The impact of SARS-CoV-2 infection at different stages of pregnancy on placental inflammatory responses

doi:10.21203/rs.3.rs-5278771/v1

Background

The specific impact and pathology of SARS-CoV-2 infection on maternal and fetal health have not been comprehensively investigated. Therefore, we investigated the inflammatory response of fetal tissues in pregnant women infected with SARS-CoV-2 at different stages of pregnancy.

Methods

We collected placenta samples from 52 patients at Tai’an Central Hospital, who underwent delivery between November 2022 and September 2024. We analyzed general patient data and maternal-fetal outcomes and conducted histological observations using HE staining. Furthermore, we used ELISA to quantitatively analyze the concentration of IL-6 in umbilical cord blood and amniotic fluid. Additionally, Western blot analysis was conducted to evaluate the expression levels of TNF-α and IL-1β in the placental tissues.

Results

Among participants, 33 pregnant women were diagnosed with SARS-CoV-2 infection. Patients infected SARS-CoV-2 during mid-pregnancy developed thrombosis, stromal protein deposition, and villous interstitial inflammation compared to the control group (P < 0.05). However, No significant placental pathology differences were found between late-term stages with the control group (P > 0.05). Western blot analysis revealed elevated TNF-α and IL-1β levels in infected placental tissues, with no significant difference between mid-term and late-term pregnancies. IL-6 levels in amniotic fluid showed no significant difference, and IL-6 expression was not detected in umbilical cord blood.

Conclusion

SARS-CoV-2 infection during pregnancy appears to have limited impact on overall maternal and fetal outcomes. However, the infection may lead to inflammatory changes in placental tissues, particularly during the mid-trimester. These findings suggest the importance of careful monitoring and management of SARS-CoV-2 infection in pregnant women. Nonetheless, larger studies are necessary to confirm these observations and explore the long-term effects on both maternal and fetal health.

SARS-CoV-2

Pregnancy

Inflammatory reaction

Maternal-fetal outcomes

On March 11, 2020, the World Health Organization (WHO) officially declared coronavirus disease 2019 (COVID-19), caused by the novel coronavirus SARS-CoV-2, as a global pandemic [1, 2]. SARS-CoV-2 is an enveloped RNA virus containing a nucleocapsid protein, primarily transmitted through respiratory droplets and close contact, and is known for its high infectivity. Pregnant women are particularly vulnerable to SARS-CoV-2 infection due to physiological changes during pregnancy [3]. To meet the elevated metabolic demands for fetal development, pregnant women experience a significant increase in oxidative stress. Additionally, the altered physiological and immunosuppressive states during pregnancy may cause the clinical outcomes of SARS-CoV-2 infection in pregnant women to differ from those in the general population. Consequently, the diagnosis and management of SARS-CoV-2 infection during pregnancy may pose heightened health risks to both the mother and fetus [4–6].

The long-term effects of COVID-19, referred to as "post-acute sequelae of SARS-CoV-2 infection" (PASC), can result in prolonged symptoms such as weakness and multi-organ system involvement [7, 8]. Emerging research suggests that SARS-CoV-2 may affect the reproductive system, potentially leading to decreased ovarian reserve and endocrine dysfunctions in affected patients, which could impair ovarian hormone production and uterine response [8–10]. Additionally, infants born to women infected with COVID-19 during pregnancy may be at higher risk for neurodevelopmental disorders in their first year of life, although the exact mechanisms and extent of these impacts require further investigation [11, 12]. Understanding how SARS-CoV-2 infection at different stages of pregnancy influences maternal and fetal health, along with the long-term effects of infection, is crucial for guiding the postnatal care of newborns after maternal infection [12].

This study examines the clinical outcomes of pregnant women recovering from SARS-CoV-2 infection and their maternal-fetal health outcomes. Histopathological changes in the placenta were analyzed using H&E staining. Western blotting was employed to assess the expression levels of TNF-α and IL-1β in placental tissues, while ELISA was used to measure IL-6 levels in umbilical cord blood and amniotic fluid. Investigating the immune response of the placenta to SARS-CoV-2 infection will provide important reference for developing strategies to mitigate adverse outcomes in pregnancies affected by SARS-CoV-2 infection [13].

