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Pathogenesis of Pregnancy-Related Complication
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Pathogenesis of Pregnancy-Related Complication

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 42998

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Ilona Hromadnikova

E-Mail Website
Guest Editor
Head, Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
Interests: pregnancy-related complications; pathogenesis; diagnosis/prognosis biomarkers; epigenetics; extracellular nucleic acids in maternal circulation; postpartum/postnatal short-term and long-term consequences
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Preeclampsia, HELLP syndrome, fetal growth restriction, gestational diabetes mellitus, preterm birth (preterm, prelabor rupture of membranes and spontaneous preterm labour), and invasive placenta are major complications responsible for maternal and perinatal morbidity and mortality. Elucidation of the pathogenetic mechanisms related to the initiation and onset of severe pregnancy-related complications enables the identification of potential biomarkers for early stratification of at-risk patients. Additionally, pregnancy-related complications induce long-term metabolic and vascular abnormalities that might increase the overall risk of metabolic, cardiovascular, cerebrovascular, kidney, and other diseases later in life in mothers and their offspring. This Special Issue aims to provide an overview of the latest research on the mechanisms associated with pregnancy-related complications, as well as the contribution of pregnancy-related complications to the later development of various diseases. This will include underlying mechanisms, diagnostics/prognostics, and treatment strategies associated with pregnancy-related complications, and will be of interest to scientists and clinicians working in this quickly expanding area.

Topics will include, but are not limited to, the following: 

  • Pathogenesis of pregnancy-related complications;
  • Diagnosis and prognosis of pregnancy-related complications;
  • Short-term and long-term follow-up visits after pregnancy-related complications (mothers and offspring);
  • Novel treatment modalities of pregnancy-related complications and their short-term and long-term consequences.

Prof. Dr. Ilona Hromadnikova
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • gestational hypertension

  • preeclampsia
  • HELLP syndrome
  • fetal growth restriction
  • gestational diabetes mellitus
  • preterm birth
  • invasive placenta

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Editorial

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3 pages, 192 KiB  
Editorial
Pathogenesis of Pregnancy-Related Complications
by Ilona Hromadnikova
Int. J. Mol. Sci. 2023, 24(6), 5584; https://doi.org/10.3390/ijms24065584 - 15 Mar 2023
Viewed by 885
Abstract
In this special edition (closed on 31 October 2022), 4 reviews, 13 original papers, 1 communication, and 1 case report are published [...] Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)

Research

Jump to: Editorial, Review, Other

25 pages, 1284 KiB  
Article
Similar Pro- and Antiangiogenic Profiles Close to Delivery in Different Clinical Presentations of Two Pregnancy Syndromes: Preeclampsia and Fetal Growth Restriction
by Weronika Dymara-Konopka, Marzena Laskowska, Ewelina Grywalska, Anna Hymos, Anna Błażewicz and Bożena Leszczyńska-Gorzelak
Int. J. Mol. Sci. 2023, 24(2), 972; https://doi.org/10.3390/ijms24020972 - 04 Jan 2023
Cited by 7 | Viewed by 1700
Abstract
The purpose of this study was to evaluate serum levels of anti- and pro-angiogenic substances measured using enzyme-linked immunosorbent assays and their ratios in pregnancies complicated by different clinical subsets of placental ischemic syndrome: preeclampsia and/or fetal growth restriction. A prospective case-control study [...] Read more.
The purpose of this study was to evaluate serum levels of anti- and pro-angiogenic substances measured using enzyme-linked immunosorbent assays and their ratios in pregnancies complicated by different clinical subsets of placental ischemic syndrome: preeclampsia and/or fetal growth restriction. A prospective case-control study was performed consisting of 77 singleton pregnancies complicated by preeclampsia, preeclampsia with concurrent fetal growth restriction (FGR), and isolated normotensive FGR pairwise matched by gestational age with healthy pregnancies. The entire study cohort was analyzed with respect to adverse pregnancy outcomes that occurred. In all investigated subgroups, placental growth factor (PlGF) was lower and soluble endoglin (sEng), the soluble fms-like tyrosine kinase-1—sFlt-1/PlGF and sFlt-1*sEng/PlGF ratios were higher than in the control group. The differences were most strongly pronounced in the PE with concurrent FGR group and in the sFlt-1/PlGF ratio. The highest sFlt-1 values in preeclamptic patients suggest that this substance may be responsible for reaching the threshold needed for PE to develop as a maternal manifestation of ischemic placental disease. The FGR is characterized by an elevated maternal sFlt-1/PlGF ratio, which boosts at the moment of indicated delivery due to fetal risk. We concluded that angiogenic imbalance is reflective of placental disease regardless of its clinical manifestation in the mother, and may be used as support for the diagnosis and prognosis of FGR. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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11 pages, 1982 KiB  
Article
SLC38A4 Amino Acid Transporter Expression Is Significantly Lower in Early Preterm Intrauterine Growth Restriction Complicated Placentas
by Elif Kadife, Alesia Harper, Natasha De Alwis, Keegan Chien, Natalie Hannan and Fiona C. Brownfoot
Int. J. Mol. Sci. 2023, 24(1), 403; https://doi.org/10.3390/ijms24010403 - 26 Dec 2022
Cited by 2 | Viewed by 1331
Abstract
Intrauterine growth restriction (IUGR), predominantly caused by placental insufficiency, affects partitioning of nutrients to the fetus. The system A sodium-coupled transporters (SNAT or SLC38), of types A1, A2, and A4, control non-essential amino acid uptake and supply. Here, we aimed to investigate the [...] Read more.
