Hello. You know what I was doing? A United States Army Medical Department Continuing Education Program, the 22nd Annual Armed Forces Seminar on Obstetrics and Gynecology. Prenatal detection of Genetic Disorders with Henry Nadler, M D professor and chairman of Pediatrics, Northwestern University. The slide is a little bit out of date that cannot be made fast enough. Thio Keep up with him. The number is well over 2000. Now , pregnancies have been monitored to detect fetal abnormality. The single most common group is an unquestionably will remain , certainly for the foreseeable future. Unless some overwhelming new development in screening for biochemical disorders occurs. And I personally do not believe that it will, uh , theme. Most common indications are gonna be for chromosomal defect. And clearly the most common indication single one within that particular group is going to be maternal age. If you took the numbers that I told you about and you would Thio say that you wanted to screen women past the age of 35 or 36 those women who wish to be screened for chromosomal defects , one could make a very significant argument that the yield would be quite high if you screen women above 40. You're going to find, in fact, that you yield for a chromosomal abnormality is probably gonna be in the order of about 2%. If you screen above 36 or 37 will probably be about 1% . This means down syndrome and other chromosomal aberrations Out of this group, you see, roughly nine out of 350 were detected. So the numbers that I'm talking about on an ideal fashion really are not significantly different. There is some argument as to what the ages that one would consider a maternal age indication. I don't think that's particularly important. I think that you can choose whichever you prefer. But you should recognize this phenomenon, and I personally believe that it should be presented to parents. Parents can opt as to whether or not they like to have this test performed, but I think it should. They should be made aware that this is so. And as a matter of fact, I think even if you might not like to do it, you may, in a medical legal point of view, in fact , be placed in doing it. There is one lawsuit which is about to be ruled on, and it's unquestionably is gonna be removed. Is unquestionably going thio come out? I think that the physician will be judged guilty of malpractice because ah, year and a half ago in a large center in the United States, such a physician did not make a wear to a 45 year old woman. That, and their synthesis wasn't available. Technique. She gave birth to a baby with Down Syndrome and has brought a lawsuit against the obstetrician from not informing her off the availability of this test. That's an unfortunate way to practice medicine, But it has become enough of yeah , public knowledge, at least about this particular test , that it's likely to be a fuzzy area for a while. The second group, which will continue to be a fairly high indication Ah, women who have previously given birth to Children with Down syndrome, who, even though the recurrence risks are essentially usually less than 1%. Unless there 38 or 39 or 41 it would be three times. Whatever the number I gave you would be, uh, these women , even though the overwhelming odds are that the baby will be perfectly normal are going to continue to request and the S and thesis. That's because of the fact that they have already had a baby with Down syndrome, and, uh, they really will have an amniocentesis for two reasons. Some unquestionably would opt to terminate the pregnancy if they found that the baby were affected with Down syndrome. On the other hand , some who might not even do that would be willing to take a gamble at the risks of the procedure. And I'll get into those in a minute just on buying the last five months of their pregnancy . Peace of mind, knowing that they were in fact really not carrying another baby with down syndrome. So I think one can make a logical argument that although the risks are small, but they certainly are there, that the ability to reassure the family perfectly well in a significant number of instances may well be itself an indication for MGs and pieces X linked disorders . The majority of those will continue to be hemophilia , excellent muscular dystrophy and a whole host of other ones, which will be extremely rare on a whole variety of metabolic disorders, and I will give you an example of many of the metabolic disorders and how they can be done again. The important thing is not to try to remember here each of the disorders that can be detected. But when you do have a patient with an unusual metabolic disorder, etcetera, find out. You can just pick up a telephone and call any number of centers, which would be readily available to you. The information. Is this a disease that is detectable in utero? Yes or no. It's the test of ballot, one ISAT reliable on. Then you can handle particular situation. You can see in this group obviously the highest yield about normal in terms of potential, because most of the metabolic disorders that we talked about today are inherited as either excellent recessive on the overwhelming majority them at the present time order somewhat recessive disorders. Now I haven't gotten to a whole other group, which we'll get to later Now, the potential risks of the procedure of the ones which are well known to you obviously infection abortion in terms of the fetus. Maternal bleeding, the possibility of Rh sensitization, uh, intra uterine