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Advances in Adverse Pregnancy Outcomes
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Advances in Adverse Pregnancy Outcomes

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Developmental and Reproductive Biology".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 30520

Special Issue Editors

Dr. Shibin Cheng

E-Mail Website
Guest Editor
Department of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI 02905, USA
Interests: preeclampsia; inflammation; oxidative stress; ER stress, autophagy-lysosomal machinery; mitochondria; cell death; protein aggregation; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Aihua Liao

E-Mail Website
Guest Editor
Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Interests: immunological, metabolic-immunological and epigenetic-immunological pathogenesis of pregnancy-related diseases (e.g. pre-eclampsia, recurrent miscarriage, repeated implantation failure); immune-privilege mechanism of testis
Dr. Atsushi Fukui

E-Mail Website
Guest Editor
Hyogo College of Medicine, Nishinomiya 663-8501, Japan
Interests: infertility; endometrium; recurrent pregnancy loss (RPL); natural cytotoxicity receptor (NCR); pregnancy diabetes; seminal plasma; reproductive immunity; in vitro fertilization and embryo transfer

Special Issue Information

Dear Colleagues,  

Pregnancy demands increased maternal metabolic and physiological activities to support fetal development. Pregnancy has been recognized as a physiological stress condition and a window to maternal and fetal future health. During pregnancy, pathological factors such as genetics, environmental exposures, chronic hypoxia/ischemia, pathogen infection, and inflammation may negatively affect implantation, placentation, vascular remodeling, and maternal immune tolerance at the maternal–fetal interface, leading to the occurrence of adverse pregnancy outcomes, including abortion, fetal growth restriction, preterm birth, pregnancy hypertension, preeclampsia, and gestational diabetes mellitus. The incidence of adverse pregnancy outcomes is steadily rising globally, contributing to the major causes of maternal and fetal morbidity and mortality. Accumulating studies have strongly suggested that pregnancy complicated by pre-eclampsia, preterm birth, and diabetes entail long-term consequences for mothers and their offspring later in life. Women with a history of these conditions and their offspring are at a high risk of developing chronic diseases, including cardiovascular disease, neurodegenerative diseases, type 2 diabetes, autism, and renal diseases. Adverse pregnancy outcomes have become a heavy financial and emotional burden on caregivers and families. The underlying mechanisms of these devastating conditions remain poorly understood, and prediction and efficacious treatment are still lacking. However, our understanding of the pathophysiological paradigms that are implicated in adverse pregnancy outcomes has increased greatly over recent decades. While these conditions have distinct molecular mechanisms, they share pathophysiological similarities in areas such as inflammation, endoplasmic reticulum stress, oxidative stress, cell death, and dysregulated maternal–fetal interaction.

This Special Issue focuses on all aspects of adverse pregnancy complications, reproductive immunology, and diseases in women with a history of these conditions and their children. We invite basic and clinical investigators to submit high-quality research and review articles that will stimulate the continuing efforts to understand the molecular mechanisms of adverse pregnancy outcomes, develop the strategies for treating these conditions, identify predictive biomarkers, and generate animal models using contemporary cutting-edge approaches.

Dr. Shibin Cheng
Prof. Dr. Aihua Liao
Dr. Atsushi Fukui
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biology is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • preeclampsia
  • preterm birth
  • gestational diabetes mellitus
  • abortion
  • placenta
  • spiral artery remodeling
  • hypoxia
  • inflammation
  • autophagy–lysosome
  • endoplasmic reticulum stress
  • oxidative stress
  • mitochondria
  • protein aggregation
  • trophoblast
  • angiogenic factors
  • maternal–fetal immune tolerance
  • predisposition

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Published Papers (9 papers)