Intrauterine growth restriction (IUGR), predominantly caused by placental insufficiency, affects partitioning of nutrients to the fetus. The system A sodium-coupled transporters (SNAT or SLC38), of types A1, A2, and A4, control non-essential amino acid uptake and supply. Here, we aimed to investigate the expression of these transporters across different placental disease cohorts and cells. To determine disease impact, transporter expressions at the gene (qPCR) and protein (western blots) level were assessed in gestationally matched placental tissues. Early (<34 weeks), and late (34–36 weeks) onset IUGR cases with/out preeclampsia were compared to preterm controls. We also investigated level of transporter expression in primary trophoblasts under glucose deprivation (n = 6) and hypoxia conditions (n = 7). SLC38A4 protein was significantly downregulated in early preterm pregnancies complicated with IUGR with/out preeclampsia. There were no differences in late preterm IUGR cohorts. Furthermore, we demonstrate for the first time in primary trophoblast cells, that gene expression of the transporters was sensitive to and induced by glucose starvation. SLC38A4 mRNA expression was also significantly upregulated in response to hypoxia. Thus, SLC38A4 expression was persistently low in early preterm IUGR pregnancies, regardless of disease aetiology. This suggests that gestational age at delivery, and consequently IUGR severity, may influence loss of its expression. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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11 pages, 1430 KiB  
Communication
Modeling Preeclampsia In Vitro: Polymorphic Variants of STOX1-A/B Genes Can Downregulate CD24 in Trophoblast Cell Lines
by Marei Sammar, Clara Apicella, Peter Altevogt, Hamutal Meiri and Daniel Vaiman
Int. J. Mol. Sci. 2022, 23(24), 15927; https://doi.org/10.3390/ijms232415927 - 14 Dec 2022
Cited by 2 | Viewed by 1518
Abstract
CD24 is a mucin-like immunosuppressing glycoprotein whose levels increase during pregnancy and decrease in the syncytio- and cytotrophoblasts in early and preterm preeclampsia. We used two modified cell lines that mimic in vitro features of preeclampsia to identify if this phenomenon could be [...] Read more.
CD24 is a mucin-like immunosuppressing glycoprotein whose levels increase during pregnancy and decrease in the syncytio- and cytotrophoblasts in early and preterm preeclampsia. We used two modified cell lines that mimic in vitro features of preeclampsia to identify if this phenomenon could be reproduced. Our model was the immortalized placental-derived BeWo and JEG-3 cell lines that overexpress the STOX1 A/B transcription factor gene that was discovered in familial forms of preeclampsia. BeWo and JEG-3 cells stably transduced with the two major isoforms of STOX1-A/B or by an empty vector (control), were propagated, harvested, and analyzed. CD24 mRNA expression was determined by quantitative real-time polymerase nuclear chain reaction (qRT-PCR). CD24 protein levels were determined by Western blots. In STOX1-A/B overexpressing in BeWo cells, CD24 mRNA was downregulated by 91 and 85%, respectively, compared to the control, and by 30% and 74%, respectively in JEG-3 cells. A 67% and 82% decrease in CD24 protein level was determined by immunoblot in BeWo overexpressing STOX1-A/B, respectively, while the reduction in JEG-3 cells was between 47 and 62%. The immortalized BeWo and JEG-3 cell lines overexpressing STOX1-A/B had reduced CD24. Although both cell lines were affected, BeWo appears to be more susceptible to downregulation by STOX-1 than JEG-3, potentially because of their different cell origin and properties. These results strengthen the in vivo results of reduced CD24 levels found in early and preterm preeclampsia. Accordingly, it implies the importance of the reduced immune tolerance in preeclampsia, which was already demonstrated in vivo in the STOX1-A/B model of preeclampsia, and is now implied in the in vitro STOX-1 model, a subject that warrants further investigations. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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16 pages, 2042 KiB  
Article
Placental Transcriptome Profiling in Subtypes of Diabetic Pregnancies Is Strongly Confounded by Fetal Sex
by Sarah M. Kedziora, Benedikt Obermayer, Meryam Sugulle, Florian Herse, Kristin Kräker, Nadine Haase, Immaculate M. Langmia, Dominik N. Müller, Anne Cathrine Staff, Dieter Beule and Ralf Dechend
Int. J. Mol. Sci. 2022, 23(23), 15388; https://doi.org/10.3390/ijms232315388 - 06 Dec 2022
Cited by 5 | Viewed by 1849
Abstract
The placenta is a temporary organ with a unique structure and function to ensure healthy fetal development. Placental dysfunction is involved in pre-eclampsia (PE), fetal growth restriction, preterm birth, and gestational diabetes mellitus (GDM). A diabetic state affects maternal and fetal health and [...] Read more.