puncture of the fetus. Suffice it to say the experience of amnesty thesis early in pregnancy up to the present time. And there will be a study completed by the end of this year in which eight centers in the United States have done a prospective collaborative study with controls. Age matched parody matched income matched etcetera to determine the accurate risks to mother and fetus of amniocentesis early in the second trimester of pregnancy . At the present time, that does not appear to be any significant increase or any increase, really in congenital malformations of the fetus or of the newborn . And the only possible thing, at least at a preliminary plants, is that the incidence of spontaneous abortion may be somewhat higher in our own group. And I can only talk about our own groups experience at the present time over 500 pregnancies that have been monitored since we've been doing a control study. It's interestingly enough in our center, uh, or in the data that we've collected in our center, women in the control group managed so far had a higher incidences of abortion, uh, than the control group , then the group having, um yes and pieces . There is very poor data in the obstetrical literature . At least faras. I'm concerned as to what the accurate risk of spontaneous abortion in the second trimester of pregnancy is. There is reasonable data about the first trimester of a very poor data about the second , including the collaborative study. Now, theoretically, the way one could go about decreasing the risk of maternal fetal bleeding, fetal puncture, etcetera, eyes on this particular technique. And this is a slide of Dr Valenti. And I guess Dr Valenti ran a session here two years ago. Uh, I'll take a little bit of the other tack with this procedure. This is an ultrasonic localization, theoretically of the placenta, so that one could very niftily get the needle around it, miss the fetal head and put it in to the present time. Uh, if one says that this is a reasonable technique to use for this procedure early in pregnancy, I think it is, but not for the reasons that it's been originally proposed. The incidents in those groups who've done it a bloody taps is identical to the groups who don't use it. There's no decrease at all . There's been no difference in the ability to obtain amniotic fluid I think the one rial plus that it has is that it has the ability to localize a twin pregnancy, which those of us who don't use it have blown in each pregnancy in which we've done . In an instant thesis, uh, one potential disadvantage was published in a might as well get controversial and extremely poor. Article in The American Journal of Obstetrics and Gynecology about the risks of them use and thesis early in pregnancy that appeared a couple of weeks ago by the group from Denver. They suggested in this as faras the ability to culture the cells that they had some or greater difficulty when ultrasonic localization of the placenta was performed prior to the analysis. This article, By the way, which is entitled, I Think the Hazards of mes and thesis early in the second trimester or something else, I think we'll give you, if you will look at it. A nada quit example of how difficult it is to interpret any kind of data as to the risk figure almost all of the things that they listed his complications in almost every instance. When they did the end their synthesis, they had a marked abnormality when they got that original fluid brown, black amniotic fluid. Uh, no fetal heart tones, etcetera, which are obviously fetal deaths. Prior to the M. E s and thesis, we routinely recommend that this be done at roughly 15 weeks of fetal gestation. Uh, now, this could be quarrel with me 14 to 16. It really doesn't make much difference . The point is that you'd like an answer in roughly three or four weeks, which you should get in the overwhelming majority of instances. And conceivably, this will give you some time in those states in which termination of pregnancy after 20 weeks is a problem on if any of you are practicing in other countries , this may be a really legal restriction. Here's an example of a fetus with down syndrome that really doesn't show you very much. So just go on . Here's one which again shows you e don't know if this projects very well the horizontal palma crease at 19 weeks, uh, in a fetus with down syndrome, and this will show you the difficulties when one monitors routinely for chromosomal aberrations. This fetus on this is, I think a 20 week gestational fetus , uh, was detected under routine screening for a woman of advanced maternal age. In this particular instance , the amniotic fluid cells were cultivated in a chromosome . Elaboration a 47 x y y carry a type was determined. This, as you remember yesterday, was the one that Dr Hershon referred to as being one conceivably associated with tall stature and male criminality. Well, and with criminal behavior, abnormal social behavior . Now, if one reviews the literature is Doctor Hershon tried to do yesterday, we really don't know what we're talking about with this disease. The ascertainment Aziz, how this disease was discovered in maximum security prisons obviously placed a huge bias on it. Now , when it will be that there is some relationship between this extra Y chromosome and psychosocial abnormal psycho social behavior. This all of this information was presented to the parents who in this particular instance, phrased it very nicely. Uh, I think in an interesting way, at any rate that they did not wish