International Journal of Molecular Sciences

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Open AccessEditorial

Special Issue of Pathogenesis of Pregnancy-Related Complications, 2023

by Ilona Hromadnikova

Int. J. Mol. Sci. 2024, 25(5), 2487; https://doi.org/10.3390/ijms25052487 - 20 Feb 2024

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Abstract

This Special Issue mainly focuses on preeclampsia (PE), haemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, gestational diabetes mellitus (GDM), foetal growth restriction (FGR), small-for-gestational-age foetuses (SGA), miscarriage, stillbirth, first-episode psychosis (FEP) during pregnancy, and pregnancy-related acute kidney injury (PR-AKI) [...] [...] Read more.

This Special Issue mainly focuses on preeclampsia (PE), haemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, gestational diabetes mellitus (GDM), foetal growth restriction (FGR), small-for-gestational-age foetuses (SGA), miscarriage, stillbirth, first-episode psychosis (FEP) during pregnancy, and pregnancy-related acute kidney injury (PR-AKI) [...] Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication 2023)

Research

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9 pages, 1056 KiB

Open AccessArticle

Indoxyl Sulfate Administration during Pregnancy Contributes to Renal Injury and Increased Blood–Brain Barrier Permeability

by Ashley Griffin, Brittany Berry, Shauna-Kay Spencer, Teylor Bowles and Kedra Wallace

Int. J. Mol. Sci. 2023, 24(15), 11968; https://doi.org/10.3390/ijms241511968 - 26 Jul 2023

Cited by 1 | Viewed by 1271

Abstract

Rates of pregnancy-related acute kidney injury (PR-AKI) have increased in the U.S over the past two decades, but how PR-AKI affects the blood–brain barrier (BBB) is understudied. AKI is associated with increased amounts of uremic toxins, like indoxyl sulfate (I.S), whose chronic administration [...] Read more.

Rates of pregnancy-related acute kidney injury (PR-AKI) have increased in the U.S over the past two decades, but how PR-AKI affects the blood–brain barrier (BBB) is understudied. AKI is associated with increased amounts of uremic toxins, like indoxyl sulfate (I.S), whose chronic administration leads to BBB and cognitive changes. This study’s objective was to determine if (1) PR-AKI increases I.S and (2) if administration of I.S during pregnancy elicits renal injury and/or increases BBB permeability. From gestational day (GD) 11 to GD19, Sprague Dawley rats were given either 100 or 200 mg/kg body-weight dose of I.S. PR-AKI was induced on GD18 via 45 min bilateral renal ischemic reperfusion surgery. On GD18, metabolic cage metrics and metabolic waste was collected and on GD19 blood pressure, and BBB permeability (by Evan’s Blue infusion) were measured. I.S and creatinine were measured in both urine and circulation, respectively. One-way ANOVA or student t-tests were performed using GraphPad Prism with a p < 0.05 significance. I.S and PR-AKI led to oliguria. I.S administration led to increased BBB permeability compared to normal pregnant and PR-AKI animals. These results suggest that I.S administration during pregnancy leads to increased BBB permeability and evidence of renal injury comparable to PR-AKI animals. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication 2023)

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16 pages, 2983 KiB

Open AccessArticle

Assessment of Tissue Expression of the Oxytocin–Vasopressin Pathway in the Placenta of Women with a First-Episode Psychosis during Pregnancy

by Miguel A. Ortega, Cielo García-Montero, Óscar Fraile-Martinez, Diego De Leon-Oliva, Diego Liviu Boaru, Coral Bravo, Juan A. De Leon-Luis, Miguel A. Saez, Angel Asúnsolo, Ignacio Romero-Gerechter, Alejandro Sanz-Giancola, Raul Diaz-Pedrero, Laura Lopez-Gonzalez, Luis G. Guijarro, Silvestra Barrena-Blázquez, Julia Bujan, Natalio García-Honduvilla, Melchor Alvarez-Mon, Miguel Ángel Alvarez-Mon and Guillermo Lahera

