Trophoblast Inclusions Are Significantly Increased in the Placentas of Children in Families at Risk for Autism

  • Cheryl K. Walker
    Department of Obstetrics and Gynecology, School of Medicine, University of California, Davis, Davis, California

    Center for Children’s Environmental Health, University of California, Davis, Davis, California

    Medical Investigations of Neurodevelopmental Disorders Institute, University of California, Davis, Davis, California
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  • Kaitlin W. Anderson
    Nurse-Midwifery Program, School of Nursing, Yale University, New Haven, Connecticut
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  • Kristin M. Milano
    Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, Yale University, New Haven, Connecticut
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  • Saier Ye
    Department of Statistics, Yale University, New Haven, Connecticut
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  • Daniel J. Tancredi
    Department of Pediatrics and Center for Healthcare Policy and Research, University of California, Davis, Davis, California
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  • Isaac N. Pessah
    Center for Children’s Environmental Health, University of California, Davis, Davis, California

    Medical Investigations of Neurodevelopmental Disorders Institute, University of California, Davis, Davis, California

    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, California
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  • Irva Hertz-Picciotto
    Division of Epidemiology, Department of Public Health Sciences, School of Medicine, University of California, Davis, Davis, California

    Center for Children’s Environmental Health, University of California, Davis, Davis, California

    Medical Investigations of Neurodevelopmental Disorders Institute, University of California, Davis, Davis, California
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  • Harvey J. Kliman
    Address correspondence to Harvey J. Kliman, M.D., Ph.D., Yale University School of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive and Placental Research Unit, 333 Cedar Street, 339 FMB POB 208063, New Haven, CT 06520-8063
    Nurse-Midwifery Program, School of Nursing, Yale University, New Haven, Connecticut
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      Gestation is a critical window for neurodevelopmental vulnerability. This study examined whether the presence of trophoblast inclusions (TIs) in the placenta could serve as a predictor for children at elevated risk for autism spectrum disorder (ASD).


      Placentas were obtained from 117 births in the MARBLES (Markers of Autism Risk in Babies—Learning Early Signs) cohort of families who have one or more previous biological children with ASD, placing their newborn at elevated risk for neurodevelopmental compromise. Control samples were obtained from 100 uncomplicated term pregnancies of multiparous women with one or more typically developing biological children. Frequency of TIs was compared across the two groups.


      Placentas from at-risk pregnancies had an eightfold increased odds of having two or more TIs compared with control samples (odds ratio: 8.0, 95% confidence interval: 3.6–18.0). The presence of≥2 TIs yielded a sensitivity of 41% and a specificity of 92% for predicting ASD risk status, whereas≥4 TIs yielded a sensitivity of 19%, a specificity of 99.9%, and a positive likelihood ratio of 242 and conservatively predicted an infant with a 74% probability of being at risk for ASD.


      Our findings suggest that the placentas from women whose fetuses are at elevated risk for autism are markedly different from control placentas. These differences are manifested histologically as TIs. Their identification has the possibility of identifying newborns at risk for ASD who might benefit from targeted early interventions aimed at preventing or ameliorating behavioral symptoms and optimizing developmental outcomes.

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