 Good morning. Thank you very much for coming. It's an honor to be able to give this memorial lecture, and I hope I do good service to Jay, who's in name in which this has been supported. So some of you have probably come to this series on genomics, and this is going to be probably entirely different because we're now going to take genomics into the realm of people making reproductive decisions going forward. And I want to start by trying to put this into some kind of context in our society because that's important to many of the dimensions of the choices that are available both to practitioners and to their patients these days. I'm going to give you tremendous evidence, like you need any more, that we live in a market-based economy, and we have a lack of an organized or structured healthcare system in terms of implementing new technologies. We're a society that's rather enamored with the use of technologies and tend to put our energy and monies to support them above and beyond perhaps cognitive interventions. And we as a society embrace a notion of individual freedoms and personal choices to use things that we can afford and want to avail ourselves of. And these are not necessarily bad things, but I think you can't talk about the technologies that have come on board without thinking about the context in which this has happened. And from my perspective, how in some ways we stand out is different from other developed countries in how we approach these things. So I'm going to talk about maternal child health from three vantage points, and because I trained as a genetic counselor and I train genetic counselors on a daily basis, I'm going to talk about the ways that we interface with clients, which is before they're pregnant. Wouldn't that be nice if that were the most frequent, but that's the rarest. Sometimes people think about concerns and risks that they may have and come to seek us out before they're pregnant. And then I'm going to talk about choices that are available during pregnancy, and then I'll end with talking about newborn screening. So in preconceptual counseling, this is much more cognitive and less technical than the choices that are available during pregnancy. And when we see a couple, I'm going to actually do that two hours after I finish this lecture, who come to see us, because they're concerned about risks to future children, the first thing we do is take a family history. And for any of you in this room who are OBGYNs, this would be very parallel to your approach. And I just put an example of something that we might find or might be an indication why somebody comes to see us, because there's a strong family history of the loss of men shortly after birth. And as genetic counselors, we're looking for patterns of inheritance. So if that's happened in what we call a vertical way over a number of different generations, we get a hint that there may be an autosomal dominant condition that's resulting in male lethality. And it gives us a clue about the things that we might want to think about testing this woman for before she were to undergo pregnancy. Similarly, we're paying a lot of attention to the woman herself and her own personal medical history. Not probably in exactly the same way an OBGYN might, but we're thinking about whether or not there's any chance that this woman or her husband have a genetic condition that they could directly pass on to a developing child. And in all honesty, this is often the reason that somebody has sought out genetic counseling services. So in this case, I use the example of a woman coming in to see us who's affected with an obvious dwarfing syndrome. Now, there are a number of dwarfing syndromes, and most of them are autosomal dominant, but not all of them. They can be recessive. And so we need to make sure we understand what the correct diagnosis is before we're counseling her about the chances that she could have an affected child. An OBGYN is thinking about the same thing, but maybe even more thinking about the woman's ability to carry a pregnancy to term, because many women who are Doris, although they can have children, have a compromised space and ability to carry the pregnancy. And then the other tool we have in our back pocket, and it's in taking a family to determine if there's any recommended practice standards for screening that might help us identify whether or not this couple is a carrier for autosomal recessive conditions that are more common in their ethnic background. And I'm going to give you an example of this. So this is just a current working definition of genetic counseling, and I highlighted the parts that are most relevant to the conversation that we're having today, which is to interpret family and medical histories, to figure out what occurrence or recurrence risks there are in the family, and then importantly to promote informed choices. And I'm going to talk about what we mean by that. So I'm starting with a case. As a case example, to talk a little bit about what a preconception session might look like. This was a couple, a 35 and 37 year old couple prior to pregnancy. So for those of you who don't broker in pedigrees like I do, men are squares, but you all knew that right. And women are circles. And this shows you just, I abbreviated the family history. We typically take a three generation family history just to show you what's particularly relevant to the case at hand. And this couple didn't come because they had particular concerns about the family history. In fact, they came because they're both of Ashkenazi Jewish extraction, and their physician had recommended that they talk to a genetic counselor about potential screening and because they were of quote advanced maternal age. This a phrase that many women have come to disdain. So she is 37 years old, not yet pregnant. So she has, as you see at the bottom, she has an age related risk of aneuploidy based on, we all have an age related risk of aneuploidy, but hers is slightly increased as a result of her age. And there is recommended carrier screening that I'll show you in a minute. And in taking the family history, we find out that her brother has a very, very rare form of sarcoma. And genetic counselors pay attention to things that are rare. And when they occur early on in the area of cancer at 42, that's unusual and causes us to think more about genetics. And her mother had breast cancer at age 60, which is post-menopausal and probably not anything we would pay a lot of