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Research

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13 pages, 5624 KiB  
Article
Gestational Age-Dependent Regulation of Transthyretin in Mice during Pregnancy
by Shibin Cheng, Zheping Huang, Akitoshi Nakashima and Surendra Sharma
Biology 2023, 12(8), 1048; https://doi.org/10.3390/biology12081048 - 26 Jul 2023
Cited by 1 | Viewed by 1302
Abstract
Our prior studies have shown that protein misfolding and aggregation in the placenta are linked to the development of preeclampsia, a severe pregnancy complication. We identified transthyretin (TTR) as a key component of the aggregated protein complex. However, the regulation of native TTR [...] Read more.
Our prior studies have shown that protein misfolding and aggregation in the placenta are linked to the development of preeclampsia, a severe pregnancy complication. We identified transthyretin (TTR) as a key component of the aggregated protein complex. However, the regulation of native TTR in normal pregnancy remains unclear. In this study, we found that pregnant mice exhibited a remarkable and progressive decline in serum TTR levels through gestational day (gd) 12–14, followed by an increase in late pregnancy and postpartum. Meanwhile, serum albumin levels showed a modest but statistically significant increase throughout gestation. TTR protein and mRNA levels in the liver, a primary source of circulating TTR, mirrored the changes observed in serum TTR levels during gestation. Intriguingly, a similar pattern of TTR alteration was also observed in the serum of pregnant women and pregnant interleukin-10-knockout (IL-10−/−) mice with high inflammation background. In non-pregnant IL-10−/− mice, serum TTR levels were significantly lower than those in age-matched wild-type mice. Administration of IL-10 to non-pregnant IL-10−/− mice restored their serum TTR levels. Notably, dysregulation of TTR resulted in fewer implantation units, lower fetal weight, and smaller litter sizes in human TTR-overexpressing transgenic mice. Thus, TTR may play a pivotal role as a crucial regulator in normal pregnancy, and inflammation during pregnancy may contribute to the downregulation of serum TTR presence. Full article
(This article belongs to the Special Issue Advances in Adverse Pregnancy Outcomes)
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17 pages, 7328 KiB  
Article
TMBIM4 Deficiency Facilitates NLRP3 Inflammasome Activation-Induced Pyroptosis of Trophoblasts: A Potential Pathogenesis of Preeclampsia
by Yuanyao Chen, Lin Xiao, Guoqiang Sun, Min Li, Hailan Yang, Zhangyin Ming, Kai Zhao, Xuejun Shang, Huiping Zhang and Chunyan Liu
Biology 2023, 12(2), 208; https://doi.org/10.3390/biology12020208 - 29 Jan 2023
Cited by 4 | Viewed by 2490
Abstract
Impaired invasion of EVTs results in inadequate remodelling of arteries and poor placentation, leading to PE. TMBIM4 was found to promote the migration and invasion of human osteosarcoma U2-OS and breast cancer MCF7 cell lines. However, the effect of TMBIM4 on trophoblast biological [...] Read more.
Impaired invasion of EVTs results in inadequate remodelling of arteries and poor placentation, leading to PE. TMBIM4 was found to promote the migration and invasion of human osteosarcoma U2-OS and breast cancer MCF7 cell lines. However, the effect of TMBIM4 on trophoblast biological behaviour and its relevance to PE pathophysiology remain unclear. In this study, we confirmed that TMBIM4 was highly expressed in cytotrophoblasts, syncytiotrophoblasts, and EVTs of the human placenta during early pregnancy. By comparing the expression levels of TMBIM4 in the placenta of women with normal-term pregnancy and PE, TMBIM4 was found to be significantly decreased in PE. Thereafter, we determined the expression of TMBIM4 in the LPS-treated first-trimester human trophoblast cell line HTR-8/SVneo (mimicking a PE-like cell model), and determined the effect of TMBIM4 on trophoblast function and its underlying mechanism. LPS treatment reduced the expression of TMBIM4 and induced NLRP3 inflammasome activity in HTR-8/SVneo cells. KO of TMBIM4 in the HTR-8/SVneo cell line impaired cell viability, migration, and invasion, which was more severe in the LPS/ATP-treated TMBIM4-KO cell line. Moreover, TMBIM4 deficiency enhanced NLRP3 inflammasome activity and promoted subsequent pyroptosis, with or without LPS/ATP treatment. The negative relationship between TMBIM4 expression and NLRP3 inflammatory activity was verified in PE placentas. Inhibiting the NLRP3 inflammasome with MCC950 in HTR-8/SVneo cells alleviated LPS/ATP-induced pyroptosis and damaged cell function in the TMBIM4-KO cell line. Overall, this study revealed a new PE-associated protein, TMBIM4, and its biological significance in trophoblast pyroptosis mediated by the NLRP3 inflammasome. TMBIM4 may serve as a potential target for the treatment of placental inflammation-associated PE. Full article
