PLACENTAL GENE EXPRESSION ASSOCIATED WITH SARS-COV-2 INFECTION AND POSTPARTUM DEPRESSION
Authors: Perez-Rodriguez *M Mercedes , Moore Kendall , Jessel Rebecca , Camacho-Castro Juliana , Smith Emma , Dubois Bethany , Mills Alexandra , Kaplowitz Elianna , Ibroci Erona , Orm Sophie , Graziani Mara , Dekio Fumiko , Brody Rachel , Ma Yula , Gigase Frederieke , Lieb Whitney , Janevic Teresa , Bergink Veerle , De Witte Lotje , Rommel Anna-Sophie , Chen Jia , Lesseur Corina 
Published: February 2025

Background

Recent meta-analyses showed that around 30% of women suffered postpartum depression during the COVID-19 pandemic, a two-fold increase compared to before the pandemic (1,2,3). The immune system plays a key role in responding to infections, and is a potential mechanism in the development of psychiatric disorders. The placenta is a driver of immune changes during pregnancy, modulating the maternal immune response to perinatal infections (4).

Aims & Objectives

To investigate:

1) whether SARS-CoV2 infection during pregnancy is associated with expression of immune and inflammation-related genes in the placenta;

2) whether genes that are differentially expressed in the placenta after gestational SARS-coV-2 infection are in turn associated with postpartum depression.

Method

Placental samples were collected from 141 pregnant women enrolled in Generation C, a CDC- funded cohort study (4/2020-2/2022) at the Mount Sinai Health System, New York City. Gestational SARS-CoV-2 infection was assessed through SARS-CoV-2 antibodies, PCR test results, and electronic medical records (EMR). Edinburgh Postnatal Depression Scale scores (EPDS) at 6-weeks postpartum were extracted from EMR. An EPDS score of 11 is a previously validated cut-off for postpartum depression (5). Placental expression of 347 immune/inflammation related genes from the Molecular Signatures Database (MSigDB) (6) was profiled with RNA-sequencing. First, we conducted differential gene expression analysis by gestational SARS-CoV-2 status using the Limma R package to fit linear regression models adjusted for maternal age, gestational age at delivery, and infant sex. Next, we interrogated the relationship between the differentially-expressed genes from the previous analysis (predictor variable) and EPDS scores around 6 weeks postpartum (continuous outcome variable) with linear regression analysis adjusted for gestational age, Distressed Communities Index scores (a measure of economic wellbeing of communities) based on participant zip code, lifetime history of anxiety/depression, pre- pregnancy BMI, and timing of EPDS assessment.

Results

10 (7%) participants had an EPDS score of 11 or higher. 24 (17%) participants had gestational SARS-CoV-2 infection. In the placenta, gestational SARS- CoV-2 infection was associated with downregulated expression of PTGER2 (logFC=-0.50, adjusted p=0.022) and of 37 additional genes (p&lt;0.05). Linear regression analysis of these 38 genes to examine the effect of placental immune gene expression on maternal EPDS scores at 6-weeks postpartum revealed 4 genes (FZD5, CXCR6, BANK1, MET) negatively associated (p&lt;0.05)

Discussion And Conclusions

Gestational SARS-CoV-2 infection was linked to placental down regulation of four genes (FZD5, CXCR6, BANK1, MET), whose expression was in turn inversely associated with EPDS scores (i.e., lower expression associated with higher postpartum depression scores). SARS-CoV-2 infection has been previously associated with lower expression of CXCR6 in lung tissue (7), and lower expression of MET has been linked to depression (8).We also found that gestational SARS-CoV-2 infection may impact placental function, such as expression of PTGER2, the gene encoding the receptor for prostaglandin E2.While these preliminary results are limited by sample size, the results suggest the need for further exploration of these immune-related genes and their potential role in postpartum depression.

References

1.W.H.O. Maternal mental health 2020. Available from: https://www.who.int/mental_health/maternal- child/maternal_mental_health/en/.

2.Chen Q, Li W, Xiong J, Zheng X. Prevalence and Risk Factors Associated with Postpartum Depression during the COVID-19 Pandemic: A Literature Review and Meta-Analysis. Int J Environ Res Public Health. 2022;19(4). Epub 2022/02/26. doi: 10.3390/ijerph19042219. PubMed PMID: 35206407; PMCID: PMC8872263.

3.Safi-Keykaleh M, Aliakbari F, Safarpour H, Safari M, Tahernejad A, Sheikhbardsiri H, Sahebi A. Prevalence of postpartum depression in women amid the COVID-19 pandemic: A systematic review and meta-analysis. Int J Gynaecol Obstet. 2022;157(2):240-7. Epub 2022/02/06. doi: 10.1002/ijgo.14129. PubMed PMID: 35122433; PMCID: PMC9087783.

4.Svensson-Arvelund, J., Ernerudh, J., Buse, E., Cline, J. M., Haeger, J. D., Dixon, D., Markert, U. R., Pfarrer, C., De Vos, P., &Faas, M. M. (2014). The placenta in toxicology. Part II: Systemic and local immune adaptations in pregnancy. Toxicologic pathology, 42(2), 327–338. https://doi.org/10.1177/0192623313482205

5.Levis, B., Negeri, Z., Sun, Y., Benedetti, A., Thombs, B. D., &DEPRESsion Screening Data (DEPRESSD) EPDS Group (2020). Accuracy of the Edinburgh Postnatal Depression Scale (EPDS) for screening to detect major depression among pregnant and postpartum women: systematic review and meta-analysis of individual participant data. BMJ (Clinical research ed.), 371, m4022. https://doi.org/10.1136/bmj.m4022

6.Liberzon, A., et al., The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst, 2015. 1(6): p. 417-425.

7.Dai, Yulin et al. “Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation.” Human genetics vol. 140,9 (2021): 1313-1328. doi:10.1007/s00439-021- 02305-z

8.Ciuculete, Diana M et al. “Longitudinal DNA methylation changes at MET may alter HGF/c-MET signalling in adolescents at risk for depression.” Epigenetics vol. 15,6-7 (2020): 646-663. doi:10.1080/15592294.2019.1700628