Int. J. Mol. Sci. 2023, 24(12), 10254; https://doi.org/10.3390/ijms241210254 - 16 Jun 2023

Cited by 4 | Viewed by 1136

Abstract

Psychosis refers to a mental health condition characterized by a loss of touch with reality, comprising delusions, hallucinations, disorganized thought, disorganized behavior, catatonia, and negative symptoms. A first-episode psychosis (FEP) is a rare condition that can trigger adverse outcomes both for the mother [...] Read more.

Psychosis refers to a mental health condition characterized by a loss of touch with reality, comprising delusions, hallucinations, disorganized thought, disorganized behavior, catatonia, and negative symptoms. A first-episode psychosis (FEP) is a rare condition that can trigger adverse outcomes both for the mother and newborn. Previously, we demonstrated the existence of histopathological changes in the placenta of pregnant women who suffer an FEP in pregnancy. Altered levels of oxytocin (OXT) and vasopressin (AVP) have been detected in patients who manifested an FEP, whereas abnormal placental expression of these hormones and their receptors (OXTR and AVPR1A) has been proven in different obstetric complications. However, the precise role and expression of these components in the placenta of women after an FEP have not been studied yet. Thus, the purpose of the present study was to analyze the gene and protein expression, using RT-qPCR and immunohistochemistry (IHC), of OXT, OXTR, AVP, and AVPR1a in the placental tissue of pregnant women after an FEP in comparison to pregnant women without any health complication (HC-PW). Our results showed increased gene and protein expression of OXT, AVP, OXTR, and AVPR1A in the placental tissue of pregnant women who suffer an FEP. Therefore, our study suggests that an FEP during pregnancy may be associated with an abnormal paracrine/endocrine activity of the placenta, which can negatively affect the maternofetal wellbeing. Nevertheless, additional research is required to validate our findings and ascertain any potential implications of the observed alterations. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication 2023)

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19 pages, 4711 KiB

Open AccessArticle

First-Trimester Screening for Miscarriage or Stillbirth—Prediction Model Based on MicroRNA Biomarkers

by Ilona Hromadnikova, Katerina Kotlabova and Ladislav Krofta

Int. J. Mol. Sci. 2023, 24(12), 10137; https://doi.org/10.3390/ijms241210137 - 14 Jun 2023

Cited by 3 | Viewed by 1325

Abstract

We evaluated the potential of cardiovascular-disease-associated microRNAs to predict in the early stages of gestation (from 10 to 13 gestational weeks) the occurrence of a miscarriage or stillbirth. The gene expressions of 29 microRNAs were studied retrospectively in peripheral venous blood samples derived [...] Read more.

We evaluated the potential of cardiovascular-disease-associated microRNAs to predict in the early stages of gestation (from 10 to 13 gestational weeks) the occurrence of a miscarriage or stillbirth. The gene expressions of 29 microRNAs were studied retrospectively in peripheral venous blood samples derived from singleton Caucasian pregnancies diagnosed with miscarriage (n = 77 cases; early onset, n = 43 cases; late onset, n = 34 cases) or stillbirth (n = 24 cases; early onset, n = 13 cases; late onset, n = 8 cases; term onset, n = 3 cases) and 80 selected gestational-age-matched controls (normal term pregnancies) using real-time RT-PCR. Altered expressions of nine microRNAs (upregulation of miR-1-3p, miR-16-5p, miR-17-5p, miR-26a-5p, miR-146a-5p, and miR-181a-5p and downregulation of miR-130b-3p, miR-342-3p, and miR-574-3p) were observed in pregnancies with the occurrence of a miscarriage or stillbirth. The screening based on the combination of these nine microRNA biomarkers revealed 99.01% cases at a 10.0% false positive rate (FPR). The predictive model for miscarriage only was based on the altered gene expressions of eight microRNA biomarkers (upregulation of miR-1-3p, miR-16-5p, miR-17-5p, miR-26a-5p, miR-146a-5p, and miR-181a-5p and downregulation of miR-130b-3p and miR-195-5p). It was able to identify 80.52% cases at a 10.0% FPR. Highly efficient early identification of later occurrences of stillbirth was achieved via the combination of eleven microRNA biomarkers (upregulation of miR-1-3p, miR-16-5p, miR-17-5p, miR-20a-5p, miR-146a-5p, and miR-181a-5p and downregulation of miR-130b-3p, miR-145-5p, miR-210-3p, miR-342-3p, and miR-574-3p) or, alternatively, by the combination of just two upregulated microRNA biomarkers (miR-1-3p and miR-181a-5p). The predictive power achieved 95.83% cases at a 10.0% FPR and, alternatively, 91.67% cases at a 10.0% FPR. The models based on the combination of selected cardiovascular-disease-associated microRNAs had very high predictive potential for miscarriages or stillbirths and may be implemented in routine first-trimester screening programs. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication 2023)