(This article belongs to the Special Issue Advances in Adverse Pregnancy Outcomes)
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11 pages, 642 KiB  
Article
SARS-CoV-2 Infection: A Clinical and Histopathological Study in Pregnancy
by Angelica Perna, Eleonora Hay, Paolo De Blasiis, Marco La Verde, Francesca Caprio, Marco Torella, Maddalena Morlando, Carmine Sellitto, Germano Guerra, Angela Lucariello, Alfonso Baldi and Antonio De Luca
Biology 2023, 12(2), 174; https://doi.org/10.3390/biology12020174 - 21 Jan 2023
Cited by 5 | Viewed by 2782
Abstract
During pregnancy, SARS-CoV-2 infection is associated with several adverse outcomes, including an increased risk of pre-eclampsia, preterm delivery, hypertensive disorders, gestational diabetes, and fetal growth restriction related to the development of placenta vascular abnormalities. We analyzed human placenta from full-term, uncomplicated pregnancies with [...] Read more.
During pregnancy, SARS-CoV-2 infection is associated with several adverse outcomes, including an increased risk of pre-eclampsia, preterm delivery, hypertensive disorders, gestational diabetes, and fetal growth restriction related to the development of placenta vascular abnormalities. We analyzed human placenta from full-term, uncomplicated pregnancies with SARS-CoV-2 infection during the first, second, or third trimesters of gestation. We studied, by the immunohistochemistry technique, the expression of CD34 and podoplanin (PDPN) as markers of vasculogenesis to find any differences. As secondary outcomes, we correlated maternal symptoms with placental histological alterations, including fibrin deposits, lymphocyte infiltration in the villi, edema, and thrombi. Our results showed a PDPN expression around the villous stroma as a plexiform network around the villous nucleus of fetal vessels; significant down-regulation was observed in the villous stroma of women infected during the third trimester. CD34 showed no changes in expression levels. During SARS-CoV-2 infection, the most common maternal symptoms were fever, anosmia, ageusia and asthenia, and the majority were treated with paracetamol, corticosteroids and azithromycin. Patients that required multiple symptomatic treatments evidenced a large amount of fibrin deposition in the villi. Certainly, PDPN plays a key role in healthy placental vasculogenesis and thus in its proper physiology, and SARS-CoV-2 surely alters its normal expression. Further studies are necessary to understand what mechanisms are being altered to try to avoid possible complications for both the mother and fetus in terms of the contagions that will still occur. Full article
(This article belongs to the Special Issue Advances in Adverse Pregnancy Outcomes)
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13 pages, 1896 KiB  
Article
First Trimester Evaluation of Maternal Visceral Fat and Its Relationship with Adverse Pregnancy Outcomes
by Francisco Brenes-Martín, Victoria Melero-Jiménez, Miguel Ángel López-Guerrero, María Mercedes Calero-Ruiz, Luis Vázquez-Fonseca, Jessica Ábalos-Martínez, Rocío Quintero-Prado, Rafael Torrejón, Francisco Visiedo and Fernando Bugatto
Biology 2023, 12(2), 144; https://doi.org/10.3390/biology12020144 - 17 Jan 2023
Cited by 1 | Viewed by 3033
Abstract
Obese women are more likely to experience pregnancy complications. The distribution of fat, and more particularly the rise in visceral fat, is well established to be more closely linked to the onset of cardiovascular disease and metabolic syndrome than obesity itself. We aim [...] Read more.
Obese women are more likely to experience pregnancy complications. The distribution of fat, and more particularly the rise in visceral fat, is well established to be more closely linked to the onset of cardiovascular disease and metabolic syndrome than obesity itself. We aim to examine the relationship between maternal visceral fat assessment in the first trimester and the appearance of adverse pregnancy outcomes. A prospective cohort study including 416 pregnant women was conducted. During the first trimester scan (11–13 + 6 weeks), all individuals had their visceral fat and subcutaneous thicknesses measured by ultrasonography. Blood samples were obtained, and maternal demographics and clinical information were documented. After delivery, the obstetric outcomes were evaluated. We contrasted two groups: