Angiogenesis Drives Neurogenesis: Fetal-Placental Vascular Network Structure in a Population Based Cohort of ASD and Matched Controls

Background: The placenta is a fetal organ that is reflective of the effect of fetal genes, and is also the direct interface with the maternal environment. It has a branched vascular structure that grows across gestation. There is evidence that angiogenesis drives neurogenesis, and that measures of the branched network structure of vascular beds may inform on neuroanatomy or connectivity.

Objectives: To determine whether placental chorionic surface vascular features are measurably different in children with autism or at high risk for autism and its spectrum disorders (ASD).

Methods: The Avon Longitudinal Study of Parents And Children (ALSPAC) recruited mothers delivering over a one year period 1991-1992. Followup was performed to diagnose autism/ASD. All children with ASD who retained placentas, and 3 controls per case were selected for this nested case control study. The placental chorionic surface was photographed. The surface vasculature was traced from the digital images by a dedicated team. Tracings were reviewed by one observer before analysis by a computer algorithm that extracted counts, lengths and distances between structures, branching angles and a measure of tortuosity. Data were analyzed in SPSS 20.0.

Results: There was a bimodal distribution of vascular branch point numbers in ALSPAC ASD cases, with the majority of ASD cases with reduced numbers and 6 cases with strikingly increased vascular branching, greater than 1 standard deviation above the mean expected for normal (ALSPAC control). Excluding the 6 outliers, there are striking differences in the placental chorionic surface arterial networks, with similar but generally smaller effects seen in the venous networks, including total reduction in the number of branch generations (although not in a change in the number of vessels originating off the umbilical cord), a reduction of 42% in vascular branch points, reduced total vascular surface length and decreased placental chorionic surface vessel extension to the perimeter, and altered branching angles (all p,0.05). There was no gender distinction; small sample sizes for female ALSPAC ASD cases limits the power of significance tests.

Conclusions:  These data point to a difference in network structure of a key vasculature laid down in the fetal placenta contemporaneous to the evolution of fetal vasculature in the central nervous system. Placentas, most commonly discarded as medical waste, present an excellent opportunity to develop a panel of perinatal biomarkers for ASD risk assessment and may inform on the causal chain leading to ASD. We speculate that the observed bimodality reflects heterogeneity in ASD diagnosis in the 1990’s compared with contemporary practice, as Rett’s Syndrome and Fragile X Syndrome were not distinguished from ASD proper at that time.