attention to accept its potential relationship to this. And so a good genetic counselor would also recognize that there is a risk of a rare cancer syndrome called leafromini, which this is consistent with. But leafromini is one of the rarest things we deal with and extremely unlikely that that's going on. But it still needs to be talked about because if her mother carries a p53 mutation there is a 50% chance that she inherited it. So this gives you an illustration of the kind of detective work the genetic counselors are doing before somebody is pregnant. And this is a list of screening tests. This has been expanded a little bit. If you're Ashkenazi Jewish, many of the testing labs have something they call a Jewish testing panel. And these are four common diseases that are on that panel. But now many of the labs are offering seven and eight different conditions to people who have Ashkenazi Jewish background. And what they're looking for is carrier status. So they're looking to determine if the woman carries an abnormal variant and a gene for these disorders. If she does then they would offer testing to her spouse because a child cannot be affected unless both parents are carriers. And I will come back to this case as we go on. So in doing genetic counseling you've already seen an illustration that one of our main goals is to take a family history. I just wanted to put in a plug for an effort that our institute played with the Surgeon General in promoting collection of your own family health history. If you're curious it's kind of a fun program to go online and play with where you can enter your own family history information. You can share it with relatives. You can update it over time. You can print it off and take it in to your doctor next time you see them. And all of us believe that it's important to understand what your potential risk factors are in your family. That said there is a recent consensus development conference looking at evidence for the efficacy of family history in preventing disease or promoting health. And there are not very many studies of the efficacy of family history but they're equivocal at this point and we need a lot more research to demonstrate how to what degree taking a family history is an important added tool when we're predicting risk factors. We still think it's a good idea. And now I'm going to move to pregnancy. So that's an illustration of what happens before somebody's pregnant. But now the woman shows up in your office and she's already pregnant. So you've lost that window of time to do some prior screening and to predict risks beforehand and now there's a developing fetus in front of you and you need to think about things a little bit differently. And so there are many tools for screening and testing that exist today. And I've divided my talk into two sections. One the sort of usual suspects. The things that have been offered to women in the last five to ten years fairly routinely even though that has been changing. And then I'm going to talk about some of the newer technologies that have come on board very recently. And I was actually chuckling to myself last night because if I had given this talk when I agreed to give it when the series was set up many, many, many months ago, my talk would not have a lot of the slides in it that it has today. Things have been changing extremely fast with the integration of new technologies. And I'm going to give you some examples of what they are and talk a little bit about how that integration has been happening. And you may wonder how a veteran NIH researcher has any idea what's happening in the clinic. And the reason is because I train genetic counseling students. We have 37 training sites in Washington D.C. and around Bethesda and up in Baltimore. And our students tape record all their cases. And I have the privilege, and it is a privilege, of listening to those cases on a weekly basis. So I listen to six or eight hours of actual cases every week. So most of my information comes from what they're dealing with in the clinic in our greater metropolitan area. So the screening tests are to identify those who are at highest risk. And we do that given a lot of different approaches. And then ultimately once we've identified those who are at highest risk, then we want to offer further testing if people are interested in it so that we can find out who actually has an affected fetus. Now all of this sounds very cold and stale. These are very personal decisions. Not everybody wants to know this information. It is not equitably offered because of our healthcare system. These tests and screening options are not available to everybody. So I want to remind us of that. And I think that it's important to all of us to ensure that people make informed decisions. So even if they're not interested in screening and they don't want to avail themselves of any invasive testing, they should know that they're available. They should know what they test for. And they should know what they could do if an abnormality is found. So we hope to promote informed choices. We don't hope to promote use. But that's something I want to talk more about. So what I'm calling contemporary tests are the ones that have been around for a little while. And one of the things we do in working with pregnant women is to help them differentiate screening tests from diagnostic tests. And this is not as easy as you would hope that it is. In much of my social life and interactions with people, when I unfortunately tell them I'm a genetic counselor in a social setting, the first thing people say to me is, you know, my sister had that test and her doctor told her that her baby had Down syndrome and the baby was perfectly fine. I've heard that story. I cannot tell you how many hundreds of times. So what's going on? How could that be true? It's because many, many women are screened these days to determine if they're at increased risk. And they understand that to be a diagnostic test, not a screening test. And so they may have not gone back to their doctor for further counseling because they didn't want to do anything about it. They somehow misunderstood that a diagnosis had been made. So we try and spend a lot of time helping people understand that we're identifying people at higher probabilities. But the general population doesn't necessarily broker in probabilities. If you do a test, you're doing it to get information to act on. It's somewhat counterintuitive. And people are not as