one with healthy pregnancies and the other with adverse pregnancy outcomes (APO), defined as the development of at least one of the following complications: gestational diabetes mellitus, hypertensive disorders of pregnancy, abnormal fetal growth, preterm delivery or preterm premature rupture of membranes. Median maternal age was 33 and 34 years old for the uncomplicated and adverse pregnancy outcomes groups, respectively. We found that women with adverse pregnancy outcomes had higher VFT (median 30 vs. 26.5 mm, p = 0.001) and SFT (median 18.9 vs. 17.1 mm, p = 0.03). However, the visceral/subcutaneous fat ratio was not statistically different between groups. Finally, we performed a subanalysis for metabolic and placental vascular dysfunction complications. After performing a multivariate logistic regression analysis adjusted for maternal age, smoking, and mean arterial pressure, both the VFT (aOR 1.03, p < 0.001) and the ratio of visceral/subcutaneous fat (aOR 1.37, p = 0.04) were significantly associated with the development of adverse pregnancy outcomes; however, the associations of VFT and the VFT-to-SFT ratio were higher for the occurrence of gestational diabetes (aOR 1.07, p < 0.001; aOR 2.09, p = 0.001; respectively) and showed no relationships with placental complications. When conducting a first-trimester ultrasound assessment, sonographers may measure VFT without additional time or cost involved. Identification of pregnant women with increased VFT (>37 mm) may benefit from a close follow-up, especially for the development of gestational diabetes, independent of BMI. Full article
(This article belongs to the Special Issue Advances in Adverse Pregnancy Outcomes)
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13 pages, 904 KiB  
Article
Development and Validation of a Predictive Tool for Postpartum Hemorrhage after Vaginal Delivery: A Prospective Cohort Study
by Line Bihan, Emmanuel Nowak, François Anouilh, Christophe Tremouilhac, Philippe Merviel, Cécile Tromeur, Sara Robin, Guillaume Drugmanne, Liana Le Roux, Francis Couturaud, Emmanuelle Le Moigne, Jean-François Abgrall, Brigitte Pan-Petesch and Claire de Moreuil
Biology 2023, 12(1), 54; https://doi.org/10.3390/biology12010054 - 29 Dec 2022
Cited by 4 | Viewed by 3094
Abstract
Postpartum hemorrhage (PPH) is one of the leading causes of maternal morbidity worldwide. This study aimed to develop and validate a predictive model for PPH after vaginal deliveries, based on routinely available clinical and biological data. The derivation monocentric cohort included pregnant women [...] Read more.
Postpartum hemorrhage (PPH) is one of the leading causes of maternal morbidity worldwide. This study aimed to develop and validate a predictive model for PPH after vaginal deliveries, based on routinely available clinical and biological data. The derivation monocentric cohort included pregnant women with vaginal delivery at Brest University Hospital (France) between April 2013 and May 2015. Immediate PPH was defined as a blood loss of ≥500 mL in the first 24 h after delivery and measured with a graduated collector bag. A logistic model, using a combination of multiple imputation and variable selection with bootstrap, was used to construct a predictive model and a score for PPH. An external validation was performed on a prospective cohort of women who delivered between 2015 and 2019 at Brest University Hospital. Among 2742 deliveries, PPH occurred in 141 (5.1%) women. Eight factors were independently associated with PPH: pre-eclampsia (aOR 6.25, 95% CI 2.35–16.65), antepartum bleeding (aOR 2.36, 95% CI 1.43–3.91), multiple pregnancy (aOR 3.24, 95% CI 1.52–6.92), labor duration ≥ 8 h (aOR 1.81, 95% CI 1.20–2.73), macrosomia (aOR 2.33, 95% CI 1.36–4.00), episiotomy (aOR 2.02, 95% CI 1.40–2.93), platelet count < 150 Giga/L (aOR 2.59, 95% CI 1.47–4.55) and aPTT ratio ≥ 1.1 (aOR 2.01, 95% CI 1.25–3.23). The derived predictive score, ranging from 0 to 10 (woman at risk if score ≥ 1), demonstrated a good discriminant power (AUROC 0.69; 95% CI 0.65–0.74) and calibration. The external validation cohort was composed of 3061 vaginal deliveries. The predictive score on this independent cohort showed an acceptable ability to discriminate (AUROC 0.66; 95% CI 0.62–0.70). We derived and validated a robust predictive model identifying women at risk for PPH using in-depth statistical methodology. This score has the potential to improve the care of pregnant women and to take preventive actions on them. Full article
(This article belongs to the Special Issue Advances in Adverse Pregnancy Outcomes)
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Review