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16 pages, 2939 KiB

Open AccessArticle

Dissecting Rubella Placental Infection in an In Vitro Trophoblast Model

by Juliane Schulz, Erik Schilling, Claire Fabian, Ana Claudia Zenclussen, Violeta Stojanovska and Claudia Claus

Int. J. Mol. Sci. 2023, 24(9), 7894; https://doi.org/10.3390/ijms24097894 - 26 Apr 2023

Cited by 1 | Viewed by 1700

Abstract

Vertical transmission of rubella virus (RuV) occurs at a high rate during the first trimester of pregnancy. The modes of vertical transmission including the response of trophoblasts to RuV are not well understood. Here, RuV-trophoblast interaction was studied in the BeWo trophoblast cell [...] Read more.

Vertical transmission of rubella virus (RuV) occurs at a high rate during the first trimester of pregnancy. The modes of vertical transmission including the response of trophoblasts to RuV are not well understood. Here, RuV-trophoblast interaction was studied in the BeWo trophoblast cell line. Analysis included early and late time-point kinetics of virus infection rate and the antiviral innate immune response at mRNA and protein level. BeWo characteristics were addressed through metabolic activity by extracellular flux analysis and syncytiotrophoblast formation through incubation with forskolin. We found that RuV infection of BeWo led to profuse type III interferon (IFN) production. Transfecting trophoblast cells with dsRNA analog induced an increase in the production of type I IFN-β and type III IFNs; however, this did not occur in RuV-infected BeWo trophoblasts. IFN-β and to a lesser extent type III IFN-λ1 were inhibitory to RuV. While no significant metabolic alteration was detected, RuV infection reduced the cell number in the monolayer culture in comparison to the mock control and resulted in detached and floating cells. Syncytia formation restricted RuV infection. The use of BeWo as a relevant cell culture model for infection of trophoblasts highlights cytopathogenicity in the absence of a type I IFN response as a pathogenic alteration by RuV. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication 2023)

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19 pages, 3418 KiB

Open AccessArticle

First-Trimester Screening for HELLP Syndrome—Prediction Model Based on MicroRNA Biomarkers and Maternal Clinical Characteristics

by Ilona Hromadnikova, Katerina Kotlabova and Ladislav Krofta

Int. J. Mol. Sci. 2023, 24(6), 5177; https://doi.org/10.3390/ijms24065177 - 08 Mar 2023

Cited by 4 | Viewed by 2099

Abstract

We evaluated the potential of cardiovascular-disease-associated microRNAs for early prediction of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Gene expression profiling of 29 microRNAs was performed on whole peripheral venous blood samples collected between 10 and 13 weeks of gestation using [...] Read more.