The placenta is a temporary organ with a unique structure and function to ensure healthy fetal development. Placental dysfunction is involved in pre-eclampsia (PE), fetal growth restriction, preterm birth, and gestational diabetes mellitus (GDM). A diabetic state affects maternal and fetal health and may lead to functional alterations of placental metabolism, inflammation, hypoxia, and weight, amplifying the fetal stress. The placental molecular adaptations to the diabetic environment and the adaptive spatio–temporal consequences to elevated glucose or insulin are largely unknown (2). We aimed to identify gene expression signatures related to the diabetic placental pathology of placentas from women with diabetes mellitus. Human placenta samples (n = 77) consisting of healthy controls, women with either gestational diabetes mellitus (GDM), type 1 or type 2 diabetes, and women with GDM, type 1 or type 2 diabetes and superimposed PE were collected. Interestingly, gene expression differences quantified by total RNA sequencing were mainly driven by fetal sex rather than clinical diagnosis. Association of the principal components with a full set of clinical patient data identified fetal sex as the single main explanatory variable. Accordingly, placentas complicated by type 1 and type 2 diabetes showed only few differentially expressed genes, while possible effects of GDM and diabetic pregnancy complicated by PE were not identifiable in this cohort. We conclude that fetal sex has a prominent effect on the placental transcriptome, dominating and confounding gene expression signatures resulting from diabetes mellitus in settings of well-controlled diabetic disease. Our results support the notion of placenta as a sexual dimorphic organ. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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11 pages, 290 KiB  
Article
Association of the FCN2 Gene Promoter Region Polymorphisms with Very Low Birthweight in Preterm Neonates
by Agnieszka Szala-Poździej, Anna S. Świerzko, Gabriela Gajek, Maja Kufelnicka-Babout, Karolina Chojnacka, Paulina Kobiela, Dariusz Jarych, Katarzyna Sobczuk, Jan Mazela, Iwona Domżalska-Popadiuk, Jarosław Kalinka, Hideharu Sekine, Misao Matsushita and Maciej Cedzyński
Int. J. Mol. Sci. 2022, 23(23), 15336; https://doi.org/10.3390/ijms232315336 - 05 Dec 2022
Cited by 3 | Viewed by 1423
Abstract
Single nucleotide polymorphisms (SNPs) localised to the promoter region of the FCN2 gene are known to influence the concentration of ficolin-2 in human serum and therefore potentially have clinical associations. We investigated the relationships between SNPs at positions −986 (A > G), −602 [...] Read more.
Single nucleotide polymorphisms (SNPs) localised to the promoter region of the FCN2 gene are known to influence the concentration of ficolin-2 in human serum and therefore potentially have clinical associations. We investigated the relationships between SNPs at positions −986 (A > G), −602 (G > A), −64 (A > C) and −4 (A > G) and clinical complications in 501 preterms. Major alleles at positions −986 and −64 and A/A homozygosity for both polymorphisms were less frequent among babies with very low birthweight (VLBW, ≤1500 g) compared with the reference group (OR = 0.24, p = 0.0029; and OR = 0.49, p = 0.024, respectively for A/A genotypes). A lower frequency of G/G homozygosity at position −4 was associated with gestational age <33 weeks and VLBW (OR = 0.38, p = 0.047; and OR = 0.07, p = 0.0034, respectively). The AGAG haplotype was protective for VLBW (OR = 0.6, p = 0.0369), whilst the GGCA haplotype had the opposite effect (OR = 2.95, p = 0.0249). The latter association was independent of gestational age. The AGAG/GGAA diplotype favoured both shorter gestational age and VLBW (OR = 1.82, p = 0.0234 and OR = 1.95, p = 0.0434, respectively). In contrast, AGAG homozygosity was protective for lower body mass (OR = 0.09, p = 0.0155). Our data demonstrate that some FCN2 variants associated with relatively low ficolin-2 increase the risk of VLBW and suggest that ficolin-2 is an important factor for fetal development/intrauterine growth. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
13 pages, 1326 KiB  
Article
First Trimester Maternal Plasma Aberrant miRNA Expression Associated with Spontaneous Preterm Birth
by Danai Mavreli, Mariana Theodora, Margaritis Avgeris, Nikolas Papantoniou, Panagiotis Antsaklis, George Daskalakis and Aggeliki Kolialexi
Int. J. Mol. Sci. 2022, 23(23), 14972; https://doi.org/10.3390/ijms232314972 - 29 Nov 2022
Cited by 5 | Viewed by 1044
Abstract
Spontaneous Preterm Delivery (sPTD) is one of the leading causes of perinatal mortality and morbidity worldwide. The present case–control study aims to detect miRNAs differentially expressed in the first trimester maternal plasma with the view to identify predictive biomarkers for sPTD, between 32 [...] Read more.
Spontaneous Preterm Delivery (sPTD) is one of the leading causes of perinatal mortality and morbidity worldwide. The present case–control study aims to detect miRNAs differentially expressed in the first trimester maternal plasma with the view to identify predictive biomarkers for sPTD, between 320/7 and 366/7 weeks, that will allow for timely interventions for this serious pregnancy complication. Small RNA sequencing (small RNA-seq) of five samples from women with a subsequent sPTD and their matched controls revealed significant down-regulation of miR-23b-5p and miR-125a-3p in sPTD cases compared to controls, whereas miR-4732-5p was significantly overexpressed. Results were confirmed by qRT-PCR in an independent cohort of 29 sPTD cases and 29 controls. Statistical analysis demonstrated that miR-125a is a promising early predictor for sPTL (AUC: 0.895; 95% CI: 0.814-0.972; p < 0.001), independent of the confounding factors tested, providing a useful basis for the development of a novel non-invasive predictive test to assist clinicians in estimating patient-specific risk. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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15 pages, 967 KiB  
Article
Molecular Indicators of Blood-Brain Barrier Breakdown and Neuronal Injury in Pregnancy Complicated by Fetal Growth Restriction
by Natalia Misan, Sławomir Michalak, Piotr Rzymski, Barbara Poniedziałek, Katarzyna Kapska, Krystyna Osztynowicz and Mariola Ropacka-Lesiak
Int. J. Mol. Sci. 2022, 23(22), 13798; https://doi.org/10.3390/ijms232213798 - 09 Nov 2022
Cited by 6 | Viewed by 1717
Abstract
This study evaluated the damage to the endothelial tight junctions (TJs) in pregnancies complicated by fetal growth restriction (FGR) and investigated whether FGR is related to blood–brain barrier disintegration and, subsequently, to the appearance of proteins indicative of neuronal injury in maternal blood. [...] Read more.