numerate as we would like them to be. So telling people that they have a 1 in 300 chance of having a baby with a trisomy can be a very hard thing for people to actually be able to abstractly understand. There's a lot of interesting literature in math that shows that most of us can't conceptualize numbers lower than 1%. We have no frame of reference. We can still do discussions and talk about pieces of 1%, but we can't actually imagine an amount that's less than 1%, even if we're a mathematician. So when we take women off the street who aren't necessarily from math and science backgrounds and we tell them, well, your chances are 1 in 300. But if we do this test, we can reduce your chances to 1 in 1,000. People really struggle with understanding what that means. And if we can't understand fractions of 1%, what does that mean? Genetic counselors actually quickly learn in their clinical practice that people can't do much with those numbers. So they focus on the change. They say, well, your risk was 1 in 300. Now it's 1 in 1,000. That's a big difference. And it's gone in the direction to mean that you have less risk. That's also very confusing for people. They see a bigger denominator and they think their risk is increased. So I'm going to argue that we need to help people understand concepts and notions about risk rather than specific numbers, because I think they're very hard for all of us really to use to our advantage. So in a prenatal setting, we're going to use the same tool that I illustrated in a preconceptual counseling session, which is to take a good family history of less risk factors that might be present. And the people who end up in a genetic counseling office, again, often have reason. They often have a family history that's brought them there. People don't talk enough about ultrasound as a screening test. Ultrasound has become so routine for so many important aspects of OBGYN practice that the patients are often unaware that signs can be found that identify them to be at increased risk for having an affected fetus. So there can be soft ultrasound signs that identify somebody who's at higher risk for carrying a baby with a trisomy. And that's often not expected when the woman goes in for an ultrasound. So genetic counselors do a lot of follow-up to abnormal ultrasounds in helping outline what further diagnostic tests are available in order to shed some clarity on whether or not that sign is a soft sign or an actual sign of a fetus who is affected. Now, very routinely these days in this greater area, remember my area of understanding about practices in this greater region, is that many women, especially those who are insured and in Washington, D.C., even those who have access to Medicaid when they become pregnant undergo first trimester screening. So very, very, very many women have this test now. And many women don't understand that they've had the test. When you're pregnant, your physician draws a lot of blood tests and you know that they're related to pregnancy, but you may be very unaware that it is a predictive test about risk to the fetus and that you will be then faced later if it's elevated with choices about diagnostic tests. Even though we all intend those choices to be informed and the physician may have actually spent a great deal of time describing what this screening test can and can do, people tend to forget about it. They tend to put it in the general category of pregnancy tests that they've had. And so when the physician calls back and says, I've gotten a result from your screening test and you're at increased risk for carrying a baby with Down syndrome, there's a lot of surprise. The first surprise is what test? And what does it mean that I'm at increased risk for Down syndrome? Because every pregnant woman gets this test, and most of them are going to get reassuring information, it's very hard to spend your precious office hours explaining enough detail that it isn't a surprise to the 5% who are going to get abnormal results. So first trimester screening these days involves something called Nucleotranslucency, which I'll show you in a few minutes. And if people come to attention after the first trimester, there's plenty of screening that can be done. And the second trimester that's called Try or Quad Screen, and I'll show you what those things are. We differentiate these things that are offered to people who already have an indication that they're at higher risk and are now being applied to the general population of pregnant women versus diagnostic tests. And these are the ones that we offer to people who are at increased risk to further hone the chances that the fetus is affected. And I'm bringing this up explicitly because this is changing before our eyes. And I'll talk a little bit about amniote and chorionic villus sampling and the more esoteric pre-implantation genetic diagnosis. So let's go back to our clinical case. This is the same case, the same couple we saw earlier, but it's a year later. And they come in and she's pregnant. She's 17 weeks pregnant. And you'll remember that her brother had sarcoma. And since the last time you saw them, they underwent carrier screening as you recommended. She found out that she was a carrier for TASAC screening. And he never got screened to find out if he's a carrier. And they're now pregnant. And he's at above population risk because of his Ashkenazi Jewish background. And so one of the first things you want to do is order a screening test for him and find out if this pregnancy is at 25% risk. In addition, she's a year older than she was last time you saw her. So her age-related risk for carrying a fetus with Down syndrome is about 1 in 200. And unfortunately in this case, her brother's oncologist also thought about leaf romini because of the rare nature of the sarcoma that he had ordered P53 testing. And her brother is affected with leaf romini. Her mother is no longer living. And so we can't go what you would want to do is find out if he inherited it from a parent because if it started new in him, then she is not at any increased risk. How does it start new in him if it's a dominant condition? Well, de novo mutations happen frequently. In leaf romini, more often it's inherited in families rather than caused by de novo mutations. But that's a possibility. And that's something we want to get to the bottom of because it means that she's at increased risk for rare cancers and cancers that are very difficult to treat. Leaf romini is