Abnormal Placentas May Signal Autism Risk

Deborah Brauser

April 30, 2013

Abnormalities in placental folds and cell growth may help identify newborns at elevated risk for autism spectrum disorder (ASD), new research suggests.

A cohort study of 217 births showed that placentas from at-risk pregnancies (in which the families already had 1 or more children with ASD) were 8 times more likely to have 2 or more trophoblast inclusions (TIs) than placentas from uncomplicated pregnancies.

In addition, having 2 or more TIs yielded a 92% specificity rate for predicting ASD risk status — and having 4 or more TIs yielded a 99.9% specificity rate.

"The differences between the 2 groups were amazingly, awesomely different, and I'm very excited about the findings," senior author Harvey J. Kliman, MD, PhD, research scientist in the Department of Obstetrics, Gynecology, and Reproductive Sciences at the Yale University School of Medicine in New Haven, Connecticut, told Medscape Medical News.

"For me, this is the most important thing I have done in my entire career. And I think it has the potential to affect and help a tremendous number of people," said Dr. Kliman.

Lead author Cheryl K. Walker, MD, from the Department of Obstetrics and Gynecology at the University of California, Davis (UC Davis), pointed out in a release that the study does not indicate that the TIs themselves have direct impact on neurodevelopment.

"Rather, they are likely a symptom of altered physiology or a genetic predisposition, particularly given their association with other genetic abnormalities, and are almost certain to be triggered by environmental exposures," she said.

Dr. Harvey Kliman

Still, Dr. Kliman noted that this type of test has the possibility of identifying newborns at risk for ASD who might benefit from targeted treatment aimed at preventing or improving behavioral symptoms — and should become part of clinical practice.

"I hope that diagnosing this risk by examining the placenta at birth will become routine and that the children who are shown to have increased numbers of [TIs] will have early interventions and an improved quality of life as a result of this test," he said.

The study was published online April 25 in Biological Psychiatry.

Opportunity for Early Intervention

A diagnosis of ASD is usually made when a child is between 3 and 4 years of age or older. "But then the best opportunities for intervention have been lost because the brain is most responsive to treatment in the first year of life," investigators note in the release.

TIs are microscopic findings that appear as abnormal tissue-folding within the placenta.

"While working many years ago looking at pregnancy loss cases, I noticed that even when the chromosomes in the loss were normal, I kept seeing this abnormal folding pattern in the placentas. And I started thinking this was a pattern that's a marker of a genetic abnormality," said Dr. Kliman.

However, it was not until 10 to 12 years ago, when questions were being asked about the possible role that the measles, mumps, rubella (MMR) vaccine might play in risk for autism, that he revisited the role of infolding.

"That's when the lightbulb went on. People were worrying about the MMR vaccine, but I was seeing a marker that was telling me that autism was genetic," he recalled. Approximately 7 years ago, his investigative team examined 13 placentas and found an increased risk for autism in the samples that showed TIs.

"That was our preliminary study. Because of the number, we couldn't really say that it was ready for prime time. But it gave us encouragement to move forward," said Dr. Kliman.

The Markers of Autism Risk in Babies – Learning Early Signs (MARBLES) study at UC Davis was designed to investigate women at high risk of delivering a child who would develop ASD.

For the current analysis, placenta samples were assessed from 117 births from the MARBLES study and prospectively compared with placenta samples from 100 uncomplicated term pregnancies (control group). Each mother in the control group had given birth previously to 1 or more typically developing children.

False-positives "Unlikely"

Results showed that the at-risk placentas had as many as 15 TIs, whereas none of the control group placentas had more than 2 Tis, and 92% had fewer than 2 TIs.

This translated into a significantly higher increased likelihood of having 2 or more TIs for the placentas from at-risk pregnancies compared with the control group placentas (odds ratio [OR], 8.0; 95% confidence interval [CI], 3.6 - 18.0).

For predicting ASD risk status, a sensitivity rate of 41% and a specificity rate of 92% were found for the presence of 2 or more TIs in the at-risk placentas. Sensitivity and specificity rates of 19% and 99.9%, respectively, were found for the presence of 4 or more TIs.

"In other words, it is very unlikely that we will have a false-positive with this test," said Dr. Kliman.

Having 4 or more TIs also had "a positive likelihood ratio of 242 and conservatively predicted an infant with a 74% probability of being at risk for ASD," report the researchers.

"Our [overall] findings suggest that the placentas from women whose fetuses are at elevated risk for autism are markedly different from control placentas," they add.

"It will be exciting to learn sometime next year, when our MARBLES study participants are old enough to have confirmation of their developmental status, whether [TIs] are associated with autism or other forms of developmental delay," said Dr. Walker.

Still, Dr. Kliman noted that this test will not be able to identify all individuals who might develop autism.

"Some might not have these abnormal folds because they have different types of autism. But if they do have this abnormal fold in their placenta, especially more than 4, then it's very, very likely that that child is in the at-risk group for autism."

Pushing the Envelope

He also noted that currently, couples without known genetic susceptibility must rely on identification of early signs or indicators of ASD that may not manifest until the child is 2 or 3 years of age.

"At birth, a child's brain is basically unformed and is like a blank slate. So we have a really great opportunity to be able to change behavior and do interventions that will help children at risk for autism to develop normal social skills," said Kliman.

However, "there's no other test like this, and there's currently no system in place for taking a 1- or 2-month-old baby and doing these interventions. There are professionals who have been pushing the envelope themselves earlier and earlier, and I think they're down to the 12-month stage. But I'm challenging them to push it even further, to take these things they're doing and adapt it for 6 and even 3 months of age."

In addition, he pointed out that because few pathologists are trained in how to examine placentas, these tests will need to be done at centers where personnel are trained in what to look for to ensure the correct diagnosis.

"At this point, we have ramped up our laboratory at Yale to be able to receive as many cases as we can and will do that until it overflows. My hope is that people will send to places that are certified to do this compared with places that are inexperienced and untrained," said Dr. Kliman.

"This research provides what might turn out to be the first indication of a nongenetic biological marker of autism as early as birth," said principal investigator of the MARBLES study Irva Hertz-Picciotto, PhD, MPH, professor of public health sciences at the UC Davis MIND Institute, in a release.

"Further work will determine what types of maternal/prenatal exposures and conditions, as well as genetics variants, might predict these trophoblast inclusions."

The study was funded by the National Institutes of Health, the US Environmental Protection Agency through the Science to Achieve Results program, the MIND Institute at the University of California, Davis, and the Yale University Reproductive and Placental Research Unit. The study authors have reported no relevant financial relationships.

Biol Psychiatry. Published online April 25, 2013. Abstract


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