This study evaluated the damage to the endothelial tight junctions (TJs) in pregnancies complicated by fetal growth restriction (FGR) and investigated whether FGR is related to blood–brain barrier disintegration and, subsequently, to the appearance of proteins indicative of neuronal injury in maternal blood. The studied group included 90 pregnant women diagnosed with FGR. The control group consisted of 70 women with an uncomplicated pregnancy. The biochemical measurements included serum neuronal proteins (subunit of the N-methyl-D-aspartate receptor—NR1, nucleoside diphosphate kinase A—NME1, and S100 calcium-binding protein B—S100B), serum TJ proteins (occludin—OCLN, claudin-5—CLN5, zonula occludens—zo-1, and OCLN/zo-1 and CLN5/zo-1 ratios), and placental expression of TJ proteins (OCLN, claudin-4 CLN4, CLN5, zo-1). The significantly higher serum S100B and CLN5 levels and serum CLN5/zo-1 ratio were observed in FGR compared to healthy pregnancies. Moreover, FGR was characterized by increased placental CLN5 expression. Both serum NME1 levels and placental CLN4 expression in FGR pregnancies were significantly related to the incidence of neurological disorders in newborns. Mothers of FGR neonates who developed neurological complications and intraventricular hemorrhage (IVH) had statistically higher NME1 concentrations during pregnancy and significantly lower placental CLN4 expression than mothers of FGR neonates without neurological abnormalities. The serum NME1 levels and placental CLN4 expression were predictive markers of IVH in the FGR group. The blood–brain barrier is destabilized in pregnancies complicated by FGR. Neurological disorders, including IVH, are associated with higher serum concentrations of NME1 and the decreased placental expression of CLN4. The serum NME1 levels and placental CLN4 expression may serve as biomarkers, helpful in predicting IVH in FGR. It may allow for more precise monitoring and influence decision-making on the optimal delivery time to avoid developing neurological complications. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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16 pages, 1788 KiB  
Article
Impact of Placental SLC2A3 Deficiency during the First-Half of Gestation
by Cameron S. Lynch, Victoria C. Kennedy, Amelia R. Tanner, Asghar Ali, Quinton A. Winger, Paul J. Rozance and Russell V. Anthony
Int. J. Mol. Sci. 2022, 23(20), 12530; https://doi.org/10.3390/ijms232012530 - 19 Oct 2022
Cited by 5 | Viewed by 1627
Abstract
In the ruminant placenta, glucose uptake and transfer are mediated by facilitative glucose transporters SLC2A1 (GLUT1) and SLC2A3 (GLUT3). SLC2A1 is located on the basolateral trophoblast membrane, whereas SLC2A3 is located solely on the maternal-facing, apical trophoblast membrane. While SLC2A3 is less abundant [...] Read more.
In the ruminant placenta, glucose uptake and transfer are mediated by facilitative glucose transporters SLC2A1 (GLUT1) and SLC2A3 (GLUT3). SLC2A1 is located on the basolateral trophoblast membrane, whereas SLC2A3 is located solely on the maternal-facing, apical trophoblast membrane. While SLC2A3 is less abundant than SLC2A1, SLC2A3 has a five-fold greater affinity and transport capacity. Based on its location, SLC2A3 likely plays a significant role in the uptake of glucose into the trophoblast. Fetal hypoglycemia is a hallmark of fetal growth restriction (FGR), and as such, any deficiency in SLC2A3 could impact trophoblast glucose uptake and transfer to the fetus, thus potentially setting the stage for FGR. By utilizing in vivo placenta-specific lentiviral-mediated RNA interference (RNAi) in sheep, we were able to significantly diminish (p ≤ 0.05) placental SLC2A3 concentration, and determine the impact at mid-gestation (75 dGA). In response to SLC2A3 RNAi (n = 6), the fetuses were hypoglycemic (p ≤ 0.05), exhibited reduced fetal growth, including reduced fetal pancreas weight (p ≤ 0.05), which was associated with reduced umbilical artery insulin and glucagon concentrations, when compared to the non-targeting sequence (NTS) RNAi controls (n = 6). By contrast, fetal liver weights were not impacted, nor were umbilical artery concentrations of IGF1, possibly resulting from a 70% increase (p ≤ 0.05) in umbilical vein chorionic somatomammotropin (CSH) concentrations. Thus, during the first half of gestation, a deficiency in SLC2A3 results in fetal hypoglycemia, reduced fetal development, and altered metabolic hormone concentrations. These results suggest that SLC2A3 may be the rate-limiting placental glucose transporter during the first-half of gestation in sheep. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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13 pages, 4626 KiB  
Article
PEG2-Induced Pyroptosis Regulates the Expression of HMGB1 and Promotes hEM15A Migration in Endometriosis
by Yi Huang, Ruiyun Li, Rui Hu, Jia Yao and Yuan Yang
Int. J. Mol. Sci. 2022, 23(19), 11707; https://doi.org/10.3390/ijms231911707 - 03 Oct 2022
Cited by 8 | Viewed by 2038
Abstract
Endometriosis (EMS) is a common gynecological disease. Prostaglandin E2 (PGE2), which induces chronic pelvic inflammation and cell pyroptosis, a form of programmed cell death based on inflammasome activation, are involved in EMS, but the extent of their involvement and roles remain unclear. The [...] Read more.
