Measuring Outcomes of Maternal COVID-19-related Prenatal Exposure

Study Overview
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Brief Summary
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The rapidly spreading coronavirus Covid-19 pandemic is a major concern worldwide and Italy is at the forefront of this emergency. At the present moment, the effects on the offspring of Covid-19 disease in pregnant women and/or the indirect effect of COVID-19-related prenatal maternal stress are poorly understood. Epigenetic mechanisms - and especially DNA methylation - are involved in the embedding of prenatal exposures to large-scale disasters into the epigenome and phenotypic outcomes of the offspring. Specific target genes include SLC6A4, NR3C1, OXTR, BDNF, and FKBP5. The central hypothesis of this project is that the exposure to the COVID-19-related prenatal maternal stress may affect infants' outcomes from birth to 12 months partially through increased methylation of target genes involved in stress regulation. The main goal is to investigate the association between Covid-19 disease in pregnancy or COVID-19-related PMS in women pregnant during the first 9 months of the year 2020 and the emotional, social, and cognitive developmental outcomes in their infants from birth to 12 months. Additionally, the role of target genes methylation in mediating this association will be investigated. Mothers and their infants will be enrolled from the delivery units of eleven neonatal facilities located in Northern Italy's COVID-19 contagion hotspot. One group will be enrolled from April to October 2020 (COVID-Exposure Pregnancy, CEP), a second group will be enrolled from April to October 2021 (Non-Exposure Pregnancy, NEP). Moreover, the CEP group will include mothers positive or exposed to COVID-19-related MPS during different trimesters of pregnancy, allowing within-group comparisons on developmentally sensitive time windows. Within 48 hours from baby delivery, saliva samples will be obtained from CEP and NEP newborns, immediately stored at -20°C and analyzed for epigenetic analyses using Next-Generation Sequencing. At 3 and 6 months, mothers will be asked to fill-in validated and reliable questionnaires on the emotional and social-behavioral development of their infants. At 12 months, infants' stress regulation and maternal sensitivity will be evaluated through video recording of mother-infant interactions. This study will provide unprecedented relevant insights on the biochemical mechanisms underlying the impact of Covid-19 disease and the related PMS on human offspring's developmental outcomes.

Official Title
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Measuring Outcomes of Maternal COVID-19-related Prenatal Exposure

Conditions
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Prenatal Stress

Intervention / Treatment
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* Other: Maternal stress


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Italian nationality or full mastery of Italian language to access on-line questionnaires without support No prenatal pathologies or perinatal risks Maternal age higher than 18 years Newborns' gestational age equal or higher than 37 weeks Exclusion Criteria: Single-parent mothers Medically assisted conception Infants' genetic or metabolic comorbidities Perinatal injuries or sensorial deficits

Ages Eligible for Study
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Minimum Age: 0 Months
Maximum Age: 12 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| COVID-19 Exposed Pregnancy (CEP)<br>Women who were pregnant and delivered during the outbreak of COVID-19 pandemic in Italy, and their infants. | Other: Maternal stress<br>* Prenatal COVID-19-related stress retrospectively self-reported by mothers after delivery.<br>|
| Non-Exposed Pregnancy (NEP)<br>Women who were pregnant and delivered during an anticipated COVID-19 free period in Italy, and their infants. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infant negative emotionality | Measure of infant Negative Emotionality through the Infant Behavior Questionnaire - Revised questionnaire. Negative Emotionality mean score ranges from 1 to 7 and higher scores reflect higher negative emotionality. | At 12 months of infants' age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infants' target gene methylation status | Methylation status of the following target genes: BDNF, FKBP5, NR3C1, OXTR, SLC6A4 | At birth | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Epigenetics, Prenatal stress, Stress regulation, Maternal sensitivity, Pandemics, Serotonin transporter, Glucocorticoid receptor, Oxytocin receptor, Brain-derived neutropic factor