Fetal-Placental Chorionic Surface Arterial and Venous Vascular Network Structure: Quantitative Arterio-Venous Network Differences in ASD and Controls in the Avon Longitudinal Study of Parents and Children

Background: We have speculated that, since related gene families and factors promote and maintain both healthy vascular networks and healthy neoronal connectivity, that measures of a vascular bed created by the fetal genome (in the placenta) may be correlated with the neurodevelopmental disorder of ASD compared to controls with no diagnosis of developmental disability.

Objectives: To measure the arterial and venous networks on the placental chorionic surface to determine whether netowrk structures vary between ASD cases and a population-derived set of controls.

Methods: Placentas from cases diagnosed with autism/ASD in the Avon Longitudinal Study of Parents and Children were matched with cases without diagnosis of disability. Placentas were processed by a protocol that included photography of the placental chorionic surface, to document chorionic arterial and venous networks. Networks were traced by a dedicated team and over 60 variables related to branch generations, branch points, branching angles, vessel tortuosity and vessel caliber, as well as distance between vessels and from vessels to the chorionic surface perimeter were extracted. Two methods of data reduction assessed arterial and venous network differences between ASD cases and controls: Multiple Adaptive Regression Splines (MARS, Salford Systems, CA, USA) and Principal Components Analysis. 

Results: Spline regression found no gender influence on the relationship among individual placental chorionic vessel measures, or the relationship of any of 6 factors extracted by PCA. No difference in chorionic plate vessel factors, arterial or venous, was attributable to infant gender. Factors extracted in ASD were uncorrelated with a similar number of factors extracted from the same variables in the controls and again there was no effect of gender on factor relationships. More arterial variables differed between ASD and controls, at levels of  as much as 1-2 orders of magnitude increased significance, as compared to venous variables.

Conclusions: Given these observed differences in ASD placentas compared to controls,  new methodology for placental examination may be warranted to better define at risk newborns for ASD. The implications are that the maternal environment or intrinsic fetal genetic regulation may influence the growth of the nutrient supply network of the fetus in the placenta, potentially setting the stage for other environmental stressors to interfere with early neuronal sprouting. Given that a major driving force in branching angiogenesis is oscillation or pulsatility of flow, we hypothesize that potentially the decreased electrical excitability in vivo of neurons treated with valproate, a known risk factor for ASD when exposure is in the period in which major chorionic surface vascular networks are laid down, translates in changes in fetal heart rate variability that affect pulsatile flow on the placental surface in early pregnancy. We have found no association of number of branches off the umbilical cord insertion (the earliest developed and thus oldest) portions of the placental chorionic surface vascular networks in either ALSPAC ASD cases as compared to controls There appears to be no ASD- associated effect on the early vasculogenic period of placental vascular organization (<6 weeks gestation), with placental chorionic vessel associations only in later branch generations.