Endometriosis (EMS) is a common gynecological disease. Prostaglandin E2 (PGE2), which induces chronic pelvic inflammation and cell pyroptosis, a form of programmed cell death based on inflammasome activation, are involved in EMS, but the extent of their involvement and roles remain unclear. The present study aimed to evaluate PGE2-induced pyroptosis in EMS and the influence of PGE2 in EMS progression. Using western blotting, it was found that the expressions of PGE2 and pyroptosis-related proteins (NLRP3, cleaved caspase-1, interleukin (IL)-1β and IL-18) were higher in EMS tissues than in normal endometrial tissues. The levels of PGE2, IL-1β, and IL-18 in the serum of patients with EMS and cell culture fluids were also detected. Using the transwell assay, we verified that PGE2 promoted hEM15A migration via the NLRP3/caspase-1 pyroptotic pathway, and PGE2-induced pyroptosis upregulated the expressions of high mobility group box 1 (HMGB1), E-cadherin, and vimentin. Immunohistochemistry analysis confirmed that PGE2-induced pyroptosis contributed to EMS invasion. These results suggest that PGE2-induced pyroptosis affects the progression of EMS by changing the migration ability of pyroptotic cells and upregulating the expression of HMGB1, E-cadherin, and vimentin. Our findings provide crucial evidence for new treatment pathways and use of anti-inflammatory drugs in EMS. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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16 pages, 914 KiB  
Article
Genome-Wide Copy Number Variant and High-Throughput Transcriptomics Analyses of Placental Tissues Underscore Persisting Child Susceptibility in At-Risk Pregnancies Cleared in Standard Genetic Testing
by Darina Czamara, Cristiana Cruceanu, Marius Lahti-Pulkkinen, Linda Dieckmann, Maik Ködel, Susann Sauer, Monika Rex-Haffner, Sara Sammallahti, Eero Kajantie, Hannele Laivuori, Jari Lahti, Katri Räikkönen and Elisabeth B. Binder
Int. J. Mol. Sci. 2022, 23(19), 11448; https://doi.org/10.3390/ijms231911448 - 28 Sep 2022
Cited by 1 | Viewed by 2025
Abstract
Several studies have shown that children from pregnancies with estimated first-trimester risk based on fetal nuchal translucency thickness and abnormal maternal serum pregnancy protein and hormone levels maintain a higher likelihood of adverse outcomes, even if initial testing for known genetic conditions is [...] Read more.
Several studies have shown that children from pregnancies with estimated first-trimester risk based on fetal nuchal translucency thickness and abnormal maternal serum pregnancy protein and hormone levels maintain a higher likelihood of adverse outcomes, even if initial testing for known genetic conditions is negative. We used the Finnish InTraUterine cohort (ITU), which is a comprehensively characterized perinatal cohort consisting of 943 mothers and their babies followed throughout pregnancy and 18 months postnatally, including mothers shortlisted for prenatal genetic testing but cleared for major aneuploidies (cases: n = 544, 57.7%) and control pregnancies (n = 399, 42.3%). Using genome-wide genotyping and RNA sequencing of first-trimester and term placental tissue, combined with medical information from registry data and maternal self-report data, we investigated potential negative medical outcomes and genetic susceptibility to disease and their correlates in placenta gene expression. Case mothers did not present with higher levels of depression, perceived stress, or anxiety during pregnancy. Case children were significantly diagnosed more often with congenital malformations of the circulatory system (4.12 (95% CI [1.22–13.93]) higher hazard) and presented with significantly more copy number duplications as compared to controls (burden analysis, based on all copy number variants (CNVs) with at most 10% frequency, 823 called duplications in 297 cases versus 626 called duplications in 277 controls, p = 0.01). Fifteen genes showed differential gene expression (FDR < 0.1) in association with congenital malformations in first-trimester but not term placenta. These were significantly enriched for genes associated with placental dysfunction. In spite of normal routine follow-up prenatal testing results in early pregnancy, case children presented with an increased likelihood of negative outcomes, which should prompt vigilance in follow-up during pregnancy and after birth. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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44 pages, 10605 KiB  
Article
Cardiovascular Disease-Associated MicroRNAs as Novel Biomarkers of First-Trimester Screening for Gestational Diabetes Mellitus in the Absence of Other Pregnancy-Related Complications
by Ilona Hromadnikova, Katerina Kotlabova and Ladislav Krofta
Int. J. Mol. Sci. 2022, 23(18), 10635; https://doi.org/10.3390/ijms231810635 - 13 Sep 2022
Cited by 16 | Viewed by 2444
Abstract
We assessed the diagnostic potential of cardiovascular disease-associated microRNAs for the early prediction of gestational diabetes mellitus (GDM) in singleton pregnancies of Caucasian descent in the absence of other pregnancy-related complications. Whole peripheral venous blood samples were collected within 10 to 13 weeks [...] Read more.
