Maternal pre-pregnancy body mass index is associated with newborn offspring hypothalamic mean diffusivity: a prospective dual-cohort study

Abstract

Background An extensive body of animal literature supports the premise that maternal obesity during pregnancy can alter the development of the fetal hypothalamus (HTH, a critical regulator of energy balance) with implications for offspring obesity risk (i.e., long-term energy imbalance). Yet, the relationship in humans between maternal overweight/obesity during pregnancy and fetal hypothalamic development remains largely unknown. Here, using an international (Finland and California, USA) multi-site diffusion tensor imaging (DTI) dataset, we test the hypothesis that maternal pre-pregnancy BMI is associated with newborn offspring HTH mean diffusivity (HTH MD, a replicable neural correlate of BMI in adults). Methods HTH MD was independently quantified in two separate BMI-matched cohorts (up to class II obesity; BMIRange = 17–35) using a high-resolution atlas-based definition of HTH. A total of n = 231 mother-child dyads were available for this analysis (nSite,1 = 152, age at MRI = 26.7 ± 8.1 days, gestational age at birth = 39.9 ± 1.2 weeks, nM/F = 82/70, BMI = 24.2 ± 3.8; nSite,2 = 79, age at MRI = 25.6 ± 12.5 days, gestational age at birth = 39.3 ± 1.5 weeks, nM/F = 45/34, BMI = 25.1 ± 4.0). The association between maternal pre-pregnancy BMI and newborn offspring HTH MD was examined separately in each cohort using linear regression adjusting for gestational age at birth, postnatal age at scan, sex, whole white matter mean diffusivity, and DTI quality control criteria. In post hoc analyses, additional potentially confounding factors including socioeconomic status, ethnicity, and obstetric risk were adjusted where appropriate. Results The distribution of maternal pre-pregnancy BMI was comparable across sites but differed by ethnicity and socioeconomic status. A positive linear association between maternal pre-pregnancy BMI and newborn offspring HTH MD was observed at both sites ($$\hat{\beta}$$ β ^ Site,1 = 0.17, pSite,1 = 0.01; $$\hat{\beta}$$ β ^ Site,2 = 0.22, pSite,2 = 0.03) and remained significant after adjusting for cohort-relevant covariates. Conclusions These findings translate the preclinically established association between maternal obesity during pregnancy and offspring hypothalamic microstructure to the human context. In addition to further replication/generalization, future efforts to identify biological mediators of the association between maternal obesity and fetal HTH development are warranted to develop targeted strategies for the primary prevention of childhood obesity.

Identifying of immune‐associated genes for assessing the obesity‐associated risk to the offspring in maternal obesity: A bioinformatics and machine learning

“…32 A prospective human dual-cohort study observed an approximately linear association between maternal pre-pregnancy BMI and offspring hypothalamic microstructure on MRI images, further demonstrating the plasticity of prenatal hypothalamic development in the context of maternal overnutrition during pregnancy. 33 Interestingly, in the present study, the hypothalamic DEGs of offspring with maternal obesity were not only enriched in the physical functions of the hypothalamus (such as neurodevelopment and metabolic hormone regulation) but also in immune system regulation. The hypothalamic DEGs related to maternal obesity were primarily enriched in "negative regulation of immune system process,"…”

“… 32 A prospective human dual‐cohort study observed an approximately linear association between maternal pre‐pregnancy BMI and offspring hypothalamic microstructure on MRI images, further demonstrating the plasticity of prenatal hypothalamic development in the context of maternal overnutrition during pregnancy. 33 …”

Associations of radiologic characteristics of the neonatal hypothalamus with early life adiposity gain

“…Notably, prospective studies demonstrate that early rapid weight gain heightens obesity risk throughout life 12 . In addition, while previous neonatal imaging studies have proposed interindividual differences in axonal outgrowth as the cellular underpinnings of the observed variation in hypothalamic mean diffusivity, 11,16 we suggest an alternative interpretation based on these findings that this variation may also be reflective of an inflammatory response within the glial cells of the MBH. In a manner consistent with rodent models, non‐human primate studies demonstrate that in utero exposure to maternal high‐fat diet leads to hypothalamic inflammation/gliosis in 3rd trimester foetuses, and small birth weight coupled with postnatal catch‐up growth 10,17 …”

Associations between maternal pre-pregnancy BMI and infant striatal mean diffusivity

“…Two extant studies have shown that the altered functional connectivity in reward processing and cognitive control, similarly to that observed in obese adults, was also observed in 2-week-old infants with mothers who had high BMI 21,22 . In addition, decreased white matter integrity 23 and increased mean diffusivity in hypothalamus 24 were observed in infants born to mothers with high BMI. Diffusion tensor imaging (DTI) has been an indispensable method to study the white matter, since it provides quantitative scalar values to assess the microstructural integrity.…”