Participants

We admitted 52 pregnant women from the Obstetrics Department of Tai'an Central Hospital as the study population from November 2022 to September 2024. All pregnant women were singleton, and relevant examinations excluded primary diseases and other diseases. The patient group with infections totaled 33 cases, divided based on SARS-CoV-2 infection status and timing into mid-pregnancy group (13th to 28th week of pregnancy, n=14) and late-pregnancy infection group (29th week of pregnancy to delivery, n=19). There were 19 cases in the non-infection group, serving as the control group. According to the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial version 6)”, all patients were categorized as ordinary cases. All the selected pregnant women gave informed consent and signed the consent form. There were no statistical differences in age and the time of pregnancy among the groups of pregnant women (P > 0.05) (Table 1).

Table 1 Participant characteristics

	Control N=19	Mid-pregnancy infection N=14	Late-pregnancy infection N=19	P value
Age (years) Mean (SD)	29.11 (4.33)	28.43 (3.57)	30.95 (4.99)	>0.05
The time of pregnancy Mean (SD)	1.62 (1.04)	2.0 (1.52)	2.26 (1.10)	>0.05
Vaccination (n, %)	19 (100.0)	14 (100.0)	18 (94.74)	1.0

Abbreviations: N, number of participants with available data; SD, standard deviation.

Instruments and reagents

Anti-TNF-α antibody, recombinant rabbit monoclonal antibody against IL-1β, horseradish peroxidase-conjugated sheep anti-rabbit secondary antibody, and β-Actin antibody were purchased from Beijing Boaosen Biotechnology Co., LTD. Pre-stained protein markers and pre-mixed glue kits were purchased from Shanghai Biyantian Biotechnology Co., LTD. RIPA tissue lysate and protein loading buffer were purchased from Beijing Pulley Gene Technology Co., LTD. The human IL-6 ELISA test kit was purchased from Wuhan Doctor De Bioengineering Co., LTD. CKX53 inverted phase contrast microscope (OLYMPUS), microplate reader (Thermo Fisher Scientific).

Pathological

The placenta tissues of pregnant women were collected after infection in pregnancy, washed with sterile saline, and fixed in 4% paraformaldehyde for 48 hours. The slides were routinely embedded in paraffin and HE stained, and each slide was 4 μm thick. All HE-stained slides were observed and reviewed by an attending physician and an associate chief physician.

IL-6 levels in cord blood serum and amniotic fluid

Before the rupture of membranes, amniotic fluid was extracted with a syringe and centrifuged at 3000 r/min for 15 min. After separation, the supernatant was collected in EP tubes and stored in a freezer at -80℃. At delivery, 5 mL of umbilical cord blood was collected into blood collection tubes and centrifuged at 3000 r/min for 15 min. Serum was divided into 300 μL frozen tubes and stored in the refrigerator at -80 ℃. According to the kit instructions, perform the assay and calculate the corresponding concentration based on the standard curve according to the OD value of the sample.

TNF-α and IL-1β levels in the placenta

We collected two pieces of placental tissue (excluding decidua and amnion) in sterile conditions immediately after delivery. After cleaning with sterile saline, the placenta tissue was quickly frozen in a -180℃ liquid nitrogen tank and then transferred to the -80℃ refrigerator for storage. Added RIPA lysate and ground the tissues at low temperatures. The grinding solution was centrifuged at 12000 r/min for 20 min, the supernatant was collected, and the protein concentration was determined using the BCA method. Prepared a 12% separation gel and concentration gel, loaded 200 μg protein; the electrophoresis conditions were set to 80 V and 120 V. Membrane transfer was performed at 200 mA for 30 minutes. Blocking was done at room temperature for 1 h in blocking solution, followed by incubation with primary antibody (TNF-α antibody 1∶500 dilution, IL-1β antibody 1∶2000 dilution), overninght at 4℃ overnight, and then washed with TBST. The membrane was then incubated with secondary antibodies (diluted 1∶2000) for 2 hours at room temperature before being washed with TBST. Protein expression was calculated based on the gray value of the bands.

