Effects of gestational age at birth on perinatal structural brain development in healthy term‐born babies

Multiple studies have demonstrated less favourable childhood outcomes in infants born in early term (37-38 weeks gestation) compared to those born at full term (40-41 weeks gestation). While this could be due to lower birthweight and greater perinatal morbidity, gestational age at birth may also have a direct effect on the brain and subsequent neurodevelopment in term-born babies. Here we characterise structural brain correlates of gestational age at birth in healthy term-born neonates and their relationship to later neurodevelopmental outcome. We used T2 and diffusion weighted Magnetic Resonance Images acquired in the neonatal period from a cohort (n=454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor based morphometry (TBM) and tract based spatial statistics (TBSS). Neurodevelopment was subsequently assessed at age 18 months using the Bayley-III Scales of Infant and Toddler Development (n=281), and the effects of gestational age at birth and related neuroimaging findings on outcome were analysed with linear regression. Infants born earlier had areas of higher relative ventricular volume, and lower relative brain volume in the basal ganglia, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley-III subscales at age 18 months. Linear regression models predicting outcome from gestational age at birth were significantly improved by adding neuroimaging features associated with gestational age at birth. This work adds to the growing body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term-born babies.

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DNA methylation and brain dysmaturation in preterm infants

10.1101/2021.04.08.21255064 ◽

2021 ◽

Author(s):

Emily N W Wheater ◽

Paola Galdi ◽

Daniel McCartney ◽

Manuel Blesa ◽

Gemma Sullivan ◽

...

Keyword(s):

Dna Methylation ◽

Functional Analysis ◽

Preterm Birth ◽

Brain Development ◽

Gestational Age ◽

Principal Component ◽

Genome Wide ◽

Gestational Age At Birth ◽

Age At Birth ◽

Atypical Brain Development

Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation (DNAm) is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation data from saliva of 258 neonates, we investigated the impact of gestational age on the methylome and performed functional analysis to identify enriched gene sets from probes that contributed to differentially methylated probes (DMPs) or regions (DMRs). We tested the hypothesis that variation in DNAm could underpin the association between preterm birth and atypical brain development by linking DMPs with measures of white matter connectivity derived from diffusion MRI metrics: peak width of skeletonised mean diffusivity (PSMD), fractional anisotropy (PSFA) and neurite density index (PSNDI). Gestational age at birth was associated with widespread differential methylation, with genome-wide significant associations observed for 8,870 CpG probes (p<3.6x10-8) and 1,767 differentially methylated regions. Functional analysis identified 14 enriched gene ontology terms pertaining to cell-cell contacts and cell-extracellular matrix contacts. Principal component analysis of probes with genome-wide significance revealed a first principal component (PC1) that explained 23.5% of variance in DNAm, and this was negatively associated with gestational age at birth. PC1 was associated with PSMD (β=0.349, p=8.37x10-10) and PSNDI (β=0.364, p=4.15x10-5), but not with PSFA (β=-0.035, p=0.510); these relationships mirrored the imaging metrics associations with gestational age at birth. Gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome. Enriched gene ontology terms related to cell-cell contacts reveal pathways that could mediate the effect of early life environmental exposures on development. Finally, associations between differential DNAm and image markers of white matter tract microstructure suggest that variation in DNAm may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterises atypical brain development in preterm infants.

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Mapping the critical gestational age at birth that alters brain development in preterm-born infants using multi-modal MRI

NeuroImage ◽

10.1016/j.neuroimage.2017.01.046 ◽

2017 ◽

Vol 149 ◽

pp. 33-43 ◽

Cited By ~ 9

Author(s):

Dan Wu ◽

Linda Chang ◽

Kentaro Akazawa ◽

Kumiko Oishi ◽

Jon Skranes ◽

...