to do a control study on that particular child and up to terminate the pregnancy and did. The important point here is that unlike the women who have already had a baby with down syndrome. Unlike the people who are known carriers of chromosomal defects or of water , some will recessive disorders you have here a patient population who doesn't really know anything at all about Mangal is, um, they come in and the obstetrician or somebody informs them, or they pick up the Ladies Home Journal or Good Housekeeping and they talk about intruder in diagnosis. And do you know that 42 year it increased? They risk of having a baby with Mongol is, um, and the mother says , Well, that's a horrible thing. I'd better have that test. But she, in fact, didn't know anything at all about the disease. And so when you start detecting disease, you suddenly have a population which is not based and not has has really not even thought of the majority of the therapeutic abortion. They don't know anything about the disorder. And so you're placed in the position of having to describe the findings of on a routine screening procedure of a laboratories test with very difficult implications, implications which may be a bit more difficult to handle, and some of the problems that Dr Davidson pointed out about screening for disease and the neonatal period about what nobody is really sure about, so that this will be a real problem for you. And I think that if you do broach this and I think that you should broach this with increasing maternal age with patients that you describe what could be done, what the potential risks are the procedure and you ask them point blank . You know, what do you think you would do if you had an affected child? And the answer is that most times most patients don't really know the answer, so you can't tie them into a yes or no. Answer is. Some people have suggested that you do not do the procedure unless they tell you right then and there that they will have a pregnancy terminated. Now here's an example of one of the biochemical defects that can be detectable in utero . The reason for showing it is because I think it's we've learned a great deal about the potential problems of interview during diagnosis from this disease. This is a baby who died at a little over three months of age with a large heart big liver. If you look at the cross section of the heart. You'll see the glycogen is the positive and tremendous amounts within the heart. This is an example of so called type two glycogen storage disease of Pompeii's disease. It's an absent of a particular acid, multi, uh, enzyme, which is present within the license zones. And so the glycogen accumulates and can be broken down. You can use a histological techniques to make this diagnosis, as we've done a number of years ago, and here you'll see an amniotic fluid cells. Large double membrane bounded, presumably license owns with increased amount of like kitchen. Now in about 1967 or 68. I think we reported the first instances of the intra uterine detection of this disease, and the first pregnancy that we monitored very nicely did all the things that we would like it to dio . The enzyme, which we knew was present in amniotic fluid, was absent. It was absent in uncultured cells. Then, if you grew the cells up in culture, you could then make the diagnosis and confirm it. And so we predicted that one could use probably amniotic fluid alone are uncultured cells, but we suggested that until a tely east were a little bit cautious that one should rely on cultivated sells for the diagnosis. Since that time, I think six or seven instances we have detected Pompey's disease in utero, and in none of them was there ever an absent Alfa glucose ideas in the amniotic fluid again ? Uh, needless to say, when the second one came around where it was present and then we didn't find any activity in the cells, we were really quite concerned about it. And so they started us off on a major research project, which is just a nice way of saying that we probably should have done it before we did. The first study on what we were able to show was that the enzyme which was present in amniotic fluid, was in fact, not even the enzyme that had anything to do with the disease it interacted with the substrate was just another form. And I think if people try to sell you and we'll come back to this a little bit later on using cell free amniotic fluid for the diagnosis of biochemical defects, at least using enzyme assets, we best know first of all, what the normal levels are. That's easy whether that form of the enzyme has anything to do with the disease , whether it is a fetal form of an enzyme which has nothing again whatsoever the disease but would be confusing you. Now here's an example. We showed you a picture before of a child with Hurler syndrome . One of them You go Polish sacra doses. This is perfectly evident. See, big liver, big spleen, protruding abdomen, the claw like hands again, This disorder can be screened in a variety of ways in utero. The easiest way at least , I think, at the present time. Although this will not be three easiest way within a matter of four or five months from now is to just grow the cells, exposed them to a sulfate labeled compound, and the cells from patients with this disease accumulate uh s 35 labeled compounds that are abnormal. And if you want to confirm it, you just take a normal and mix it and you can correct the defect. If you take another heroism, mix it, it stays abnormal. This is the easiest