We assessed the diagnostic potential of cardiovascular disease-associated microRNAs for the early prediction of gestational diabetes mellitus (GDM) in singleton pregnancies of Caucasian descent in the absence of other pregnancy-related complications. Whole peripheral venous blood samples were collected within 10 to 13 weeks of gestation. This retrospective study involved all pregnancies diagnosed with only GDM (n = 121) and 80 normal term pregnancies selected with regard to equality of sample storage time. Gene expression of 29 microRNAs was assessed using real-time RT-PCR. Upregulation of 11 microRNAs (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-23a-3p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-181a-5p, miR-195-5p, miR-499a-5p, and miR-574-3p) was observed in pregnancies destinated to develop GDM. Combined screening of all 11 dysregulated microRNAs showed the highest accuracy for the early identification of pregnancies destinated to develop GDM. This screening identified 47.93% of GDM pregnancies at a 10.0% false positive rate (FPR). The predictive model for GDM based on aberrant microRNA expression profile was further improved via the implementation of clinical characteristics (maternal age and BMI at early stages of gestation and an infertility treatment by assisted reproductive technology). Following this, 69.17% of GDM pregnancies were identified at a 10.0% FPR. The effective prediction model specifically for severe GDM requiring administration of therapy involved using a combination of these three clinical characteristics and three microRNA biomarkers (miR-20a-5p, miR-20b-5p, and miR-195-5p). This model identified 78.95% of cases at a 10.0% FPR. The effective prediction model for GDM managed by diet only required the involvement of these three clinical characteristics and eight microRNA biomarkers (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-100-5p, miR-125b-5p, miR-195-5p, miR-499a-5p, and miR-574-3p). With this, the model identified 50.50% of GDM pregnancies managed by diet only at a 10.0% FPR. When other clinical variables such as history of miscarriage, the presence of trombophilic gene mutations, positive first-trimester screening for preeclampsia and/or fetal growth restriction by the Fetal Medicine Foundation algorithm, and family history of diabetes mellitus in first-degree relatives were included in the GDM prediction model, the predictive power was further increased at a 10.0% FPR (72.50% GDM in total, 89.47% GDM requiring therapy, and 56.44% GDM managed by diet only). Cardiovascular disease-associated microRNAs represent promising early biomarkers to be implemented into routine first-trimester screening programs with a very good predictive potential for GDM. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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13 pages, 1079 KiB  
Article
Evaluation of the Effect of the Fibroblast Growth Factor Type 2 (FGF-2) Administration on Placental Gene Expression in a Murine Model of Preeclampsia Induced by L-NAME
by Margarita L Martinez-Fierro, Idalia Garza-Veloz, Maria Eugenia Castañeda-Lopez, Dorothy Wasike, Claudia Castruita-De la Rosa, Iram Pablo Rodriguez-Sanchez, Ivan Delgado-Enciso and Jose Flores-Mendoza
Int. J. Mol. Sci. 2022, 23(17), 10129; https://doi.org/10.3390/ijms231710129 - 04 Sep 2022
Cited by 4 | Viewed by 2188
Abstract
The abnormal implantation of the trophoblast during the first trimester of pregnancy precedes the appearance of the clinical manifestations of preeclampsia (PE), which is a hypertensive disorder of pregnancy. In a previous study, which was carried out in a murine model of PE [...] Read more.
The abnormal implantation of the trophoblast during the first trimester of pregnancy precedes the appearance of the clinical manifestations of preeclampsia (PE), which is a hypertensive disorder of pregnancy. In a previous study, which was carried out in a murine model of PE that was induced by NG-nitro-L-arginine methyl ester (L-NAME), we observed that the intravenous administration of fibroblast growth factor 2 (FGF2) had a hypotensive effect, improved the placental weight gain and attenuated the fetal growth restriction, and the morphological findings that were induced by L-NAME in the evaluated tissues were less severe. In this study, we aimed to determine the effect of FGF2 administration on the placental gene expression of the vascular endothelial growth factor (VEGFA), VEGF receptor 2 (VEGFR2), placental growth factor, endoglin (ENG), superoxide dismutase 1 (SOD1), catalase (CAT), thioredoxin (TXN), tumor protein P53 (P53), BCL2 apoptosis regulator, Fas cell surface death receptor (FAS), and caspase 3, in a Sprague Dawley rat PE model, which was induced by L-NAME. The gene expression was determined by a real-time polymerase chain reaction using SYBR green. Taking the vehicle or the L-NAME group as a reference, there was an under expression of placental VEGFA, VEGFR2, ENG, P53, FAS, SOD1, CAT, and TXN genes in the group of L-NAME + FGF2 (p < 0.05). The administration of FGF2 in the murine PE-like model that was induced by L-NAME reduced the effects that were generated by proteinuria and the increased BP, as well as the response of the expression of genes that participate in angiogenesis, apoptosis, and OS. These results have generated valuable information regarding the identification of molecular targets for PE and provide new insights for understanding PE pathogenesis. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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12 pages, 1691 KiB  
Article
Mesenchymal Stem Cells-Induced Trophoblast Invasion Is Reduced in Patients with a Previous History of Preeclampsia
by Reyna Peñailillo, Stephanie Acuña-Gallardo, Felipe García, Lara J. Monteiro, Gino Nardocci, Mahesh A. Choolani, Matthew W. Kemp, Roberto Romero and Sebastián E. Illanes
Int. J. Mol. Sci. 2022, 23(16), 9071; https://doi.org/10.3390/ijms23169071 - 13 Aug 2022
Cited by 3 | Viewed by 2005
Abstract
Endometrial stromal cells play an important role in reproductive success, especially in implantation and placentation. Although Mesenchymal stem cells (MSCs) have been studied to assess decidualization disorders in preeclampsia (PE), their role during trophoblast invasion remains unclear. This study aims to determine: (i) [...] Read more.