Statistical analysis

Image J was used to quantify the grayscale values in the analysis of Western blot bands. For sample data analysis, one-way ANOVA was conducted using SPSS 22.0. Statistical plotting was performed with Graph Pad Prism 8, and the data results are presented as mean ± standard deviation (SD), considering a P<0.05 as statistically significant. Categorical data were reported in actual values or percentages, and intergroup differences (control group, mid-pregnancy infection group, late-pregnancy infection group) were analyzed using parametric and non-parametric descriptive statistics. The means were compared using the t-test, while the Wilcoxon rank-sum test was used for median comparison and the chi-square test for categorical variables. Fisher's exact test was applied for any variable with ≤ 5 cases. P-values were not adjusted for multiple comparisons.

Maternal and Fetal Outcomes

Among the 33 pregnant women infected with SARS-CoV-2, in the mid-pregnancy infection group, 1 patient had pregnancy complicated with hypothyroidism (1/14, 7.14%), 1 patient had pregnancy complicated with hyperthyroidism (1/14, 7.14%), 1 patient had gestational diabetes (1/14, 7.14%), and 1 patient had gestational hypertension (1/14, 7.14%). In the late-pregnancy infection group, 1 patient had pregnancy complicated with hypothyroidism (1/19, 7.14%), 1 patient had pregnancy complicated with hyperthyroidism (1/19, 7.14%), 5 patients had gestational diabetes (5/19, 26.32%), and 1 patient had gestational hypertension (1/19, 7.14%). Among the 19 pregnant women in the control group, 2 patient had pregnancy complicated with hypothyroidism (2/14, 10.53%), 1 patient had pregnancy complicated with hyperthyroidism (1/14, 5.26%), 1 patient had pregnancy complicated with arrhythmia (1/14, 5.26%), 4 patient had gestational diabetes (4/14, 21.05%). There was no statistically significant difference in complications between the infection group and the control group (P>0.05) (Table 2).

Among the 52 newborns, there were no significant differences in birth weight and Apgar scores (P>0.05) (Table 3). Among the 33 newborns in the infection group, 2 newborns born after mid-pregnancy infection had preterm birth with low birth weight (2/14, 14.29%), 3 had premature rupture of membranes (PROM) (3/14, 21.43%), 1 had amniotic fluid contamination (1/14, 7.14%), and 1 had intrauterine distress (1/14, 7.14%). Among the newborns born after late-pregnancy infection, 2 had amniotic fluid contamination (2/19, 10.53%). In the control group, 2 newborns had PROM (2/19, 10.53%). There was no significant difference in complications among newborns between the infection group and the control group (P>0.05) (Table 3).

Table 2 Comparison of general data of maternal

	Control N=19	Mid-pregnancy infection N=14	Late-pregnancy infection N=19	P value
Hypothyroidism during pregnancy (n, %)	2 (10.53%)	1 (7.14%)	1 (5.26%)	1.0
Hyperthyroidism during pregnancy (n, %)	1 (5.26%)	1 (7.14%)	1 (5.26%)	1.0
Arrhythmia during pregnancy (n, %)	1 (5.26%)	0 (0.00%)	0 (0.00%)	1.0
Gestational diabetes (n, %)	4 (21.05%)	1 (7.14%)	5 (26.32%)	0.376
Gestational hypertension (n, %)	0 (0.00%)	1 (7.14%)	1 (5.26%)	0.728

Abbreviations: N, number of participants with available data.

Table 3 Comparison of fetal outcomes

	Control N=19	Mid-pregnancy infection N=14	Late-pregnancy infection N=19	P value
neonatal birth weight (kg) Mean (SD)	3.43 (0.52)	3.17 (0.69)	3.35 (0.37)	>0.05
Apgar scores Mean (SD)	9.89 (0.46)	9.86 (0.53)	10 (0)	>0.05
Premature birth (n, %)	0 (0.00%)	2 (14.29%)	0 (0.00%)	0.069
PROM (n, %)	2 (10.53%)	3 (21.43%)	0 (0.00%)	0.114
Meconium-stained amniotic fluid (n, %)	0 (0.00%)	1 (7.14%)	2 (10.53%)	0.477
Fetal distress (n, %)	0 (0.00%)	1 (7.14%)	0 (0.00%)	0.269
Low birth weight infant (n, %)	0 (0.00%)	2 (14.29%)	0 (0.00%)	0.069
Neonatal asphyxia (n, %)	0 (0.00%)	0 (0.00%)	0 (0.00%)	>0.05
Neonate transferred to NICU (n, %)	0 (0.00%)	0 (0.00%)	0 (0.00%)	>0.05

Abbreviations: N, number of participants with available data; SD, standard deviation.