one to screen for the Mucha Polish sack right disorders , in which known abnormalities occur in many of them . in cell culture. It will not be the procedure of choice, though specifically for Hurler syndrome war hunter syndrome in a matter of a matter of months . As for almost all of these diseases, the precise by chemical defect is known, and secondly, that we do have. There is now available artificial substrate or made available in the last month or so , which will convert this into a disease that could be done or handled in very few laboratories in 12 laboratories with a great deal more, um, larger numbers. At any rate, there are other techniques that can be used here. Amniotic fluid cells were a history. Chemical technique is used. And here you see, read the blue materialism beta, go outside a scram mules here the cells where there's no beta Glock decide days. Remember that little baby I showed you with generalized cannula psychosis with the large L Villa hypertrophy. This shows you that this fetuses, in fact affected with the disease it takes a matter of a week to do it after the animals and thesis. Uh, here's a slide of Dr Davidson's demonstrating the absence of the enzyme uh, Hexcel cemented a say, uh conceivably a fetus with haystacks disease . Uh, Dr Davidson was a little bit for hurry, and I'm not quite sure. He mentioned one of the confusing factors about this disease, which isn't so nice. It is nice that you can screen the population for carrier status. Those were two carriers are at risk you can provide, interviewed her and diagnosis. The little thing, which is the hooker, as it always is, is that there are at least two families described now who don't have any heck so cemented, they say, in which the patient's perfectly normal doesn't have the disease. So if somebody would routinely screen, you could get yourself into a bit of difficulty with this. Despite that , I would still think it's a perfectly reasonable test to use in pregnancies at risk for this disease. And there are a whole host of other license on the enzyme deficiency diseases where qualitative differences as well as quantitative differences can be used test. Um, uh , now that this next disease is one where I think the questions, uh, that are raised as to whether or not this is a disease capable or important for intrigue and diagnosis, uh, raises. I think some interesting questions. This baby has died five weeks of age, totally preventable disease. If the physician caring for the infant had even thought of it, this baby was probably joined. Us had vomiting, diarrhea, big liver of explain. Probably died of E. Coli. Septicemia had total reducing substance in his urine when the baby, when she was fed a galactus containing formula, which is routine milk. Most of the perfect preparations that have given this baby has died of Galactus e mia and still one out of every five infants in this country in which this diagnosis is one can clearly show that the diagnosis is missed and the infants died. Now, this is an enzyme deficiency disease. The enzyme assay is easy to do. You can tell if a hetero zygotes around and you can detect it in you to rose we first did in 1968. Now this disease, unlike fennel keeping area, does not have all the squabbles relating to therapy that have permeated literature in that disease. And the reason for it is I think most everybody would accept the fact that dietary restriction of galactus for these infants in the newborn period and for the first certainly years of life may be lifesaving. Whether it needs to be carried on later in life is unknown as it is in federal keep Nouriel. But I think there's no quarrel that this is a life threatening therapeutic approach. Therapeutic model in terms of this disease, albeit some patients have escaped to adulthood and then been detected having galactus galactus Siemian . Invariably they had vomiting, diarrhea, and somebody substituted a formula of some kind that did not contain lactose or galactus. Now I think that mhm there are in this slide demonstrates what I consider to be , uh, absolutely critical point in terms of intra uterine diagnosis and maybe more importantly, in terms of what were first beginning to appreciate about inborn errors of metabolism, if you will, and the fetus this is a photograph taken at the time of I may have put the wrong one in there. I'm sorry . The photograph that was supposed to be shown that may may not be it, I'm not sure, but Isa cataract there's no question about that, but cataract at in in the neonatal period of an infant with Galactus e mia. Now what is this telling you there are a number of such infants have been described. This tells you, as have all of the license on the enzyme deficiency diseases, for example , in which the fetus has been studied during the second trimester that the fetus does not escape all of the consequences of an inborn error of metabolism during intra uterine life. Just because the mother may go around metabolizing that particular substance every one of the license on mill enzyme deficiency diseases studied in fetuses at 20 weeks of gestation have Aled demonstrated abnormal accumulation of material. In the case of the Galactic Simic, you have the child with Galactus senior who may have cataracts. This may account for why all of the P K used don't in fact get up to with optimal therapy the identical like you of their siblings and I. It's because the fetus does, in fact suffer the consequences of his or her genetic disease. And this probably in the