Placental Features in ASD Compared to Controls: A Community Based Cohort in Brooklyn

Background:  The prenatal environment is increasingly appreciated to conribute to ASD risk, but the precise mechanisms or causal pathways are unclear. The placenta is a fetal organ commonly discarded at birth but which is the fetal interface with the maternal environment and its growth is the reflection of fetal genetic regulation. Do placentas of children diagnosed with ASD at>2 years of age differ from developmentally normal controls? If angiogenesis drives neurogenesis, and placental angiogenesis drives villous arborization, is the ASD placenta structurally different? Does placental evidence of prenatal exposure to acute or chronic inflammation occur more commonly in ASD?

Objectives:  To study the placental pathology, maternal diagnoses and newborn factors of all children followed at New York Methodist Hospital with ASD diagnosis and population based controls in a setting with universal placental pathology examination.

Methods:  Billing codes were searched to identify all children with ASD diagnosis followed by either a pediatric neurologist or developmental pediatrician. Newborns matched for gender, birthweight (BW) and gestational age (GA) were also identified and maternal medical records, placental pathology report and newborn charts were reviewed. Data were analyzed in SPSS 20.0, with p<0.05 significant.

Results:  34 children with ASD (29 males and 5 females) and 124 controls had mean BW 3170 and 3328 g, GA 37.8 and 38.5 weeks. There was no difference in placental weight or the ratio of birth to placental weight. However, disk thickness differed significantly, with ASD placentas 10% thinner on average (2.56+ .44 v 2.81+ .54, p=0.015). There was no difference in chorionic plate surface area or ellipsivity of the disk. There was no association of labor induction or maternal fever with ASD case status. However, acute fetal inflammation of chorionic plate and chronic placental inflammation were each more common in ASD cases (0.01>p<0.05). Chronic placental inflammation was associated with reduced disk thickness at the p=0.05 level.

Conclusions: Placental disk thickness reflects the extent of branching villous arborization that creates the tissue interface between the mother’s and the fetal bloodstreams. Villi are formed when vessels branch; reduced villous branching means reduced branching angiogenesis. Reduced disk thickness –implying reduced villous branching growth-- without a change in placental weight implies a difference in placental  villous “composition”. Given the evidence that angiogenesis drives neurogenesis, we propose that the placenta in ASD shows reduction in branching growth that may be paralleled by neuronal connectivity in the ASD brain. Prenatal exposure to inflammation has been suggested to underlie as many as 1/3 of ASD cases; we have preliminary evidence that placental measures of acute inflammation and chronic inflammation differ in ASD cases compared to population –based controls. Fetal inflammatory response was increased in ASD despite no association of ASD with maternal fever. Thus, these cases of prenatal exposure to acute inflammation were clinically silent. Chronic inflammation appears to be correlated with altered disk thickness; additional studies are needed to determine a potential link of inflammation and abnormal branching angiogenesis that could result in both our placental observations of abnormal villous “composition”, and increased risk of ASD.