We evaluated the potential of cardiovascular-disease-associated microRNAs for early prediction of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Gene expression profiling of 29 microRNAs was performed on whole peripheral venous blood samples collected between 10 and 13 weeks of gestation using real-time RT-PCR. The retrospective study involved singleton pregnancies of Caucasian descent only diagnosed with HELLP syndrome (n = 14) and 80 normal-term pregnancies. Upregulation of six microRNAs (miR-1-3p, miR-17-5p, miR-143-3p, miR-146a-5p, miR-181a-5p, and miR-499a-5p) was observed in pregnancies destined to develop HELLP syndrome. The combination of all six microRNAs showed a relatively high accuracy for the early identification of pregnancies destined to develop HELLP syndrome (AUC 0.903, p < 0.001, 78.57% sensitivity, 93.75% specificity, cut-off > 0.1622). It revealed 78.57% of HELLP pregnancies at a 10.0% false-positive rate (FPR). The predictive model for HELLP syndrome based on whole peripheral venous blood microRNA biomarkers was further extended to maternal clinical characteristics, most of which were identified as risk factors for the development of HELLP syndrome (maternal age and BMI values at early stages of gestation, the presence of any kind of autoimmune disease, the necessity to undergo an infertility treatment by assisted reproductive technology, a history of HELLP syndrome and/or pre-eclampsia in a previous gestation, and the presence of trombophilic gene mutations). Then, 85.71% of cases were identified at a 10.0% FPR. When another clinical variable (the positivity of the first-trimester screening for pre-eclampsia and/or fetal growth restriction by the Fetal Medicine Foundation algorithm) was implemented in the HELLP prediction model, the predictive power was increased further to 92.86% at a 10.0% FPR. The model based on the combination of selected cardiovascular-disease-associated microRNAs and maternal clinical characteristics has a very high predictive potential for HELLP syndrome and may be implemented in routine first-trimester screening programs. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication 2023)

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16 pages, 6745 KiB

Open AccessArticle

Gestational Diabetes Mellitus and Small-for-Gestational-Age: An Insight into the Placental Molecular Biomarkers

by Christian Giommi, Marta Lombό, Nina Montik, Michela Paolucci, Valentina Notarstefano, Giovanni Delli Carpini, Andrea Ciavattini, Antonio Ragusa, Francesca Maradonna, Elisabetta Giorgini and Oliana Carnevali

Int. J. Mol. Sci. 2023, 24(3), 2240; https://doi.org/10.3390/ijms24032240 - 23 Jan 2023

Cited by 2 | Viewed by 2380

Abstract

Gestational diabetes mellitus (GDM) and small-for-gestational-age (SGA) are two metabolic-related diseases that could affect women during pregnancy. Considering that the chorionic villi (CVs) are crucial structures for the feto-maternal exchange, the alterations in their conformation have been linked to an imbalanced metabolic environment [...] Read more.

Gestational diabetes mellitus (GDM) and small-for-gestational-age (SGA) are two metabolic-related diseases that could affect women during pregnancy. Considering that the chorionic villi (CVs) are crucial structures for the feto-maternal exchange, the alterations in their conformation have been linked to an imbalanced metabolic environment of placenta. In this study, a multidisciplinary approach has been carried out to describe the changes occurring in the placental CVs of GDM and SGA patients. The results revealed higher levels of superoxide dismutase 1 (SOD-1) and catalase (CAT), especially in the GDM placentae, which could be correlated with the hyperglycemic environment characteristic of this pathology. Furthermore, spectroscopy and histologic analyses revealed that both pathologies modify the placental lipid composition altering its structure. However, SGA induces lipid peroxidation and reduces collagen deposition within the CVs. Since the endocannabinoid system (ECS) is involved in placentation and different metabolic activities, the cannabinoid receptor 1 (CB1) and transient receptor potential cation channel subfamily V member 1 (TRPV-1) were analyzed. No changes have been observed either at general or specific levels in the CVs comparing control and pathological samples, suggesting the non-involvement of the cannabinoid system in these two pathologies. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication 2023)