a very difficult syndrome that includes brain tumors and leukemia and breast cancer as well as rare sarcomas. And we get the records on her brother and see the specific mutation in P53 that he has and we're able to order testing for her. But imagine her thinking at this point. I'm pregnant. Do I want to know this about my developing baby that this baby will potentially grow up to be at increased risk for developing cancers late in life? Well, leaf romini is tricky because sometimes these cancers actually appear in childhood. And most of them, with the exception of breast cancer, are not very amenable to treatment. Do I want to know that about myself while I'm pregnant? How is that information helpful to my husband and I as we go forward deciding whether or not we want to have more children? So what started out looking like a fairly benign case, all of a sudden has a lot of things that have presented. And in this case he was not a Tay-Sachs carrier. So the baby was not at increased risk for Tay-Sachs. She had a quad screen which included Nucleotranslucency which I'll show you in a minute which actually was within normal limits but right on the edge. So her age-related risk was 1 in 200. After she had her quad screen it was increased to 1 in 50. And it was the Nuclefold actually suggested she might be on the higher end of that risk range. So here's the kind of scope of information we're trying to explain to people. And again you can imagine if you don't broke her in numbers it's hard to make heads or tails out of this. And what does it mean that you're at a 1 in 50 risk for Down syndrome? Is that significant enough that you would want to undergo diagnostic testing? And how do you do that at the same time you're finding out you're at 50% risk, little less than 50% risk that you also inherited this P53 mutation that has implications for your family. I know these things sound like obscure rare cases but when you're a genetic counselor this is what we broke her in every day. It's not so rare. So I said I would talk a little bit about first trimester screening and this is the use of ultrasound to examine Nucle Translucency. It's a fancy word for looking at the neck fold on the back of the fetus's neck. Sorry about the text being off at the bottom. And this has been used in clinical practice for a number of years now to identify and increase risk for trisomies. And it's used in combination with Beta HDG and PAPA-A to estimate risk for trisomy 21, 18 and 13. This is considered a test preferable to second trimester screening both because you're earlier in pregnancy and because of its predictive ability. About 85 out of every 100 affected fetuses will be identified. So that means that women will miss 15% of affected pregnancies. That's why this is a screening test, not a diagnostic test. And this is what women have a hard time understanding. So women will have this test and go on to deliver an affected child. It will happen. 15% of the time. And unfortunately about 5% of the time people with normal pregnancies with fetuses who are unaffected will receive a positive result. It's very harrowing and not something that women who go through this process are very happy about. Because in fact they will be happy they get a positive result if they go on to diagnostic testing. But feel that they've been put through quite a bit of worry and trauma as a result of the way that we design screening tests. So when people have a positive screening test they will be given a pretty exact figure based on the analytes and the nucleotranslucency about what their chances are. But it usually ranges in, remember what I said about 1% numbers, it usually ranges between 1 in 100 and 1 in 300. We just had a very interesting presentation from Evelyn Carson who is a local OBGYN who's board certified in genetics who's been doing this her whole adult life in this area. And she was one of the first in this area to start doing nucleotranslucency. And she made an argument that nucleotranslucency identifies many fetuses in trouble beyond these trisomies. And she uses it as a screening test for cystic hygroma and the unrelated to an aneuploidy and other problems like impending fetal demise regardless of this screening. So people who are expert at using this technique use it for additional means of assessing risk. In the second trimester screen is to look at analytes. If you add to AFP and Estriol and HCG you can make it a quad test. This is an illustration of the triple test and it's showing you how for these different conditions, neural tube defect is spina bifida and further abnormalities up the top of the neck. You can see that there is a different pattern in these analytes according to what's going on with the fetus and it can differentiate the likelihood of these problems by virtue of the results. So we all consider it a quote a good screening test because of this differentiation. But it's a very hard one to implement when you have a false positive and a false negative rate that's going to affect your patients. But this has become relatively routine use in pregnancy. And for those who are identified at increased risk and choose to go further these are cartoons of the most common and existing invasive prenatal tests. The first one is chorionic villus sampling. This is obviously an illustration of cervical and this is amniocentesis. And depending on the position of the placenta overall, chorionic villus sampling sometimes has to be done trans-abdominally in order to have the best access to the chorion. But this is actually literally what it sounds like a small biopsy of the chorion which represents the chromosomes or the genetic makeup of the developing fetus. CVS is done earlier in pregnancy generally between about 10 to 12 weeks and amniocentesis is done later in pregnancy through a longer window and in some cases can be done all the way through two weeks gestation. There are higher risks of miscarriage two weeks after the procedure in CVS than there is with amniocentesis but both of these tests are offered routinely to people who are at increased risk. These are diagnostic tests. There is always error rates as we all know in every test that's done but the error rates would be most likely due to a mix up in specimens in the lab or occasionally there's maternal cell contamination in the sample and you're actually culturing the maternal cells rather than the fetus but overall these are very good diagnostic tests that are rarely wrong and it's