Epigenetic signatures of prenatal exposures to the COVID-19 pandemic: findings from a longitudinal multi-centric study

• In Event: The biological signatures of exposure to COVID-19 lockdown during the first 1000 days of life.

Abstract

Introduction. The COVID-19 pandemic has been an unprecedented stressful event which has brought many challenges both for people and society worldwide. Pregnant women represent a vulnerable population where the stress-related sequelae might hinder not only women’s well-being but also the development of their offspring. Epigenetic mechanisms such as DNA methylation of stress-related genes (i.e., glucocorticoid receptor gene, NR3C1, and serotonin transporter gene, SLC6A4), may contribute to the embedding of maternal prenatal pandemic-related stress (MPPS) into infant outcomes. Furthermore, gestational timing of stress exposure might moderate some of these effects.
Aims and hypotheses. We investigated the association between MPPS, NR3C1 and SLC6A4 methylation status and infant development in a cohort of Italian infants who were exposed to the COVID-19 pandemic lockdown during pregnancy. We also explored possible differences related to timing of exposure (i.e. first, second or third trimester). We anticipated higher MPPS to be associated with greater methylation of the target genes. We also hypothesized a negative association between methylation levels and infant developmental outcomes. We made no a priori predictions concerning possible effects of timing of gestation.
Study population. From May 2020 to February 2021, 283 mother-infant dyads were enrolled at delivery as part of a longitudinal multi-centric cohort study in Italy and follow-up at 3 (N=261), 6 (N=220) and 12 (N=91) months of age.
Methods. MPPS was retrospectively assessed at birth through an ad hoc form. Within 24 hours from delivery, mother and infant buccal cells were collected to assess NR3C1 (44 CpG sites) and SLC6A4 (13 CpG sites) methylation status. Infants’ temperament was assessed at 3 and 6 months of age using the Infant Behavior Questionnaire-Revised (IBQ-R), whereas socio-cognitive behaviors were assessed at 12 months through a face-to-face remote observational paradigm.
Results. Greater MPPS was significantly associated with higher infants’ SLC6A4 methylation in seven CpG sites. SLC6A4 methylation at these sites predicted infants’ temperament at 3 months. Greater MPPS was also significantly associated with less-than-optimal socio-cognitive behaviors at 12 months. Explorative analyses also revealed that mothers and infants who were exposed to the lockdown during the first trimester of pregnancy had lower NR3C1 and SLC6A4 methylation when compared to counterparts exposed during the second or third trimesters. Further analyses on infants’ long-term outcomes will be presented. Findings suggest that MPPS might be a risk factor for infant’s development and that methylation of stress-related genes might mediate these effects. These results may inform the development of strategies to promote mothers and infants’ well-being during and after the pandemic.

Authors

• Sarah Nazzari, University of Pavia
  Presenting Author

• Serena Grumi, IRCCS Mondino Foundation

• Roberto Giorda, Scientific Institute IRCCS E. Medea

• Renato Borgatti, University of Pavia

• Livio Provenzi, University of Pavia