and that's one of the reasons why we've tried to keep the data collection methods very very simple a digital photograph is something if you can take a picture of your kids at the beach you can photograph a placenta you know we use the same camera and I not exactly the same camera but honest and the slides that we are using to develop the branching and segmentation they're not fancy slides they are routine stain slides that any Hospital in the country and most hospitals in the developing world can make for a few dollars so what we're trying to do is make sure that you don't have to do a five-hundred-dollar immuno special staying with all of the stances that is we'd like this to be useful and that would be the use that we would hope that could be fashioned from it yes did you ever oh yeah what the thinking this may be of a livid detail but in your one of your slides you're comparing the center of three different kind of areas and you're saying when they are most misaligned and almost affect the size of the baby is there a reasonable explanation for that okay um I I think okay this is my hypothesis and I would like to be able to prove it is that first of all a deviation from this let's and then you have the area and then you have the vascular area which is going to be smaller and because we just mark down where the blood vessels go away you know where it with it it's it's jagged so this would be optimal right so if the umbilical cord is here and the weighted centroid is here what this implies is that the placenta initially was round but its growth progressively became deviated and the placenta that results is not organized as efficiently as it would be if if it were like this it's not an isentropic okay and again if the umbilical cord is here or is is here for example and the vasculature grew and develop you know what's interesting is that this difference is important this difference is important and when you put them together these differences each have their own predictive value so there's something about the achieved area being off from the umbilical cord and this type of forcing the development early on the major branches there's 40 to 60 placental functional units those are thought to be established by around 14 weeks gestation so if you've got 40 to 60 and early on their radio here half of them may not have grown well at all or may have died back and what you may have is hypertrophy you know an abnormal growth of so instead of them all being the size of a quarter you have some that are SOT teeny-weeny and then you have some that are really big out here you know and that that is an inefficiency as well okay this I understand less well why these two should be completely independent because you might think that that this is going to be closely related to you know the vascular area is going to be closely related to this area but it's it's independent and I don't know what it is about the stimulation of chorionic vascular growth so that this distance has independent predictive value I don't know whether it's actually this area I don't know whether it's vascular number i don't know if it's branching density i don't know i don't have enough other ways of assessing the vasculature to know whether it's area or something else so this one's a lot cloudier for me that looks like the pleasures of symmetry any other questions i also want to acknowledge the cultural impact of a research like that when you announced that the effect of nutrition is half an ounce but the knowledge about the test structure before has so much more impact the services woman from a big burden of being muscled from everything that goes wrong there which is really a heavy burden yeah I mean I mean I do post-mortem examinations I talk to a lot of parents and I was just talking to a woman last week who feels that it's all her fault that her uterine environment was not a good home for the placenta and her child died of chronic congestive heart failure because the placenta was so badly grown obviously they want to know what happened will it happen again how can I be protected but I think that that the ultrasound and modern medical technology has created the illusion that we actually see and understand the approach of obstetricians towards my favorite organ is that if the baby is okay the placentas got to be pretty damn good you know and playing the numbers playing the odds they tend to be right however the pathologist sees all the times when yeah the baby is reasonably normal so the baby has been compensating the placenta is not normal the baby has no brain you know above the above the brain stem or has a massive stroke or is dead or is you know badly damaged so they play the numbers and most of the time they figure if the baby is okay the placenta has to be doing fine and of every tissue that comes out of you in a surgical procedure even a hernia sac has to go to the laboratory to make sure that the doctor did the procedure right the placenta is the only tissue that comes out of somebody during a delivery or during an operation that can legitimately be thrown straight into the garbage so yes because you really can't make these observations on humans in a controlled fashion I mean how is it that you are able to classify these various factors that contribute to low birth weight in a you know objective nature by taking population studies and measuring those as quick as carefully as possible and you know to be totally honest there is a group of people who don't believe in what's called fetal programming and they feel that it is impossible with statistical methods and regression and confounding and all of these other Corrections that we can make that all of what we see is just another way of saying that to be disadvantaged socially disadvantaged is a bad thing so they don't believe any of this they believe that it's all social disadvantage everything is outside of the womb and all of this apparent association with birth weight is just that social disadvantage children tend to be smaller you know so there's still some arguments as to whether or not there's any biology to this at all and your measurement your question is an extremely good one because what you know and and North Carolina has problems with their cohorts because you can imagine that there's some bias in who agrees to give a hair sample and who agrees to have blood taken and what have you and when I was in Chattanooga we were trying to get fingernails and what have you and you know to look for heavy metals and we we couldn't get anybody to do this because everybody watched CSI and they were afraid we were going to run drug studies and sent him off to them you know I mean nobody wanted to give a specimen you know because they they they didn't want it you know so it's a years as an extremely good point so what you do is you try to do a population not just one hospital or your own experience you try to do things more broadly and then you have multiple people in different parts of the world all trying to do the same thing and you look at what might sort out of the background noise and what I've given you is what tends to sort out of the background noise the human body is usually very resilient to abuse um what's good for yourself what what percentage of light typically you would say you know bad mothers end up having you know healthy placenta is an average or you know normal birth weight baby um that would you know sort of say skew your data or you know can try to skeered well one of the problems is it's hard to know it's hard to know what birth weight you should have been okay and people have asked me why I use cut offs of less than 2,500 grams and greater than 4,000 grams well those tend to be where the population distribution is about ten percent here actually now it's closer to 15 and about ten percent here okay so and within that every other birth weight is normal so when you're asking me how many women who don't take care of themselves or who have other problems in pregnancy have babies whose birth weight is within the normal range that's not the same question as how many women have babies whose birth weight is what you would have predicted them to be given the mothers but you see where me okay so those are two different questions and predicting ideal birth weight is problematic there are a couple of algorithms that people have used that include the variables that i told you about mainly maternal age pre-pregnancy weight parental a paternal height and weight also kicks in half of the dad jeans are in the baby and dad jeans are preferentially expressed in the placenta okay parody and not only how much weight you gain from the time of your positive pregnancy test to delivery but when in pregnancy you gain it okay so all of those can be used to generate ideal weight if you asked if I knew ideal weight I would be estimating that probably between I'd say seventy-five percent of women who have problems in pregnancy don't have babies with ideal weight but i would say that are not ideal but i would say that eighty-five percent to ninety percent of the birth weights are within the normal range and thus don't give us any clues that that is a child that might be at some future risk okay and that's what we're hoping that we can improve outcomes the best way for example if you are low risk your chances of having a baby died after the seventh month before birth is one in a hundred and if you're high risk it's one in a thousand why because if we know to worry about you we worry about you and we can do something and you have a lower chance of having the baby died but if you're just walking around what have you you're ten times more likely to have your baby died so you know i failed ivf my kids are adopted from korea they're twins okay really wonderful kids um but you know I was sitting here going I'm gonna be high risk I'm also having my c-section of 35 weeks but you know in any case doctors were very relieved when I didn't get pregnant because they figured I was going to drive them absolutely apeshit and they were right or they would have been right but in any case um that's that would be my best answer to that okay once you're at risk you can optimize your outcome because there's a lot of things that we can do and right now risk assessment is poor you

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