important for people making these decisions about these things to weigh the likelihood that they're going to get a sound diagnostic result. Importantly I've already alluded to the fact that both of these procedures put the pregnancy at increased risk for miscarriage and again the risks of amnio are lower but you're much farther along in the pregnancy and so choices about what to do if the fetus is affected are much more dramatic for the couple people are well aware that they're pregnant is a difficult time to make those decisions I want to talk about the fact that this is a very value laden example in many many ways some people will choose to have invasive testing because they want to prepare themselves and know but intend to continue the pregnancy well that's fine that makes it pretty hard to accept that there's a risk of knowing and is the risk worth the quote peace of mind one way or the other to put the pregnancy at higher risk and I think it's important that all of us remember that the way that these services developed in our country was to promote informed choice for people to make decisions for themselves but the way we offer these things suggest that people should use them suggest they're important and suggest if you don't avail yourselves of them that you've somehow not been a good parent and I'll talk a little bit more about what I mean by that pre implantation genetic diagnosis is much more rarely used it's very expensive and this is a procedure that genetic counselors talk to their patients about because it's available for people who know that they're developing fetuses at increased risk for a disorder that we can test for in the early embryonic stages and so this is a test that where we use IVF and the early embryo is literally one of the embryos are removed and there's genetic interrogation there the attempt is to get a number of early embryos to test and we can do both karyotyping which is to look at chromosomes or molecular testing depending on what the developing embryo is at risk for and then implant the embryos that don't have the gene variant that's in the family or the chromosome abnormality it's expensive it means that women have to go through IVF and implantation once the embryos implant these are almost always not infertile women they are monitored as average pregnancies and no longer at high risk but there's a lot of technical work that goes into getting into that position and so we're helping families decide if it's important enough to them to avoid having an affected child and this is a procedure that's chosen by people who have resources as this is not an inexpensive procedure and people who would never consider termination of pregnancy under any circumstances so I think it's important not to talk about these tests as though they don't have something to do with the outcome this is just a smattering of pictures that are available on the internet there's so many hundreds of them I had a hard time choosing of people who are affected with down syndrome genetic counselors work with affected individuals and families as well as in the prenatal arena and this is a real source of tension for all of us as professionals and I hope it's a source of tension for all of us in our society I think it's very difficult to assess anybody's quality of life but it's really hard to understand what the joys and benefits and disappointments and heart aches are in raising a child who has cognitive differences and families who have affected children, adult children or young children are very very concerned about the use and onslaught of prenatal testing and what it says about the worth of their children in our society there clearly is the risk that many affected children with down syndrome there will be many less affected children with down syndrome as a result of these tests and I think we should all be having some really hard conversations with ourselves about whether or not that's the desired outcome I don't mean to suggest that we can control all things that happen and that we will test all pregnancies but even proportionately for those who have access to it the result is that many many decisions will be made not to bring a child into this world and I want to tell you of all the difficult things that genetic counselors do in the reproductive arena the most difficult is to try and help a couple who has never had an affected child with down syndrome or another condition imagine what their life would be like if they brought this pregnancy to term and raise an affected child and when you work with families not every family of course I'm grossly generalizing but many of them talk about how they found strengths they never knew that they had they viewed the world differently their definition of quality of life is not the same as a result of their child they would never want to have had an experience not having this affected person in their lives but it's a retrospective current and retrospective position rather than a prospective position and how do we help people understand their own values and beliefs and resources and possibilities before they have that chance add to that that they have very small windows of time to make a decision whether to continue a pregnancy or not add to that that these decisions are wrought with spiritual and religious values and beliefs about abortion in our country we are very divided on and people hear some things wrong and they stop thinking very clearly and it's very hard to make good informed choices when all you've heard is that something is wrong so I want to remind all of us that I think we have to spend some time thinking about what we're doing and this is what I promise the sort of latest prenatal screening and testing approaches that are now being implemented and I literally mean now in the last few months there is now something that's called universal carrier screening which is not specific to any ethnic group and I'll show you some examples of that there is now evidence that prenatal microarray analysis may be a very effective way for looking not only at the kind of aneuploidies we now look for in doing chromosome analysis but also identifying small duplications and deletions there is now the advent of what's being called non-invasive prenatal testing which can identify a higher low risk of trisomy 21 without putting the pregnancy at increased risk and people are now talking about the possibility of using whole genome sequencing of the fetus to get all the information