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15 pages, 335 KiB  
Review
Breast Carcinogenesis during Pregnancy: Molecular Mechanisms, Maternal and Fetal Adverse Outcomes
by Georgia Margioula-Siarkou, Chrysoula Margioula-Siarkou, Stamatios Petousis, Eleftherios Vavoulidis, Kosmas Margaritis, Aristarchos Almperis, Costas Haitoglou, George Mavromatidis and Konstantinos Dinas
Biology 2023, 12(3), 408; https://doi.org/10.3390/biology12030408 - 6 Mar 2023
Cited by 5 | Viewed by 2753
Abstract
Breast cancer is a common type of cancer diagnosed during pregnancy, with increasing incidence over the last years, as more women choose to delay childbearing. Compared to breast cancer in general population, pregnancy-associated breast cancer (PABC) is significantly different in its terms of [...] Read more.
Breast cancer is a common type of cancer diagnosed during pregnancy, with increasing incidence over the last years, as more women choose to delay childbearing. Compared to breast cancer in general population, pregnancy-associated breast cancer (PABC) is significantly different in its terms of epidemiology, diagnostic and therapeutic management, while it exhibits particularly aggressive behavior, deriving from its unique molecular and biological profile. Although not fully elucidated, the pathophysiological basis of PABC can be traced back to a combination of hormonal and immune changes during pregnancy, breast involution and altered gene expression. There is considerable controversy in the existing literature about the influence of PABC on pregnancy outcomes, regarding both short- and long-term effects on maternal and fetal/neonatal health. The majority of PABC patients have advanced-stage disease at initial diagnosis and face a significantly poorer prognosis, with decreased survival rates. The most commonly reported adverse obstetrical–fetal events are preterm delivery and prematurity-associated neonatal morbidity, while other neonatal treatment-associated complications might also occur, even when safe therapeutic options are applied during pregnancy. The objective of the present comprehensive review was to summarize current knowledge and up-to-date evidence about the pathophysiological, molecular and biological basis of PABC, as well as its association with adverse maternal, obstetrical, fetal and neonatal outcomes. Full article
(This article belongs to the Special Issue Advances in Adverse Pregnancy Outcomes)
21 pages, 1157 KiB  
Review
Innate and Adaptive Immune Systems in Physiological and Pathological Pregnancy
by Jessica Weng, Camille Couture and Sylvie Girard
Biology 2023, 12(3), 402; https://doi.org/10.3390/biology12030402 - 3 Mar 2023
Cited by 20 | Viewed by 5156
Abstract
The dynamic immunological changes occurring throughout pregnancy are well-orchestrated and important for the success of the pregnancy. One of the key immune adaptations is the maternal immune tolerance towards the semi-allogeneic fetus. In this review, we provide a comprehensive overview of what is [...] Read more.
The dynamic immunological changes occurring throughout pregnancy are well-orchestrated and important for the success of the pregnancy. One of the key immune adaptations is the maternal immune tolerance towards the semi-allogeneic fetus. In this review, we provide a comprehensive overview of what is known about the innate and adaptive immunological changes in pregnancy and the role(s) of specific immune cells during physiological and pathological pregnancy. Alongside this, we provided details of remaining questions and challenges, as well as future perspectives for this growing field of research. Understanding the immunological changes that occur can inform potential strategies on treatments for the optimal health of the neonate and pregnant individual both during and after pregnancy. Full article