Endometrial stromal cells play an important role in reproductive success, especially in implantation and placentation. Although Mesenchymal stem cells (MSCs) have been studied to assess decidualization disorders in preeclampsia (PE), their role during trophoblast invasion remains unclear. This study aims to determine: (i) whether MSCs isolated from menstrual fluid (MenSCs) from nulliparous, multiparous, and women with a previous history of preeclampsia exhibited different patterns of proliferation and migration and (ii) whether reproductive history (i.e., prior pregnancy or prior history of PE) was able to produce changes in MenSCs, thus altering trophoblast invasion capacity. MenSCs were collected from nulliparous and multiparous women without a history of PE and from non-pregnant women with a history of PE. Proliferation and migration assays were performed on MenSCs with sulforhodamine B and transwell assays, respectively. Trophoblast invasion was analyzed by culturing HTR-8/SVneo trophospheres on a matrigel overlying MenSCs for 72 h at 5% O2, simulating a 3D implantation model. A previous history of pregnancy or PE did not impact the proliferative capacity or migratory behavior of MenSCs. Following exposure to physiological endometrial conditions, MenSCs demonstrated upregulated expression of IGFBP-1 and LIF mRNA, decidualization and window of implantation markers, respectively. The mRNA expression of VIM, NANOG, and SOX2 was upregulated upon trophosphere formation. Relative to co-culture with multiparous MenSCs, co-culture with PE-MenSCs was associated with reduced trophoblast invasion. The findings of this study suggest a potential role for communication between maternal MenSCs and invading trophoblast cells during the implantation process that could be implicated in the etiology of PE. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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22 pages, 3582 KiB  
Article
Chronic Venous Disease during Pregnancy Causes a Systematic Increase in Maternal and Fetal Proinflammatory Markers
by Miguel A. Ortega, Ana M. Gómez-Lahoz, Lara Sánchez-Trujillo, Oscar Fraile-Martinez, Cielo García-Montero, Luis G. Guijarro, Coral Bravo, Juan A. De Leon-Luis, Jose V. Saz, Julia Bujan, Natalio García-Honduvilla, Jorge Monserrat and Melchor Alvarez-Mon
Int. J. Mol. Sci. 2022, 23(16), 8976; https://doi.org/10.3390/ijms23168976 - 11 Aug 2022
Cited by 8 | Viewed by 1792
Abstract
Chronic venous disease (CVD) is a common vascular disorder characterized by increased venous hypertension and insufficient venous return from the lower limbs. Pregnancy is a high-risk situation for developing CVD. Approximately a third of the women will develop this condition during pregnancy, and [...] Read more.
Chronic venous disease (CVD) is a common vascular disorder characterized by increased venous hypertension and insufficient venous return from the lower limbs. Pregnancy is a high-risk situation for developing CVD. Approximately a third of the women will develop this condition during pregnancy, and similarly to arterial hypertensive disorders, previous evidence has described a plethora of alterations in placental structure and function in women with pregnancy-induced CVD. It is widely known that arterial-induced placenta dysfunction is accompanied by an important immune system alteration along with increased inflammatory markers, which may provide detrimental consequences for the women and their offspring. However, to our knowledge, there are still no data collected regarding cytokine profiling in women with pregnancy-induced CVD. Thus, the aim of the present work was to examine cytokine signatures in the serum of pregnant women (PW) with CVD and their newborns (NB). This study was conducted through a multiplex technique in 62 PW with pregnancy-induced CVD in comparison to 52 PW without CVD (HC) as well as their NB. Our results show significant alterations in a broad spectrum of inflammatory cytokines (IL-6, IL-12, TNF-α, IL-10, IL-13, IL-2, IL-7, IFN-γ, IL-4, IL-5, IL-21, IL-23, GM-CSF, chemokines (fractalkine), MIP-3α, and MIP-1β). Overall, we demonstrate that pregnancy-induced CVD is associated with a proinflammatory environment, therefore highlighting the potentially alarming consequences of this condition for maternal and fetal wellbeing. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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Review

Jump to: Editorial, Research, Other

14 pages, 960 KiB  
Review
Association of B Cells with Idiopathic Recurrent Pregnancy Loss: A Systematic Review and Meta-Analysis
by Miguel Ângelo-Dias, Catarina Martins, Sara Simões Dias, Luís Miguel Borrego and Jorge Lima
Int. J. Mol. Sci. 2022, 23(23), 15200; https://doi.org/10.3390/ijms232315200 - 02 Dec 2022
Cited by 3 | Viewed by 1886
Abstract
Recurrent pregnancy loss (RPL) affects 1–2% of women and is defined as having experienced two or more failed pregnancies. In almost 50% of cases, the causes are idiopathic (IRPL), but increasing evidence has suggested an immunological cause. B cells are known to provide [...] Read more.