regardless of our ability to interpret it so that that's on record for that particular child in perpetuity and I'll talk a little bit about that that's more of an idea than it is a reality these three things are all now being used in this area so universal screening as I said is not specific to any ethnicity nor your family history so it's being marketed to all pregnant women the companies that are marketing this are saying that it's a preconceptual screening but the vast majority of all people who are undergoing universal screening are pregnant so it's happening differently than they had originally intended the results are returned in two to three weeks it does still require a physician or a genetic counselor to order the test so you can't buy it over the internet and don't laugh because there's a lot of direct to consumer genetic testing that's available on the internet but it's not yet one of them and the cost is $350 and I put this up there because this ends up being a really important point do you remember the ethnic screening panel I showed you if you're Ashkenazi Jewish that costs more money so if there are seven or eight genes you can find out if you're a carrier about this costs $350 and this is what you get to find out about there are 109 different conditions on this panel that you can find out whether or not you're a carrier for so it is much more cost effective to do this there is only a small proportion of things on here that are recommended for screening by ACOG I think it's either 10 or 12 of the 109 some of them are extremely esoteric and extraordinarily rare the range of likelihood that these things exist is from to unknown or I can't remember the highest number I found something like over 1 in 500,000 so there's no terribly systematic reason why these things ended up on this panel I suspect it's more technology driven than it was clinically driven and so how we interpret this information and help people use it is a problem that's been left to the providers but they'll market it to you and it's inexpensive and the insurance companies will pay for it so far in this region similarly there is now evidence that microarray analysis which can be done looking at copy number variance so looking at when there is excessive amounts of DNA that could be present as a result of the fact that there is an extra chromosome present so this can identify areas large or small of missing or extra chromosome material there has been a large so I'm repeating myself so 2% of the copy number variance that can be found are of unknown significance but that's what the large studies are focusing on but our ability to interpret the data that comes from identification of a micro deletion or duplication is more complicated and I'll talk about that in a minute I guess I'm talking about it now there is often limited cases in the literature so you can find this rare micro deletion in a developing fetus and you may find one case report of something similar in the literature but a case report is not cause and effect it's an association and you have to use your best guess from what you know about medical genetics whether or not this developing fetus is likely to have the same thing that you see in this case report so I'm giving you a worst case scenario sometimes we find something that there's a wealth of information about and we can make accurate predictions but this is venturing into a new area where there's a lot of ambiguity and it's very difficult to help guide pregnant women through these decisions whether or not to continue the pregnancy so there's been a validation study that's in press now and that Dr. Wapner from the University of Pennsylvania has been talking at a lot of national meetings about it was an international collaboration done on over 4,000 samples so it was patients who were at increased risk for carrying an affected child with a trisomy who were in for amniocentesis or CVS and prior to these procedures they drew a blood sample to do microarray analysis and they did statistics to determine that they could detect additional abnormalities in about one in every 70 samples out of 4,000 that had a normal karyotype so they were able to go beyond routine chromosome testing and they also when a birth defect was imaged by ultrasound microarray was used to find additional important information in 6% of cases so the argument that's being made is that this takes us further in understanding the status of the fetus from what's routinely done now with amniocentesis and CVS so there's growing enthusiasm by this team and others and this was a large NICHD funded validation study they put in for a further validation studies to look for copy number variants in less high risk pregnancies to determine how successful this will be in helping us understand what's going on with the fetus in the meantime some of their colleagues are interviewing women who've gotten these results and they found it very very traumatizing to deal with the uncertainty about finding one of these micro deletions or duplications and to make good decisions so it's again what you would expect when it's new technology with limited information to help people make decisions. Since the late 90's we've known that it's possible to find fetal DNA in maternal serum and throughout my career there's been discussion of when are we going to be able to do a blood test on a pregnant woman and look at the fetal cells and figure out what's going on with the fetus and obviously to all of us there's a lot of attraction in that because you wouldn't be entering the pregnancy at risk by just taking a blood sample on the pregnant woman unfortunately it's taken this much time to get good validation data of getting sufficient fetal cells and being able to evaluate them to get good enough data to know what's going on oh my, sorry my graphic didn't turn out the way that I had it so I'll just try and explain this as best I can if there's a fetus that has trisomy 21 there's a higher percentage of fragments of 21 in the maternal serum as I said it's about 3-6% of maternal serum can have fetal cells in it and the companies that are offering this test now are looking for excessive fragments that are over 3 standard deviation of what would be seen in normal pregnancies and they're reporting out something that's called a Z-score so it's a statistical likelihood that the fetus actually has trisomy 21 and right now their detection rate is estimated to be around 99% this is a summary of a