long run, is going to be one of the most important aspect of what we talk about for intra uterine diagnosis at the present time. And that is the potential for really studying human fetal development. Both abnormal and normal and conceivably developing therapeutic models. Galactus e mia might be one in which , certainly, dietary restriction of Galactus when the fetus were shown to have Galactus senior would clearly be a justifiable procedure much easier to do than that of restricting fennel. Allan E uh, one would have very little problems before one gets the idea that these ideas airy, that new a unique There's a book published in 1902 that I think most obstetricians would read. I had an opportunity to read it a couple of months ago. It's called Antenatal Diagnosis by Ballentine, who is a Scottish obstetrician pathologist who described all of what's known about intra uterine diagnosis at the present time and pointed out that the only thing that had really been accomplished the major accomplishments of medicine in the, uh, 19th century were the the ability to render childbearing in case of for the mother a reasonably safe procedure. And second was the development of the pediatrician . And he pointed out that clearly the major development of the 20th century was gonna be the development of physicians and people who would start taking care of the fetus during intra uterine life on, He pointed out all of the goodies that we're talking about now. 80 years ago. These next few slides will list and probably of more benefit for the audiovisual people than the offer will. Have you been trying to remember them? The disorders which have been detected in in you carol thes air using cell free amniotic fluid alone Katrina genital syndrome cannot be accurately detected in mid trimester pregnancies. One could get a reasonable idea. Latent pregnancies toe One or not, the fetus is affected , and encephalitis and Milo Meninga Seal have been detected on the basis of elevated Alfa fetal protein. And there have been a number of instances, and where this has been used for diagnosis, it's still a little bit not sure as to what it means or how it is. It's even been elevated in the maternal serum, Uh, when the mother was carrying a baby with this at risk for anencephaly and with anencephaly. So I think we routinely would suggest that certainly this might be a reasonable procedure to start to entertain now, in terms of intruder, and management will come back to it again because there are other techniques which may be feasible, the ones at the bottom of Mucha Polly sacharow disorders and I think we need to pay attention to the particular Here are others we heard about I Cell disease, where the amniotic fluid license on hydra laces maybe increased myeloma legacy which will come back to again later on amino acids, five hydroxy Indal, acetic acid and abnormal spectrum photo metric absorption is have been described. I think they're a little bit questionable as to how reliable they are . Neonatal graves, disease, abnormal PBS and Taste Sachs disease. There are other diseases very few, uh, in which the uncultured amniotic fluid cells have been used and the problems here are those of getting some red cells and white cells in with the preparation , the ability in the fear of using up some of these cells. Why one would what needs to at any rate, grow the cells long term and culture. But again have been a number of techniques used the easiest ones that the excellent process of disorders where I think it is reasonable to do sex chromosome y chromosome fluorescence and then confirm it with chromosome analysis on the cultivated cells, there are a whole host of disorders now which have been detected. Uh, and many of these are really, in fact, reliable. I think cystic fibrosis is not a reliable test at the present time for detecting the disease in utero, and hopefully it will be within less than a year, and the one at the bottom certainly is not. But the others are relatively easily done in laboratories with experience. They are almost, or a significant number of this storage diseases and the degenerative neurologic diseases can be detected in this fashion. And I think this is the last one in the Syria's which brings the list. I think, basically up to date, there may be one or two that are not on this list, but they're essentially all of them. Uh, the point is here again that there are a variety of techniques that can be used accurately, foreign treater and detection. And I think those of you who deal with such families can quickly find out whether or not it is a reasonable procedure for your particular family. And clearly the one on the lower line will continue to be the most important one used. Now there are a whole host of Children born with multiple congenital malformations or variety of syndromes in which interviewed were in diagnosis should be reasonably entertained. Now here's the one attempting to show an abnormal spectra photo metrics can, uh, of amniotic fluid for, um, Milo Meninga seal. I really personally don't believe, although it's been abnormal once or twice, that this is a reliable index, and most of you are much more familiar with this area than I am. I. Amino acids have been done and allow the one confined that there are a number of patients in which the amino acids are greatly increased. I think it again. It's too difficult, too cumbersome black specificity and reflects many, many other things besides just the fetal. The fetus with this disorder to be a