(This article belongs to the Special Issue Advances in Adverse Pregnancy Outcomes)
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15 pages, 1533 KiB  
Review
The Role of Autophagy in the Female Reproduction System: For Beginners to Experts in This Field
by Akitoshi Nakashima, Atsushi Furuta, Kiyotaka Yamada, Mihoko Yoshida-Kawaguchi, Akemi Yamaki-Ushijima, Ippei Yasuda, Masami Ito, Satoshi Yamashita, Sayaka Tsuda, Satoshi Yoneda, Shibin Cheng, Surendra Sharma and Tomoko Shima
Biology 2023, 12(3), 373; https://doi.org/10.3390/biology12030373 - 26 Feb 2023
Cited by 4 | Viewed by 4214
Abstract
Autophagy is a fundamental process involved in regulating cellular homeostasis. Autophagy has been classically discovered as a cellular process that degrades cytoplasmic components non-selectively to produce energy. Over the past few decades, this process has been shown to work in energy production, as [...] Read more.
Autophagy is a fundamental process involved in regulating cellular homeostasis. Autophagy has been classically discovered as a cellular process that degrades cytoplasmic components non-selectively to produce energy. Over the past few decades, this process has been shown to work in energy production, as well as in the reduction of excessive proteins, damaged organelles, and membrane trafficking. It contributes to many human diseases, such as neurodegenerative diseases, carcinogenesis, diabetes mellitus, development, longevity, and reproduction. In this review, we provide important information for interpreting results related to autophagic experiments and present the role of autophagy in this field. Full article
(This article belongs to the Special Issue Advances in Adverse Pregnancy Outcomes)
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21 pages, 828 KiB  
Review
Autologous Human Mesenchymal Stem Cell-Based Therapy in Infertility: New Strategies and Future Perspectives
by Zahirrah Begam Mohamed Rasheed, Fazlina Nordin, Wan Safwani Wan Kamarul Zaman, Yuen-Fen Tan and Nor Haslinda Abd Aziz
Biology 2023, 12(1), 108; https://doi.org/10.3390/biology12010108 - 10 Jan 2023
Cited by 3 | Viewed by 4709
Abstract
Infertility could be associated with a few factors including problems with physical and mental health, hormonal imbalances, lifestyles, and genetic factors. Given that there is a concern about the rise of infertility globally, increased focus has been given to its treatment for the [...] Read more.
Infertility could be associated with a few factors including problems with physical and mental health, hormonal imbalances, lifestyles, and genetic factors. Given that there is a concern about the rise of infertility globally, increased focus has been given to its treatment for the last several decades. Traditional assisted reproductive technology (ART) has been the prime option for many years in solving various cases of infertility; however, it contains significant risks and does not solve the fundamental problem of infertility such as genetic disorders. Attention toward the utilization of MSCs has been widely regarded as a promising option in the development of stem-cell-based infertility treatments. This narrative review briefly presents the challenges in the current ART treatment of infertility and the various potential applications of autologous MSCs in the treatment of these reproductive diseases. Full article
(This article belongs to the Special Issue Advances in Adverse Pregnancy Outcomes)
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