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Review

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18 pages, 1947 KiB

Open AccessReview

Pathophysiology of Pre-Eclampsia—Two Theories of the Development of the Disease

by Jakub Kornacki, Olga Olejniczak, Rafał Sibiak, Paweł Gutaj and Ewa Wender-Ożegowska

Int. J. Mol. Sci. 2024, 25(1), 307; https://doi.org/10.3390/ijms25010307 - 25 Dec 2023

Cited by 1 | Viewed by 1636

Abstract

Pre-eclampsia (PE) continues to be a leading cause of maternal and fetal mortality and morbidity. While substantial progress has been made in understanding the pathomechanisms of PE, the pathophysiology of the disease is still not fully understood. While the “two-stage model” of the [...] Read more.

Pre-eclampsia (PE) continues to be a leading cause of maternal and fetal mortality and morbidity. While substantial progress has been made in understanding the pathomechanisms of PE, the pathophysiology of the disease is still not fully understood. While the “two-stage model” of the development of PE is the most widely accepted theory, stating that the placenta is the main source of the disease, there are some other pathophysiological models of PE. Among these other theories, the one considering heart dysfunction as serving as the primary cause of PE seems to be gaining increasing prominence. In this review, we aim to elucidate these two divergent concepts concerning the development of PE. Despite some differences in their proposed pathomechanisms, both theories share vital pathophysiological elements in common. A central and critical component in both models is impaired placental perfusion, which appears to be a crucial phenomenon in PE. A comprehensive understanding of the different pathomechanisms involved in PE may be helpful in clinical practice, prompting a more individual approach to care of patients with PE. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication 2023)

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16 pages, 2024 KiB

Open AccessReview

The Role of ncRNAs in the Immune Dysregulation of Preeclampsia

by Carlos Mora-Palazuelos, Carlos Esteban Villegas-Mercado, Mariana Avendaño-Félix, Erik Lizárraga-Verdugo, José Geovanni Romero-Quintana, Jorge López-Gutiérrez, Saúl Beltrán-Ontiveros and Mercedes Bermúdez

Int. J. Mol. Sci. 2023, 24(20), 15215; https://doi.org/10.3390/ijms242015215 - 16 Oct 2023

Cited by 2 | Viewed by 1320

Abstract

The main complications causing practically 75% of all maternal deaths are severe bleeding, infections, and high blood pressure during pregnancy (preeclampsia (PE) and eclampsia). The usefulness of ncRNAs as clinical biomarkers has been explored in an extensive range of human diseases including pregnancy-related [...] Read more.

The main complications causing practically 75% of all maternal deaths are severe bleeding, infections, and high blood pressure during pregnancy (preeclampsia (PE) and eclampsia). The usefulness of ncRNAs as clinical biomarkers has been explored in an extensive range of human diseases including pregnancy-related diseases such as PE. Immunological dysregulation show that the Th1/17:Th2/Treg ratio is “central and causal” to PE. However, there is evidence of the involvement of placenta-expressed miRNAs and lncRNAs in the immunological regulation of crucial processes of placenta development and function during pregnancy. Abnormal expression of these molecules is related to immune physiopathological processes that occur in PE. Therefore, this work aims to describe the importance of miRNAs and lncRNAs in immune dysregulation in PE. Interestingly, multiple ncRNAS are involved in the immune dysregulation of PE participating in type 1 immune response regulation, immune microenvironment regulation in placenta promoting inflammatory factors, trophoblast cell invasion in women with Early-Onset PE (EOPE), placental development, and angiogenesis, promotion of population of M1 and M2, proliferation, invasion, and migration of placental trophoblast cells, and promotion of invasion and autophagy through vias such as PI3K/AKT/mTOR, VEGF/VEGFR1, and TLR9/STAT3. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication 2023)

