Association between fetal abdominal growth trajectories, maternal metabolite signatures early in pregnancy, and childhood growth and adiposity: prospective observational multinational INTERBIO-21st fetal study

Abstract

Background: Obesity predominantly affects populations in high-income countries and those countries facing epidemiological transition. The risk of childhood obesity is increased among infants who had overweight or obesity at birth, but in low-resource settings one in five infants are born small for gestational age. We aimed to study the relationships between: (1) maternal metabolite signatures; (2) fetal abdominal growth; and (3) postnatal growth, adiposity, and neurodevelopment.

Methods: In the prospective, multinational, observational INTERBIO-21st fetal study, conducted in maternity units in Pelotas (Brazil), Nairobi (Kenya), Karachi (Pakistan), Soweto (South Africa), Mae Sot (Thailand), and Oxford (UK), we enrolled women (≥18 years, with a BMI of less than 35 kg/m², natural conception, and a singleton pregnancy) who initiated antenatal care before 14 weeks' gestation. Ultrasound scans were performed every 5±1 weeks until delivery to measure fetal growth and feto-placental blood flow, and we used finite mixture models to derive growth trajectories of abdominal circumference. The infants' health, growth, and development were monitored from birth to age 2 years. Early pregnancy maternal blood and umbilical cord venous blood samples were collected for untargeted metabolomic analysis.

Findings: From Feb 8, 2012, to Nov 30, 2019, we enrolled 3598 pregnant women and followed up their infants to 2 years of age. We identified four ultrasound-derived trajectories of fetal abdominal circumference growth that accelerated or decelerated within a crucial 20-25 week gestational age window: faltering growth, early accelerating growth, late accelerating growth, and median growth tracking. These distinct phenotypes had matching feto-placental blood flow patterns throughout pregnancy, and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood. There were 709 maternal metabolites with positive effect for the faltering growth phenotype and 54 for the early accelerating growth phenotype; 31 maternal metabolites had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype. Metabolites associated with the faltering growth phenotype had statistically significant odds ratios close to 1·5 (ie, suggesting upregulation of metabolic pathways of impaired fetal growth). The metabolites had a reciprocal relationship with the early accelerating growth phenotype, with statistically significant odds ratios close to 0.6 (ie, suggesting downregulation of fetal growth acceleration). The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid, and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was highly abundant in the early accelerating growth phenotype group.

Interpretation: Early pregnancy lipid biology associated with fetal abdominal growth trajectories is an indicator of patterns of growth, adiposity, vision, and neurodevelopment up to the age of 2 years. Our findings could contribute to the earlier identification of infants at risk of obesity.

Funding: Bill & Melinda Gates Foundation.

Figure 1

Fetal abdominal circumference growth phenotypes in the INTERBIO-21st fetal study (n=3206) Shaded bands represent 95% CIs for the splines used to summarise group trajectories.

Figure 2

Growth z-scores for abdominal circumference during pregnancy, and weight (A) and weight-for-length (B) at birth and 1 and 2 years in the INTERBIO-21st fetal study Measurements up until birth (15–20 weeks’ gestation and 25–30 weeks’ gestation) were of abdominal circumference, and subsequently were either of weight (A) or weight-for-length (B). Fetal measurements of abdominal circumference were from the ultrasound scans. Error bars represent the 95% CIs of the means.

Figure 3

Umbilical artery Doppler Pulsatility Index trajectories in the INTERBIO-21st fetal study N=3206. Group membership was established by an analysis of fetal abdominal circumference growth trajectories. Shaded bands represent the 95% CIs for splines used to summarise group trajectories.

Figure 4

Volcano plot of odds ratio distributions for each maternal metabolite according to the faltering growth and early accelerating growth phenotypes Volcano plots of odds ratios and p-values, adjusted by maternal age and newborn sex, from maternal plasma (Aand B) and linked umbilical venous cord (C and D) metabolite signatures for the faltering growth and early accelerating growth phenotypes of ultrasound-based fetal abdominal circumference growth trajectories (n=2713 women and n=2430 newborn babies). Blue dots indicate p<10⁻⁶.

Figure 5

Odds ratios for the 20 unique molecules identified that overlapped between the faltering growth and early accelerating growth phenotypes Association between early pregnancy, overlapping maternal metabolite signatures, and the faltering growth and early accelerating growth phenotypes of ultrasound-based, fetal abdominal circumference growth trajectories in the INTERBIO-21st fetal study (n=2713). Data are presented as odds ratios and 95% CIs. Models are adjusted for maternal age and fetal sex. *Or pentadecylic acid or oleic acid. †Putative.