very recent validation study that appeared in the literature again of almost 2000 pregnancies where they were divided by gestational age and this was a nested case control design where they focused on the abnormal pregnancies and they identified a small false positive rate and a small failure rate and are now using this information to estimate that there's a 99% chance that they're going to identify trisomy 21 pregnancies through a blood sample on the mother this is clinically available it has not been validated in non-high risk pregnancies remember all the women who were undergoing this were already there for routine actually made that point on the last but this was let me stop for a second I need to correct myself this figure was done on routine pregnancy so it was not done on high risk pregnancies but there is some concern about how sufficient this study is in justifying this detection rate and this false positive rate so I recently heard a presentation about two weeks ago by one of the companies and a genetic counselor got up and said my patient just decided to have your test your non-invasive prenatal testing and she got back a result that suggested that she had a high Z score so she was at high risk 99% chance that the baby had trisomy 18 they are not calling this a diagnostic test quite yet because of the limitations of the study they are calling it a screening test and so they recommend people who have a finding like this woman did follow up with amniocentesis which she did and the fetus had normal chromosomes so the genetic counselor asked how did this happen and the woman said well we are still working out our test and blah blah blah but she didn't say there is a false positive rate that we don't understand very well yet so we are not clear cut parameters yet these are first statistics that have come from the first validation study so it's hard to help our patients know how good the test is yet but there is research that's been done to show that women are massively interested in this test because they can get the same information close to the same information that they could get from prenatal testing and so the turnaround time is 10 days it can be done earlier in pregnancy right now it's only offered to women at high risk because the validation studies aren't as thorough as they should be and it's recommended that there be follow up for people who are insured this test in this area only cost $235 and when they compare it to the other tests that I reviewed with you first trimester screening second trimester screening CVS and amnio we can see that the detection rate is in the same vicinity as these two tests but in fact this is what's so significant is there is no procedure related risk to the pregnancy and they've done follow up studies with women that show that that's what they're very interested in avoiding and so they're anticipating that many women are going to want this test and I think it raises a lot of interesting questions about how well we inform people about what they're undergoing at the time when they have the test and as I mentioned earlier people are also talking about the fact that since sequencing is becoming whole genome sequencing is becoming affordable why don't we just skip all of this and go directly to the sequence and begin to look at variants prenatally and help people figure out what's going on fortunately this is a tad bit of science fiction not in the sense that we can't technically do it but interpreting it is very difficult and consuming so I think those practical aspects of it are probably going to keep it off for a while but within a relatively short period of time it's possible that all these tests I've reviewed with you are going to be replaced with prenatal screening and hopefully this is raising some bioethical issues and making you feel a bit uncomfortable and I ask a few questions related to this is there some way we're devaluing the lives of those who are affected with genetic conditions by offering this testing so widely is there an unstated intention actually to promote the termination of affected fetuses is this we say we do it for personal choice is that true is that really true is that really what our society is doing and where do these testing options leave people who choose not to use them there's a lot of parents of young children with Down syndrome who say that people want to use them and say didn't you have that test regardless of whether they did or not that's a terrible affront in terms of their relationship with their affected child and how do women with fewer resources handle things these technologies leave us in a situation where the discrepancy in our society and who has access to healthcare dollars is likely to widen and so people who are more often likely to be those who don't have resources and maybe not even resources to raise them I promise to end with newborn screening you'll remember that PKU is the first newborn screening and newborn screening is the only mandated genetic test this is the only public health genetics program we have in the United States it is state run so it varies from state to state but almost all states now have expanded to a panel of at least 29 different conditions some of them test for more and even in newborn screening there is now discussion of whether or not because of the cost whether or not we should move from this 29 disorders to just going to whole genome sequencing once the fetus is born and these are just the group of disorders that the 29 conditions come from and the incidents some of them are extremely rare most of the criteria not all but most of the criteria for the disorders ending up on the newborn screen are that we can treat them and improve outcomes for affected children but increasingly the criteria by which we make decisions to put diseases on newborn screen are changing and there's a lot of interesting policy issues that have come about I encourage you to look at the Hastings Center report July August issue my colleague Ben Berkman and his colleagues have written a commentary about prenatal whole genome sequencing asking the question just because we can should we to get people talking about what we're undergoing similarly there is a commentary in JAMA about the use of genomic sequencing in newborn screening by Aaron Goldberg and Richard Sharp that I encourage you to look for there are a lot of policy considerations in newborn screening about whether we sufficiently inform parents should we