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Maternal metabolites may influence outcomes in early childhood

By Eleanor McDermid, medwireNews Reporter


Researchers find that maternal metabolites are associated with distinct foetal growth patterns, elements of which persist until at least 2 years of age.

“Our findings, based on a systems biology approach, add to the existing evidence that understanding the influence of the maternal exposome on human development from early pregnancy onwards requires much deeper phenotyping to complement syndromic classifications, such as preterm birth”, write Jose Villar (University of Oxford, UK) and colleagues in The Lancet Diabetes & Endocrinology.

“Our approach has identified not only a strong association between distinct trajectories of fetal growth and childhood outcomes, but also the putative metabolic pathways that cause the biological mechanisms.”

The researchers identified four foetal growth trajectories among 3206 pregnant women from the INTERBIO-21st cohort. These women received antenatal care in units in Brazil, Kenya, Pakistan, South Africa, Thailand and the UK in 2012–2019 and underwent at least three scans between 14 and 37 weeks’ gestation.

The four trajectories were based on abdominal circumference growth “principally because it approximates the growth of the fetal liver and abdominal subcutaneous fat”, explains the team.

The largest differences in maternal metabolites were found between the two most extreme trajectories: the “faltering” growth trajectory (n=763) and the “early-accelerating” growth trajectory (n=504). There were 709 and 54 maternal metabolites significantly and positively associated with the faltering and early-accelerating trajectories, respectively, plus a corresponding 31 and 76 with a negative effect, and an even larger number of umbilical cord metabolites with positive and negative effects.

Twenty unique maternal molecules affected both trajectories, most of which were positively associated with faltering growth, indicating the upregulation of specific metabolic pathways, but were negatively associated with early-accelerated growth, suggesting downregulation of the same pathways.

Many of these molecules were uncharacterized, but 11 were phosphatidylcholines, and the researchers also identified a metabolite of the fungicide chlorothalonil, which was positively associated with early accelerated growth. Looking further at the molecules that most strongly affected just one of the growth trajectories, they again found strong representation of phosphatidylcholines.

One of the most common sidechains on these molecules were oxylipins, and the team speculates that these may “function as endogenous signalling molecules, serving as ligands for nutrient-sensing peroxisome proliferator-activated receptors.”

In the early-accelerating growth trajectory, abdominal circumference increased to 1.5 standard deviations (SDs) above the 50th centile for the whole cohort by week 25 and then remained stable until birth, after which the infants’ weight remained stable just over 0.5 SD above the 50th centile.

Mothers in this group tended to be taller than others, with a higher pre-pregnancy BMI and higher rates of gestational diabetes and pregnancy-induced hypertension. Their infants scored highest, at the age of 2 years, for language and positive affect, albeit restricted to those who were breastfed for at least 7 months.

In the faltering growth trajectory, abdominal circumference reduced to less than 1 SD below the 50th centile by weeks 20–23 and then remained steady. Average umbilical artery Doppler Pulsatility Index trajectories were “consistently higher” from 24 weeks’ gestation onwards in this group than in the other groups, indicating greater impedance to blood flow.

The mothers in this group tended to be shorter and less educated than other mothers, with a lower baseline BMI and a higher rate of smoking and pre-eclampsia.

These findings suggest that such babies “are not simply constitutionally small, and there is a faltering growth phenotype subgroup, associated with preeclampsia and reduced umbilical artery flow, that manifests early in pregnancy”, say Villar and co-workers.

After birth, the infants tended to catch up towards the 50th centile of weight-for-length; however, this catch-up was due to a slower increase in length rather than an acceleration of weight gain.

The researchers suggest “that an adverse maternal exposome early in pregnancy, when skeletal growth velocity is at its highest, has a lasting effect on infant length and height and adiposity”.

Also, these infants had significantly poorer visual acuity and contrast sensitivity at the age of 2 years than those in the other groups, although the risk for low visual acuity was lessened if they were breastfed for at least 7 months.


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Lancet Diabetes Endocrinol 2022; 10: 710–719