Pathological outcomes

In a comparison between 33 cases in the infection group and 19 in the control group, as shown in Table 4, 1 out of 33 patients in the infection group exhibited villous edema, with 1 case occurring in mid-pregnancy. This was not significantly different from the control group (0/19, P=0.269). Thrombosis and interstitial fibrin deposition were observed in 3 out of 33 patients during mid-pregnancy, showing significant difference compared to the control group (0/19, P=0.016). Villous angioma was found in 3 out of 33 patients, with 1 in mid-pregnancy and 2 in late pregnancy, not significantly different from the control group (1/19, P=1.0). Villous space inflammation was present in 3 out of 33 patients during mid-pregnancy, with significant difference compared to the control group (0/19, P=0.016). One out of 33 patients had chorioamnionitis in mid-pregnancy, not significantly different from the control group (0/19, P=0.269). Decidual vasculopathy was observed in 2 out of 33 patients, one in mid-pregnancy and one in late pregnancy, with no significant difference compared to the control group (1/19, P=1.0). Accelerated villous maturity was noted in 1 out of 33 patients during mid-pregnancy, not significantly different from the control group (0/19, P=0.269). Infarction was present in 2 out of 33 patients, one in mid-pregnancy and one in late pregnancy, with no significant difference compared to the control group (2/19, P=1.0). Meconium staining was observed in 2 out of 33 patients, both in mid-pregnancy, not significantly different from the control group (0/19, P=0.069).

Table 4 Results of placental pathology

Features	Control N=19	Mid-pregnancy infection N=14	Late-pregnancy infection N=19	P value
Villous edema (n, %)	0 (0.00%)	1 (7.14%)	0 (0.00%)	0.269
Thrombosis and interstitial fibrin deposition (n, %)	0 (0.00%)	3 (14.29%)	0 (0.00%)	0.016
Villous angioma (n, %)	1 (5.26%)	1 (7.14%)	2 (10.53%)	1.0
Villous space inflammation (n, %)	0 (0.00%)	3 (14.29%)	0 (0.00%)	0.016
Chorioamnionitis (n, %)	0 (0.00%)	1 (7.14%)	0 (0.00%)	0.269
Decidual vasculopathy (n, %)	1 (5.26%)	1 (7.14%)	1 (5.26%)	1.0
Accelerated villous maturity (n, %)	0 (0.00%)	1 (7.14%)	0 (0.00%)	0.269
Infarction (n, %)	2 (10.53%)	1 (7.14%)	1 (5.26%)	1.0
Infarction (n, %)	0 (0.00%)	2 (14.29%)	0 (0.00%)	0.069

Abbreviations: N, number of participants with available data.

IL-6 content in umbilical cord blood and amniotic fluid

As shown in Table 5, the levels of IL-6 in the amniotic fluid were 248.33 ± 109.11 pg/ml and 260.45 ± 78.48 pg/ml in the mid-pregnancy and late-pregnancy infection groups, respectively, compared to 262.72 ± 148.83 pg/ml in the control group. As illustrated in Figure 1, there were no significant differences in the IL-6 levels between the infection and control groups (P>0.05), nor were there significant differences between the infection groups themselves (P>0.05). IL-6 was not detected in either the infection or control groups in the umbilical cord blood.

Table 5 IL-6 content the amniotic fluid (pg/ml, ±SD)

Group	Cases	IL-6
Control	4	262.72 ± 148.83
Mid-pregnancy infection	3	248.33 ± 109.11
Late-pregnancy infection	3	260.45 ± 78.48
P value		＞0.05

Fig.1 IL-6 Levels in Amniotic Fluid. The IL-6 content in the amniotic fluid showed no significant differences between the infection and control groups (P>0.05). Additionally, there were no significant differences between the different infection groups themselves (P>0.05). Notably, IL-6 was undetectable in the umbilical cord blood for both the infection and control groups.