be testing for rare conditions for which there's no treatment should there be a uniform criteria that's very difficult when it's state by state upheld to decide whether to use new tests and if whole genome sequencing is introduced how should results for instance adult onset conditions be handled so I'm going to stop there I do social science research much of my research lately has been in informed choices about the use of prenatal testing and we can actually look at what predictors there are we can predict what factors lead to people making decisions to take up these tests and as clinicians we can develop decisions to enhance informed consent and increase satisfaction with the decisions that people make so I encourage you to actually think about what we can do to help people make decisions that are in keeping with their values and beliefs and that are sufficiently informed they understand enough about it that they make good decisions for themselves that they don't look back and regret I do still believe very much that what's right for another person is not right for another but none of us ever want somebody to make an irreversible life altering decision and look back in the mere one day and ask why they did it. Thanks very much for your attention A lot of the difference and I don't know how to think about it but for example I treat retort arthritis women of child there in age and some of those women can't have chemotherapy and currently we're told they should be off the drug for a few months before they get pregnant or there are tons of women who take antipopressant drugs that are classic and I don't have any real criteria as to what is the risk of a bad outcome and who do I send them to is any research being done on this? Yes so there are genetic counselors who actually specialize in teritogenicity of agents and so a genetic counselor should be able to help them and that's actually relevant to the case I'm going to see in two hours so this is a woman with a history of psychiatric conditions in her family and on medications and one of the main things we do in addition to interpreting the literature about the risk is to very much encourage in this example the psychiatrist and the OBGYN working together. It is very difficult for an OBGYN to make a decision about a psychiatric patient's need to be in bed because you don't flippantly say go off your antidepressants for three months prior to pregnancy and stay off of them for the first trimester and the risks may not be high enough to justify that for somebody who needs to be on the drug and similarly the psychiatrist doesn't appreciate necessarily what the potential risks are to the pregnancy so neither wants to make that decision in isolation and it happens often and the patient often feels stuck in the middle so the genetic counselor literally is sort of brokering some management there but can also insert understanding about what the risks are and I think you're sort of implying or I'm going to impute this into what you said that you know saying it's a classy drug doesn't tell you very much about what the real risks may be to the pregnancy certainly we worry more about chemo therapeutic agents the question is about regulation of testing that FDA is taking up consideration of regulating genetic testing which is an extraordinarily complicated issue in our market economy so I do agree that I have some issues with the direct to consumer approach so there are genetic tests available that you can order for yourself online I don't think they're all bad I think there's a lot of them I would question how well the data is there to interpret the results the way that they've been interpreted but I have concerns about the ways these things are being marketed and how a lot of decisions are being made on financial it seems so rational to have these carrier tests when they cost so little money and yet our ability to interpret them in a meaningful useful way the efficacy is still unknown and if regulation will help with that I would be in favor but I think it's a very complicated very complicated issue so if they both had palesemia we would offer them testing to the to the baby and to talk about what their lives have been like as people who've been affected with the condition so you're talking about carrier status that their carriers before having the baby right right so your question is what our intentions would be is to describe the condition that the baby could have and talk to them about their resources and their concerns about raising an affected child or the fact that the baby could die sort of anticipating what the outcomes could be and talking about how they feel about taking that on and if it's something they want to avoid what the options are for doing that and if it's something that they don't want to do anything about what the options are for going forward we don't advise people not to have children if that's what you're asking the 5% actually was about the screening procedure and that's the possibility that a normal pregnancy is going to be flagged as one that's at increased risk so if yeah good question that's a great question so when there's disagreement between spouses there's two levels so I'll take the easy level first where there's disagreement about use of testing and that actually is not very infrequent and genetic counselors and OBGYNs deal with that pretty often and you help broker the decisions unfortunately many many men will say it's her body and it's her choice and so in the end they'll sort of back off and while that sounds very nice most women really want to know that they're making a decision together so we work with people to get to a decision that's comfortable for both of them but it gets much harder when there's a potential abnormality and you're making a decision about an invasive test that puts the pregnancy at risk and that's when we may involve the OBGYN or the primary care provider or people who that couple value very much in making that decision unfortunately those decisions happen in short appointment times, in short time spans and it's hard to get people to the point where there's agreement if the woman wants the test and decides to discard her spouse's opinion that doesn't make us very comfortable but most physicians would go ahead and do the test because she's their patient good question thank you all very much for your time you came this is not a good use of your time absolutely I come for every one of them but I learned a lot