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28 pages, 1688 KiB

Open AccessReview

Ca²⁺-Activated K⁺ Channels and the Regulation of the Uteroplacental Circulation

by Xiang-Qun Hu and Lubo Zhang

Int. J. Mol. Sci. 2023, 24(2), 1349; https://doi.org/10.3390/ijms24021349 - 10 Jan 2023

Cited by 2 | Viewed by 2900

Abstract

Adequate uteroplacental blood supply is essential for the development and growth of the placenta and fetus during pregnancy. Aberrant uteroplacental perfusion is associated with pregnancy complications such as preeclampsia, fetal growth restriction (FGR), and gestational diabetes. The regulation of uteroplacental blood flow is [...] Read more.

Adequate uteroplacental blood supply is essential for the development and growth of the placenta and fetus during pregnancy. Aberrant uteroplacental perfusion is associated with pregnancy complications such as preeclampsia, fetal growth restriction (FGR), and gestational diabetes. The regulation of uteroplacental blood flow is thus vital to the well-being of the mother and fetus. Ca²⁺-activated K⁺ (K_Ca) channels of small, intermediate, and large conductance participate in setting and regulating the resting membrane potential of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) and play a critical role in controlling vascular tone and blood pressure. K_Ca channels are important mediators of estrogen/pregnancy-induced adaptive changes in the uteroplacental circulation. Activation of the channels hyperpolarizes uteroplacental VSMCs/ECs, leading to attenuated vascular tone, blunted vasopressor responses, and increased uteroplacental blood flow. However, the regulation of uteroplacental vascular function by K_Ca channels is compromised in pregnancy complications. This review intends to provide a comprehensive overview of roles of K_Ca channels in the regulation of the uteroplacental circulation under physiological and pathophysiological conditions. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication 2023)

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7 pages, 245 KiB

Open AccessCase Report

Beckwith–Wiedemann Syndrome in Newborn of Mother with HELLP Syndrome/Preeclampsia: An Analysis of Literature and Case Report with Fetal Growth Restriction and Absence of CDKN1C Typical Pathogenic Genetic Variation

by Jakub Staniczek, Maisa Manasar-Dyrbuś, Agnieszka Drosdzol-Cop and Rafał Stojko

Int. J. Mol. Sci. 2023, 24(17), 13360; https://doi.org/10.3390/ijms241713360 - 29 Aug 2023

Cited by 1 | Viewed by 857

Abstract

Beckwith–Wiedemann Syndrome (BWS) is an imprinting disorder, which manifests by overgrowth and predisposition to embryonal tumors. The evidence on the relationship between maternal complications such as HELLP (hemolysis, elevated liver enzymes, and low platelet count) and preeclampsia and the development of BWS in [...] Read more.

Beckwith–Wiedemann Syndrome (BWS) is an imprinting disorder, which manifests by overgrowth and predisposition to embryonal tumors. The evidence on the relationship between maternal complications such as HELLP (hemolysis, elevated liver enzymes, and low platelet count) and preeclampsia and the development of BWS in offspring is scarce. A comprehensive clinical evaluation, with genetic testing focused on screening for mutations in the CDKN1C gene, which is commonly associated with BWS, was conducted in a newborn diagnosed with BWS born to a mother with a history of preeclampsia and HELLP syndrome. The case study revealed typical clinical manifestations of BWS in the newborn, including hemihyperplasia, macroglossia, midfacial hypoplasia, omphalocele, and hypoglycemia. Surprisingly, the infant also exhibited fetal growth restriction, a finding less commonly observed in BWS cases. Genetic analysis, however, showed no mutations in the CDKN1C gene, which contrasts with the majority of BWS cases. This case report highlights the complex nature of BWS and its potential association with maternal complications such as preeclampsia and HELLP syndrome. The atypical presence of fetal growth restriction in the newborn and the absence of CDKN1C gene mutations have not been reported to date in BWS. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication 2023)

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