Placental Signs May Augur Autism

NEW HAVEN, Conn., June 27 - The placenta may hold clues to autism, researchers here reported.

Preserved placentas from children later diagnosed with autism were three times more likely to contain trophoblastic inclusions (markers for cellular abnormalities) than are placentas from children with normal development, according to Harvey J. Kliman, M.D., Ph.D., of Yale, and colleagues.

"Although probably not functionally detrimental or causative, the greater occurrence of placental trophoblast inclusions observed in autism spectrum disorder individuals may reflect altered early developmental processes," the investigators wrote in the early online and July editions of Biological Psychiatry.

Trophoblasts are among the first cells to form during fetal development and are essential for implantation and placental development, the authors said.

The presence of trophoblast inclusions in fully formed placentas may not affect the function of those placentas, but may instead be markers for genetic predispositions "that could have subtle, yet profound, effects in the developing embryo and the forming nervous system," Dr. Kliman and colleagues wrote. Trophoblast inclusions have been associated with a number of frank genetic abnormalities including triploidy, trisomy and Turner's syndrome.

To test this idea, they used archived tissues to compare the rate of occurrence of trophoblast inclusions in the placentas from 13 children with autism spectrum disorder with those from 61 controls.

On microscopic examination of tissue slides, they found that rate of inclusion-positive slides was significantly greater for tissue from children with autism spectrum disorder (six of 27 slides, or 22%) than from controls (12 of 154 slides, or 7.8; Fisher Exact Test, two-tailed, P=0.033).

As a test for autism, the presence of trophoblast inclusions had a sensitivity of 22.2%, and a specificity of 92.2%. The authors calculated a risk ratio of 2.85 (95% confidence interval, 1.17-6.95) and an odds ratio of 3.38 (95% CI, 1.15-9.97) for inclusions and autism.

In a case-comparison analysis, the investigators found that five of 13 children with autism spectrum disorder had slides that were positive for trophoblast inclusions, compared with eight of 61 controls (Fisher Exact test P=0.044; sensitivity 38.5%, specificity 86.8%, risk ratio 2.93 (95% CI. 1.14 - 7.53), odds ratio 4.14 (95% CI, 0.76 - 22.5).

Among the children with autism spectrum disorder, there were no differences in behavioral severity scores between those with trophoblast inclusions and those without, the investigators found.

"We knew that trophoblast inclusions were increased in cases of chromosome abnormalities and genetic diseases, but we had no idea whether they would be significantly increased in cases of autism spectrum disorder," Dr. Kliman said. "These results are consistent with studies by others who have shown that autism spectrum disorder has a clear genetic basis."

The investigators plan to confirm their findings in larger prospective multicenter trials.

"If the work is confirmed by the next series of studies, then the finding of trophoblast inclusions at the time of birth in the absence of any obvious genetic abnormalities would be an indication to have a child examined by a specialist to determine the presence of autism spectrum disorder," said co-author Fred R. Volkmar , M.D., also of Yale.

In addition, consideration of trophoblast physiology and developmental biology may provide insight into the neurodevelopmental abnormalities of autism.