TNF-α and IL-1β protein expression in placental tissue

Western blot was used to analyze the protein expression levels of TNF-α and IL-1β in placental tissues. Compared to the control group, the levels of TNF-α and IL-1β were significantly lower in the infection group (P<0.05). There was no statistically significant difference between the mid-pregnancy and late-pregnancy infection groups (P>0.05) (Figure 2).

Fig.2 Protein Expression Levels of TNF-α and IL-1β in Placental Tissues. Western blot analysis of placental tissues showed that the protein expression levels of TNF-α and IL-1β were significantly lower in the infection group compared to the control group (P<0.05). No statistically significant differences were observed between the mid-pregnancy and late-pregnancy infection groups (P>0.05).

This study focuses on the inflammatory response of fetal-related tissues after SARS-CoV-2 infection and explores the impact of SARS-CoV-2 infection at different stages of pregnancy on maternal and fetal outcomes. This study analyzes general patient data and maternal-fetal outcomes, and investigates the pathological changes in placental tissue of pregnant women infected with SARS-CoV-2 during pregnancy, and examines the expression levels of related inflammatory factors. The aim is to provide new insights for the prevention and management of viral infections during pregnancy.

SARS-CoV-2 is a pathogenic coronavirus that can affect multiple organs and systems, primarily targeting the respiratory system and causing symptoms ranging from the common cold to severe respiratory distress [7,14–16]. Pregnancy is a physiological state that significantly impacts a woman's body-the immune system changes during pregnancy to tolerate the fetus [17]. Although more studies have assessed the clinical outcomes of pregnant women diagnosed with COVID-19 and their infants, the causes of adverse outcomes remain unclear [18]. In addition to the virus's direct cytopathic effects, virus-mediated hyperinflammatory responses in the human body can cause tissue damage, forming a ''cytokine storm'' [19–22].

The results indicate that in mid and late pregnancy the placental tissue showed characteristics such as villous edema, thrombosis and interstitial fibrin deposition, villous angiomas, villitis, chorioamnionitis, decidual vasculopathy, accelerated villous maturity, infarction, and meconium staining. Compared to normal placentae, SARS-CoV-2 infection in the placenta was associated with a higher incidence of decidual arteriopathy and other maternal malperfusion patterns, suggesting that infection could lead to placental inflammation and changes, resulting in long-term multisystem deficits in exposed infants [4,23]. Infection may lead to placental inflammation and changes in coagulation mechanisms, potentially causing long-term multisystem defects in exposed infants. The placenta plays a critical role in immunoregulation during pregnancy, and when this regulation is abnormal, it may trigger local inflammatory responses, leading to inflammation in the villous space and immune-mediated thrombus formation. Moreover, the placental microenvironment may enhance inflammation by regulating the activity of immune cells like macrophages and lymphocytes. At the same time, maternal coagulation changes during pregnancy can cause thrombus formation, affecting placental blood flow and the function of exchanging nutrients and oxygen. Small injuries to the placenta can trigger a repair response, which may result in stromal protein deposition. The stromal protein deposition is part of the placenta’s attempt to repair damaged tissue, but excessive deposition may compromise its function. Protein deposition is often associated with chronic inflammatory processes, which may damage the placental vascular network, impairing blood flow and affecting fetal development. Placental thrombosis, stromal protein deposition, and villous space inflammation result from the interplay of various factors. These phenomena reflect the complex interactions between the maternal and placental systems, potentially involving immune responses, coagulation abnormalities, and other mechanisms. These pathological changes are also associated with certain pregnancy complications and require further examination to identify the exact causes for appropriate treatment or prevention.

Western blot results showed significantly increased levels of the inflammatory markers TNF-α and IL-1β in the placental tissues of the infection group, which could be associated with the activation of the maternal immune system [24]. As critical inflammatory mediators, TNF-α and IL-1β indicate that viral infection may trigger an inflammatory response in placental tissues [25,26]. This inflammatory state may negatively impact the structure and function of the placenta, causing placental dysfunction and thereby affecting fetal growth and development [23]. Maternal SARS-CoV-2 infection may drive the immune activation of the mother, placenta, and fetus, potentially adversely affecting fetal neural development[9]. Although most existing data concern late pregnancy infections or active infections at the time of delivery, the impact of early pregnancy infections on offspring outcomes is crucial for a comprehensive understanding of the risks.

