Harvey J. Kliman, MD, PhD, Department of Obstetrics and Gynecology at the Yale University School of Medicine, talks about using the placenta to help predict autism.
How did you get into working with placentas?
Dr. Kliman: Well, you would never plan on something like this. The only way to do something like this is by accident; that is what happened with me. I have been working on the placenta since the early 1980s when I was a resident and a research fellow at the University of Pennsylvania. I started working on the placenta and amazingly as soon as I started working on the placenta, all of the people in pathology said, ‘well you are interested in the placenta, you can look at all of these placentas then’ and they literally started giving me all of the placentas in the whole department. While I was in that lab, I figured out some basic cell biology of how the placenta is actually put together; how the cells grow; what makes a normal shaped placenta and an abnormal placenta. So, that is the basic science.
How did you come to Yale?
Dr. Kliman: I was recruited to Yale by the Chairman of Obstetrics and Gynecology. I have been here for about 22 years now. When I first came, my responsibility was to look at pregnancy loss cases and pregnancy complications and what I had noticed is that many of the cases that were pregnancy losses or complications had an abnormal feature; an abnormal folding of the way the placenta grew. Typically, what the textbook said is that when you see that, it is a specific genetic diagnosis of one egg and two sperm going into the egg and that is called triploidy. The reason you have to make that diagnosis is that a small percent of those women go onto have something called choriocarcinoma, which is a cancer of their pregnancy. So, you have to make sure that you do not have that.
What did you discover when you started looking specifically at these types of cases?
Dr. Kliman: When I started looking at those cases, I found that about half of them were these abnormal pregnancies with the one egg and two sperm. However, the other half were not triploid and I went to the genetics lab and I said, ‘what gives with these cases? They have the abnormal folding pattern, but they are not these triploid pregnancies’ and they said, ‘well Harvey, in that case, it was Trisomy 21 or it was Trisomy 13 or it was Trisomy 18. These are different genetic complications that can lead to a pregnancy loss.’ So, I thought in my head, the textbooks say that these abnormal folds are specific to one condition. I think it is a much more general marker for abnormal genetic pregnancies and that went on for many years. I did not really think too much of it. I used it in my clinical practice, so when patients came to me I would look at the placentas and I would say that is what I think it is. Then, one day, I was given two cases to look at; two placentas from children who had Asperger’s syndrome, which is a form of autism. This was about 10 to 12 years ago and unfortunately about 10 to 12 years ago, Wakefield in England published in the Lancet that the MMR vaccine caused autism. The problem with that is it has been proven to be completely wrong.
Could you tell us about the amazing study you are doing with placentas that is helping to predict autism?
Dr. Kliman: I do lots of medical legal consultations and I was asked by some lawyers to look at specific cases and I looked at them and I saw, the same abnormal folding pattern that I had been seeing for many years in genetic cases and I said, ‘wow, I do not know much about autism,’ in fact, let me rephrase it, I know nothing about autism. I know that the press now thinks it is due to this vaccine problem, but I am looking at the placentas and I think it is actually a genetic problem. There is something wrong with the genetics of the pregnancy. So I thought that was unusual, but what am I going to do about it. How will I prove that? I happened to be at a dinner party and sitting next to me was a man, a doctor with a PhD here at Yale, George Anderson who works at the Yale Child Study Center and he told me what he did and I told him what I did and I said, ‘could you get me some placentas from children with autism?’ And he said, ‘well I don’t know, but we do have a lot of children who have autism that we have seen; maybe we can go back and see which of those cases we can find the placenta.’ So, it took about four years to do the study, but we actually found 13 cases of children with proven autism; we had their placentas and we compared them to controls and we found that the children with autism had a much higher frequency of these abnormal folds. So that was encouraging.
You were right, correct?
Dr. Kliman: It sort of suggested that my initial observation was true. However, 13 cases is not enough to really go out to the public and say, hey I have a test for autism now. So, things were very quiet for a number of years. That was published in 2006. Finally on November 1, 2010 on the front page of the New York Times in the upper left hand corner was an article about the group from the University of California in Davis and they were doing a study of families who already had one child with autism and they thought that the cause of autism was environmental exposure; some toxin in the environment. That has some logic because there are more toxins in the environment, the incidence of autism by some people seems to be going up, and so maybe there is a connection. So their idea was to collect everything they could about the pregnancy, the environment and the placentas from these children who were born in families who already had one child with autism. We call those families the at risk families. In other words, they are at risk for having another child with autism. So, I called them up and I ended up talking with Cheryl Walker. She is an MD and obstetrician and she was responsible for collecting all of the placentas for the study.
How long did it take her to get back with you?
Dr. Kliman: It took her a couple of months. She sent me pieces of placenta and they came to my lab here at Yale and with the help of my technician and some students, we cut up the pieces into four different pieces. We ended up with 868 slides of pieces of placenta.
After you cut them; what did you do next?
Dr. Kliman: We mixed them all up so they were random and it took about 2 to 3 months to look through all those slides. And, when I was done, I said, ‘Cheryl, here are the results, call me in a couple of years when you know what happens to these kids.’ And she said, ‘well Harvey, I have a little something to tell you which I did not tell you before. I sort of tricked you. I was not sure that what you were talking about was real, and I did not want to do something without having the right controls, so I actually only gave you only 117 cases from the at-risk families and 100 placentas from normal controls’.
Why did she do that?
Dr. Kliman: She did it because she did not really think that I could figure out the difference between the two groups. For me, I was really excited because this now gave me the opportunity to compare the at risk placentas to the controls and see if they are different. And what we found when we actually looked at the data, there is a tremendous difference between those groups. The at-risk placentas have many of these abnormal folds and the controls have almost none. And it is very easy to tell the difference.
I bet they were shocked?
Dr. Kliman: They were shocked at UC Davis; I was shocked. This has now turned a very powerful test that we can use this test, at birth, for families that do not know if they are at-risk. Now we have something where the at-risk has a lot of these inclusions and abnormal folds and the controls don’t, so just by looking at the placenta, at birth, we can tell which group a family is in. If they are in the positive group, my goal is to be able to do things for these children, not myself personally, because I do not do this, but to have them go to specialists who will be able to observe the children, teach the parents to watch for certain milestones, and then actually intervene with newborn behavioral intervention, very early intervention, that can improve the outcomes of these children.
How significant is this in helping with the early detection of autism?
Dr. Kliman: Before this test, the PlacentASD test, as we call it, there is no method at birth to know this at all. There is zero method, so parents would normally, if they do not have a child with autism already, not notice this until the child is two or three years of age. The CDC, the Centers for Disease Control, who looks at the frequency of autism and the prevalence; how many families have it, they recently came out in March of this year with an estimate of 2%; 1 out of 50 children now born in this country are diagnosed with autism. They have actually shown that sometimes families do not know until their child goes to school in kindergarten.
Why don’t parents know?
Dr. Kliman: Parents do not know all of the different milestones that their child should be reaching, but a teacher who sees lots of children says, Johnnie is not quite the same as the rest of the kids and I would like you to take your child to a specialist to maybe look to see if something is going on. In the past, they would have to wait a long time if they had no hint that there was any autism risk in the family. Having this test be positive at birth gives us a really special opportunity to do something.
Why is that?