Metabolites linked to neurodevelopmental outcomes in high-risk ASD infants

Placental and cord serum metabolism at delivery are significantly correlated among children with high familial risk of autism spectrum disorder (ASD), according to a recent study in JAMA Network Open.¹

Healthy fetal development is dependent on multiple maternal psychological and metabolic factors during pregnancy, such as increased maternal insulin resistance and higher circulating lipids. Therefore, child outcomes such as neurodevelopment are impacted by disturbances in maternal metabolism during pregnancy.

Metabolism is influenced by a variety of factors, including maternal prepregnant nutrition and fetal size.² Adjustments may occur following changes in maternal food and physical activity behaviors during pregnancy, indicating a need for good maternal nutritional status throughout gestation.

Data has indicated significantly varied prenatal metabolic profiles between patients with a low vs high risk of having a child with ASD.¹ However, research about the associations among maternal, placental, and fetal metabolism is needed.

Investigators conducted a study to evaluate the associations between maternal serum, placental tissue, and umbilical cord serum in metabolism and their impact on neurodevelopmental outcomes among a cohort with high familial risk of ASD.

The Markers of Autism Risk in Babies, Learning Early Signs (MARBLES) study was evaluated for relevant samples. The MARBLES study included younger siblings of children with ASD, and samples included maternal third trimester serum, placenta obtained at delivery, and umbilical cord serum obtained at delivery.

Neurodevelopment was assessed at approximately 36 months using the Mullen’s Scales of Early Learning and ASD Diagnostic Observation Schedule (ADOS). ADOS scores at or beyond the ASD cutoff determined ASD diagnosis, while scores within 3 points below the cutoff indicated nontypical development (non-TD). Otherwise, typical development (TD) was reported.

Collection of whole blood and umbilical cord blood occurred during the third trimester and at delivery, respectively. The blood was then centrifuged and stored at −80 °C. Placentas were also stored at this temperature following processing at delivery.

Proton nuclear magnetic resonance spectra was obtained using an Avance 600-MHz spectrometer (Bruker). Covariates included birth year, gestational age at sample collection, fasted time at sample collection, maternal race and ethnicity, education, home ownership, and prepregnancy body mass index.

There were 152 pregnancies with a median maternal age of 34.6 years and median gestational age of 39 weeks included in the analysis. ASD was reported in 45 children, non-TD in 19, and TD in 87. One child had missing developmental outcome.

Maternal third trimester serum metabolites were not significantly associated with placental metabolites following false discovery rate (FDR) correction. There were also no associations between any metabolite pair reported after FDR correction when using rank-based regression.

Significant associations were reported between maternal third trimester serum metabolites and umbilical cord serum metabolites following Bipartite Spearman correlations and rank-based regression independently. These methods also identified associations between placental metabolites and cord serum metabolites.

A relative risk (RR) of 0.13 was identified between first placenta latent variate scores and non-TD, indicating reduced risk. However, the RR was 1.09 for ASD, indicating no association. Similar results were found for first cord serum latent variate scores, with RRs of 0.13 and 0.63, respectively.

Evaluations of 3-OHB were conducted since 3-OHB was the greatest driver of placental and cord variate scores. A positive association was found between cord 3-OHB and non-TD, with an RR of 9.03.

Cord 3-OHB was not associated with ASD, with an RR of 0.91. Similar patterns were reported for serum 3-OHB. Additionally, placental 3-OHB was not associated with non-TD or ASD, with RRs of 5.21 and 0.64, respectively.

These results indicated an association of placental and umbilical cord metabolomes with non-TD risk. Investigators concluded maternal and fetal lipid metabolisms are important in neurodevelopment.

References

1. Parenti M, Schmidt RJ, Tancredi DJ, Hertz-Picciotto I, Walker CK, Slupsky CM. Neurodevelopment and metabolism in the maternal-placental-fetal unit. JAMA Netw Open. 2024;7(5):e2413399. doi:10.1001/jamanetworkopen.2024.13399
2. King JC. Physiology of pregnancy and nutrient metabolism. The American Journal of Clinical Nutrition. 2000;71(5):1218S-1225S. doi:10.1093/ajcn/71.5.1218s