Immune activation not only affects fully differentiated cells but can also impact progenitor cells derived from the yolk sac, suggesting that early damage (for example, during early pregnancy) may still affect brain development through microglial progenitor cells [27–29]. The timing of infection, viral strains, fetal sex, other prenatal exposures (such as maternal cardiometabolic diseases, substance use, stress, environmental or drug exposures, other infections during pregnancy), and perinatal/postnatal exposures (such as subsequent SARS-CoV-2 infections in infants or children, breastfeeding status) have a critical impact on offspring neural development and are essential for comprehensively understanding the potential lasting effects of the COVID-19 pandemic on future generations [30].

Viral infections during pregnancy can induce the host to produce inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which not only activate the maternal immune system but can also cross the placental barrier [18,19]. As the placenta is located at the maternal-fetal interface, it not only plays a crucial role in protecting the fetus from infections but can also be influenced by adverse maternal environmental conditions. Infectious agents can cross the placenta, leading to fetal anomalies (e.g., microcephaly caused by Zika virus infection [31–34]); the placenta plays a vital role in maintaining fetal immune tolerance and forms a resistant barrier against pathogen entry. When the placental barrier is breached by infection, the risk of adverse outcomes for the fetus/newborn is high. Alternatively, infectious factors can directly cause placental damage (e.g., villitis caused by cytomegalovirus [35]), leading to fetal growth restriction or death. In both scenarios, it is necessary to collect samples such as villi, decidua, placenta, amniotic fluid, and umbilical cord blood from patients at different stages of pregnancy post-COVID-19 infection to investigate their inflammatory responses and determine the mechanistic links between maternal infection and fetal outcomes.

In summary, the pregnant patients in our study remained relatively stable post-infection, with no severe cases. The pregnancy outcomes were good for patients in mid to late pregnancy, with no severe neonatal complications. This study is significant for understanding the impact of viral infection on the health of pregnant women and fetuses, offering valuable insights for improving prevention and treatment strategies for infection-related pregnancy complications. During this infection period, the incidence of severe complications has significantly decreased, and most patients can recover on their own. Considering the safety of medication during pregnancy, for most mild cases, treatment mainly focuses on symptomatic observation to reduce potential side effects of drugs on the fetus. Future research could further explore the molecular mechanisms of placental inflammatory responses caused by viral infection and prevention and treatment strategies to ensure the health of pregnant women and fetuses to the greatest extent. While our study provides critical insights, it also has limitations, including relatively small sample size and the possibility that variations in viral subtypes may affect the consistency of results. Future research needs to address these limitations with larger samples and more in-depth exploration. Further investigations could explore the molecular mechanisms of the inflammatory responses induced by COVID-19 infection during pregnancy and how these inflammatory factors impact placental function and fetal development. Additionally, broader population-based studies and long-term follow-ups will help to understand maternal-fetal outcomes more comprehensively.

WHO	World Health Organization
COVID-19	Coronavirus disease 2019
SARS-CoV-2	Syndrome coronavirus 2
NBW	Neonatal birth weight
PROM	Premature rupture of membranes

Acknowledgements

The authors thank all the trial participants for making this work possible.

Author Contributions

MY, LP, CZ, XZ, MH, YW, YH, ZG, HL and LZ acquired the data and contributed to the revision of the final manuscript. Authors HL and LZ designed the study. MY and LP performed the analysis and wrote the first draft of the manuscript. CZ, XZ, MH, YW, YH, ZG interpreted the data. All authors contributed to the intellectual content of the manuscript and approved the manuscript version submitted for publication.

Funding

There are none funding during the submission process.

Ethics approval and consent to participate

The study was approved by the the Ethics Committee of the Affiliated Taian City Central Hospital of Qingdao University (accession number MR-37-23-050564) and is in compliance with the principles of the Declaration of Helsinki. Informed consent was obtained from every participant.

Consent for publication

Consent for publication was obtained from every participant included in the study.

Competing interests

The authors declare that they have no competing interests.

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No competing interests reported.

supplementaryfile.docx

The impact of SARS-CoV-2 infection at different stages of pregnancy on placental inflammatory responses

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Abstract

Background

Methods

Results

Conclusion

Figures

Background

Methods

Results

Discussion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1