value, probably the best cope for a technique, I think in the future will resort. Uh, it's nicely illustrated. I least hope that nicely illustrating these last two. These air some slides from not discriminator in Edinburgh, who has been working with a two millimeter and the A scope, which he has been used to look for central nervous system defects in utero. This shows you supposed to show you the finger of the fetus photographed through the ami a scope. Here you can see the genitalia. Uh, clearly so if you're looking for sex determination, this is certainly it might be more dangerous. And in fact, it is . But it's certainly a lot he's to do than having somebody grow up, sells for you for, uh, side of genetic diagnosis. And most of you know, you'd rather trust your own I. Then you would one of those funny looking pictures that get sent back to you. I think that's the last slide could have the slide projector off, please . The I think the development of Anam Knee a scope is to me clearly one which is technically within doing. I know there is a by medical engineer at Northwestern who's developed Anania scope of sorts. Uh , that can fit through a 21 gauge needle e think when one clearly gets down to that size. And there's no reason with all of the other things that we can do with cameras and photo electric equipment , that we can't develop some way of visualizing the fetus, which I think would make interviewed her and diagnosis and much more broadly, acceptable field and one which you would have a much more impact, I think, than we do at the present time. In terms of looking for congenital malformation syndromes, there are a number in which X ray can be used and encephalitis in a classical example of where X ray at roughly 20 or 22 weeks can clearly identify the diagnosis, as can, um, ultrasonic, uh , scan will show you an abnormal skull. I think these techniques they're all becoming available now. How do you put them into proper context and how can you utilize them? Well, first of all, everybody in this room should not be doing on GSN thesis routinely. I think, as most of you know, I think technically it's a very simple procedure , sort of make it it. Ah kin thio . I think I'd much rather have an obstetrician tried to do in MSN thesis than a pediatric intern doing a spinal tap. The difference is, I think we have a great deal of experience and know how as to what to do with that spinal fluid that we have. But most people don't have any idea really or any capability on hand locally as to what to do with the fluid. I think a reasonable way of thinking of it is that there are patients that all of you deal with who are at high risk. I think if you find such a patient and you have facilities available on your Onley, likely tohave the facilities available, uh, boast for I think doing the chromosomal work on this must be a facility which has demonstrated the capability of growing on the other fluid cells. And although we all laugh, how simply are now it's no place for you to be sending fluids. Somebody who is working on his first three to monitor pregnancy uh, you can find the laboratory. And if the procedure is done in , the laboratory is notified beforehand, they can accept the cells. The ship, very readily at ambient temperature on the cells, will be cultivated 95% of the time on one insertion of the needle in one and the S synthesis in 99% of the time. It if one needs to do a second tap in reliable laboratories at the present time so that one can get you an answer, it's accurate. Over 99% of the time in terms of chromosomal abnormalities on, I think this could be a very useful adjunct. The biochemical ones should be done clearly Onley in laboratories that have a great deal of working knowledge about the specific enzyme in question and the specific disease. I think you will find the development in all of the large cities of amniocentesis programs for chromosomal defects. Unfortunately , in the city of Chicago, which I have no reason to presume is any different than any large city anyplace else in the country. Every hospital who would do in MDS and thesis once every year is deciding. It's extremely important for them to go through the expense in setting up one of these procedures, and and they're never gonna be ableto have any sort of reasonable accuracy or reliability, so it should be regionalized. They need to be either for the armed forces, wherever the bases are locally. If they're in a large city, they could be done is part of a con joint program with one of the hospitals in that large city. They could be sent all over the country or the other possibilities of centralized laboratory available to do them within the service personnel, I think, Well, I think I'll sort of stop in a second. But I just would like toa leave the point, which is really the only rationale for, uh, I think these two days of the program genetics is not an isolated little goody , uh, that has no bearing in clinical medicine . A significant number of the patients who you take care of with nonclassical genetic disease like cost a number of the service costs a number of the breast, leukemias or other general medical problems do, in fact , as far as I'm concerned, probably have some degree of genetic basis heritage in them. Prenatal Detection of Genetic disorders With Henry Nadler, M D professor and chairman of Pediatrics, Northwestern University was produced through the mobile facilities of the TV division, Academy of Health Sciences, United States Army, Fort Sam, Houston, Texas