26498
Placental Trophoblast Inclusions Do Not Predict Adverse Neurodevelopment in the Marbles High-Risk Pregnancy Cohort
Objectives: The purpose of this study was to determine whether the presence and/or frequency of placental TIs is associated with adverse neurodevelopmental outcomes in a population at enhanced risk for ASD.
Methods: Placental samples were obtained from 117 births in the MARBLES (Markers of Autism Risk in Babies – Learning Early Signs Study) longitudinal ASD-risk birth cohort between January 11, 2008 and January 10, 2011. Four slides per specimen were examined histologically in random order for TIs, identified as a central syncytiotrophoblast nucleus surrounded by one or more cytotrophoblasts. TIs were summed across slides. Child development was evaluated at 36 months of age with Autism Diagnostic Observation Schedule (ADOS) and Mullen Scales of Early Learning (MSEL). Outcome was established by two methods: 1) clinical best estimate (CBE), categorized as ASD (n=21), other developmental concerns (ODC, n=20), or typical development (TD, n=63); and 2) an algorithm incorporating multiple clinical assessments, ADOS and MSEL scores that classified diagnoses as ASD (n=29), non-typical development (NTD, n=9) and TD (n=55). Children with final outcomes were included for statistical analysis. The pathology team was blinded to outcome and those assessing neurodevelopmental function were blinded to TI status.
Multinomial logistic regression models were performed to assess the association between TI frequency (continuous and dichotomous [0-1 negative and ≥2 positive]) and child outcome defined by CBE and algorithm, with and without adjustment for important covariates. We explored each covariate in a stepwise fashion and retained only those that altered the TI coefficient by at least 20%, considering the sample size. Final models included maternal age, education, race/ethnicity and diabetes; paternal age, and child sex as covariates.
Results: TI presence did not predict child developmental outcome in any of the permutations analyzed. For example, results comparing odds of ASD v TD by number of TIs were null and did not vary by outcome categorization (CBE: 0.84, 0.61-1.15 and Algorithm: 1.02, 0.84-1.24]). Both univariate and covariate-adjusted statistical analyses failed to identify any significant association between TIs and either ASD or more subtle neurodevelopmental impairments.
Conclusions: Because TIs have been associated with being at risk for ASD in the same way that having an older affected sibling is a marker for increased susceptibility, TIs may identify a predisposition, genetic or otherwise, for ASD. However, placental TIs demonstrated no association with the development of ASD or of other non-typical neurodevelopmental outcomes. The evidence to date provides no justification for use of placental TI presence as a predictive biomarker for ASD in either at-risk or low-risk populations.