Identification of placenta-brain axis genes associated with neurodevelopmental delay in moderate and late preterm children

1. This analysis of a prospective cohort of moderate and late preterm (MLPT) children found both MLPT-specific and MLPT-sex-specific neurodevelopmental delays. The gross motor and personal-social domains of development were most affected, particularly in males.

2. Two placental genes, apolipoprotein E (APOE) and cystatin c (CST3), were identified as predictive of neurodevelopmental delay in MLPT children and postulated to be part of a placenta-brain axis in fetal development. 

Evidence Rating Level: 2 (Good)

Preterm birth is defined as delivery before 37 weeks gestation according to the World Health Organization. However, the degree of preterm status is also an important factor in risk stratification for both mother and fetus. The literature surrounding extreme preterm (< 28 weeks) and very preterm (28 to 31+6 weeks) births is more robust than that of moderate and late preterm (32-36 weeks) births. Some more recent literature is now exploring the potential morbidity and mortality of MLPT births, as they account for a strong majority of births globally. The current analysis of a prospective cohort of 129 MLPT infants and 3136 full-term (FT) controls assessed neurodevelopmental outcomes associated with MLPT, as well as potential placental genes contributing to changes in fetal brain development (coined the “placenta-brain axis”, PBA). The Ages and Stages Questionnaire of China (ASQ-C) was used at 6, 18, and 48 months of life to assess five domains of development. Gross motor (OR = 0.58, p = 0.006) and personal-social development were significantly delayed (OR = 0.61, p = 0.013) in MLPT infants. Interestingly, delays were more pronounced in males. MLPT males were significantly delayed in gross motor (OR = 0.56, p = 0.033), fine motor (OR = 0.56, p = 0.018), and personal-social domains (OR = 0.60, p = 0.021). Significant delays when adjusting for confounding variables were not found in MLPT females, although preliminary analyses supported delays in gross motor and personal-social domains. Placental tissue was also collected and sequenced in a transcriptome-wide analysis. There were 709 upregulated and 65 downregulated genes that differed between MLPT and FT males (86 upregulated and 398 downregulated for females). Only a few overlapped between the male and female groups, possibly bolstering sex-specific findings. Fourteen PBA genes (two in all MLPT, nine in male MLPT, and four in female MLPTs) were identified for further analysis. Machine learning allowed for the building of predictive models with genes. The APOE and CST3 genes outperformed the logistic regression and decision tree models and were found to be good predictors of neurodevelopmental delay in MLPT children (Area Under the Curve = .861 and .833, respectively). Overall, this study’s findings suggest a more sex-specific interaction between MLPT birth and neurodevelopmental delay, and two genes were identified as placental biomarkers. Further in vivo and in vitro experiments may yield more information on genetic biomarkers such as APOE and CST3. 

Click to read the study in BMC Medicine

Image: PD

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