Keyword(s):

Brain Development ◽

Gestational Age ◽

Preterm Born ◽

Gestational Age At Birth ◽

Age At Birth

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Gestational Age at Birth, 1994 and 2004

PsycEXTRA Dataset ◽

10.1037/e411542008-001 ◽

2006 ◽

Keyword(s):

Gestational Age ◽

Gestational Age At Birth ◽

Age At Birth

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Faculty Opinions recommendation of Effects of gestational age at birth on health outcomes at 3 and 5 years of age: population based cohort study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14264188.15777343 ◽

2012 ◽

Author(s):

Mark Sullivan

Keyword(s):

Cohort Study ◽

Health Outcomes ◽

Gestational Age ◽

Population Based ◽

Gestational Age At Birth ◽

Age At Birth

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Prenatal household air pollutant exposure is associated with reduced size and gestational age at birth among a cohort of Ghanaian infants

Environment International ◽

10.1016/j.envint.2021.106659 ◽

2021 ◽

Vol 155 ◽

pp. 106659

Author(s):

Ashlinn K. Quinn ◽

Irene Apewe Adjei ◽

Kenneth Ayuurebobi Ae-Ngibise ◽

Oscar Agyei ◽

Ellen Abrafi Boamah-Kaali ◽

...

Keyword(s):

Gestational Age ◽

Air Pollutant ◽

Gestational Age At Birth ◽

Age At Birth

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Coeliac disease presenting atypically: A much wider spectrum

Tropical Doctor ◽

10.1177/0049475521991348 ◽

2021 ◽

pp. 004947552199134

Author(s):

Avinash Lomash ◽

Abhinaya Venkatakrishnan ◽

Meenakshi Bothra ◽

Bhavna Dhingra ◽

Praveen Kumar ◽

...

Keyword(s):

Coeliac Disease ◽

Gestational Age ◽

Dermatitis Herpetiformis ◽

Mode Of Delivery ◽

Gastrointestinal Symptoms ◽

Stunted Growth ◽

Significant Difference ◽

High Index Of Suspicion ◽

Gestational Age At Birth ◽

Age At Birth

Atypical coeliac disease in young children is frequently missed when it presents atypically as non-gastrointestinal presentations to different specialties. There was a greater delay (54 months) in establishing the diagnosis in those with atypical coeliac disease (p < 0.001). No difference was observed in the mode of delivery or duration of breast feeding, but significant difference was observed between gestational age at birth (p < 0.001). Most cases showed stunted growth and underweight. Irritability, anaemia, rickets, dermatitis herpetiformis, alopecia and intussusception were other common predictors of atypical coeliac disease. Because of a myriad spectrum of non-gastrointestinal symptoms, at any age with diverse presentation, a high index of suspicion is therefore required.

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Maternal biological age assessed in early pregnancy is associated with gestational age at birth

Scientific Reports ◽

10.1038/s41598-021-94281-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eva E. Lancaster ◽

Dana M. Lapato ◽

Colleen Jackson-Cook ◽

Jerome F. Strauss ◽

Roxann Roberson-Nay ◽

...

Keyword(s):

Risk Factors ◽

Preterm Birth ◽

Early Pregnancy ◽

Gestational Age ◽

Cellular Aging ◽

Biological Age ◽

Potential Candidate ◽

A Genome ◽

Gestational Age At Birth ◽

Age At Birth

AbstractMaternal age is an established predictor of preterm birth independent of other recognized risk factors. The use of chronological age makes the assumption that individuals age at a similar rate. Therefore, it does not capture interindividual differences that may exist due to genetic background and environmental exposures. As a result, there is a need to identify biomarkers that more closely index the rate of cellular aging. One potential candidate is biological age (BA) estimated by the DNA methylome. This study investigated whether maternal BA, estimated in either early and/or late pregnancy, predicts gestational age at birth. BA was estimated from a genome-wide DNA methylation platform using the Horvath algorithm. Linear regression methods assessed the relationship between BA and pregnancy outcomes, including gestational age at birth and prenatal perceived stress, in a primary and replication cohort. Prenatal BA estimates from early pregnancy explained variance in gestational age at birth above and beyond the influence of other recognized preterm birth risk factors. Sensitivity analyses indicated that this signal was driven primarily by self-identified African American participants. This predictive relationship was sensitive to small variations in the BA estimation algorithm. Benefits and limitations of using BA in translational research and clinical applications for preterm birth are considered.

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