Recurrent pregnancy loss (RPL) affects 1–2% of women and is defined as having experienced two or more failed pregnancies. In almost 50% of cases, the causes are idiopathic (IRPL), but increasing evidence has suggested an immunological cause. B cells are known to provide crucial support for a successful pregnancy outcome. However, their involvement in the mechanisms underlying IRPL is still unclear. This systematic review and meta-analysis aimed to comprehensively summarise the existing evidence regarding the levels and profiles of B cells in IRPL. An extensive computerized search in PubMed/Medline, Embase, Scopus, and Web of Science databases was performed with no imposed limits. Two reviewers independently screened all retrieved studies, extracted all the data, and assessed the methodological quality. Disagreements were resolved by a third reviewer. From a total of 1125 retrieved studies, 19 studies were included in the systematic review, and 8 studies were quantitatively analysed. We highlight a potential association between women with IRPL and increased levels of endometrial B cells. In addition, the flow cytometry technique seems to be preferred over immunohistochemistry for identifying those differences, while further studies are necessary to clarify the role of B cells as an immunological risk factor for RPL. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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32 pages, 932 KiB  
Review
IL-6 and IL-8: An Overview of Their Roles in Healthy and Pathological Pregnancies
by Aleksandra Vilotić, Mirjana Nacka-Aleksić, Andrea Pirković, Žanka Bojić-Trbojević, Dragana Dekanski and Milica Jovanović Krivokuća
Int. J. Mol. Sci. 2022, 23(23), 14574; https://doi.org/10.3390/ijms232314574 - 23 Nov 2022
Cited by 28 | Viewed by 6444
Abstract
Interleukin-6 (IL-6) is an acknowledged inflammatory cytokine with a pleiotropic action, mediating innate and adaptive immunity and multiple physiological processes, including protective and regenerative ones. IL-8 is a pro-inflammatory CXC chemokine with a primary function in attracting and activating neutrophils, but also implicated [...] Read more.
Interleukin-6 (IL-6) is an acknowledged inflammatory cytokine with a pleiotropic action, mediating innate and adaptive immunity and multiple physiological processes, including protective and regenerative ones. IL-8 is a pro-inflammatory CXC chemokine with a primary function in attracting and activating neutrophils, but also implicated in a variety of other cellular processes. These two ILs are abundantly expressed at the feto-maternal interface over the course of a pregnancy and have been shown to participate in numerous pregnancy-related events. In this review, we summarize the literature data regarding their role in healthy and pathological pregnancies. The general information related to IL-6 and IL-8 functions is followed by an overview of their overall expression in cycling endometrium and at the feto-maternal interface. Further, we provide an overview of their involvement in pregnancy establishment and parturition. Finally, the implication of IL-6 and IL-8 in pregnancy-associated pathological conditions, such as pregnancy loss, preeclampsia, gestational diabetes mellitus and infection/inflammation is discussed. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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12 pages, 805 KiB  
Review
Endometrium Immunomodulation to Prevent Recurrent Implantation Failure in Assisted Reproductive Technology
by Mustapha Benkhalifa, Fabien Joao, Cynthia Duval, Debbie Montjean, Molka Bouricha, Rosalie Cabry, Marie-Claire Bélanger, Hatem Bahri, Pierre Miron and Moncef Benkhalifa
Int. J. Mol. Sci. 2022, 23(21), 12787; https://doi.org/10.3390/ijms232112787 - 24 Oct 2022
Cited by 7 | Viewed by 4016
Abstract
After more than four decades of assisted reproductive technology (ART) practice worldwide, today more than 60% of women undergoing in vitro fertilization (IVF) treatments fail to become pregnant after the first embryo transfer and nearly 20% of patients are suffering from unexplained recurrent [...] Read more.
After more than four decades of assisted reproductive technology (ART) practice worldwide, today more than 60% of women undergoing in vitro fertilization (IVF) treatments fail to become pregnant after the first embryo transfer and nearly 20% of patients are suffering from unexplained recurrent implantation failures (RIFs) and repeated pregnancy loss (RPL). The literature reported different causes of RIF–RPL, mainly multifactorial, endometrial and idiopathic. RIF remains a black box because of the complicated categorization and causes of this physio-pathological dysregulation of implantation and pregnancy process after ovarian stimulation. Many options were suggested as solutions to treat RIF–RPL with controversial results on their usefulness. In this article, we reviewed different possible therapeutic options to improve implantation rates and clinical outcomes. Based on our experience we believe that endometrium immunomodulation after intrauterine insemination of activated autologous peripheral blood mononuclear cells (PBMCs) or platelet-rich plasma (PRP) can be a promising therapeutic solution. On the other hand, peripheral lymphocyte balance typing, specific cytokines and interleukins profiling can be proposed as predictive biomarkers of implantation before embryo transfer. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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22 pages, 917 KiB  
Review
Galectins: Important Regulators in Normal and Pathologic Pregnancies
by Min Chen, Jia-Lu Shi, Zi-Meng Zheng, Zhi Lin, Ming-Qing Li and Jun Shao
Int. J. Mol. Sci. 2022, 23(17), 10110; https://doi.org/10.3390/ijms231710110 - 03 Sep 2022
Cited by 5 | Viewed by 2548
Abstract
Galectins (Gal) are characterized by their affinity for galactoside structures on glycoconjugates. This relationship is mediated by carbohydrate recognition domains, which are multifunctional regulators of basic cellular biological processes with high structural similarity among family members. They participate in both innate and adaptive [...] Read more.
Galectins (Gal) are characterized by their affinity for galactoside structures on glycoconjugates. This relationship is mediated by carbohydrate recognition domains, which are multifunctional regulators of basic cellular biological processes with high structural similarity among family members. They participate in both innate and adaptive immune responses, as well as in reproductive immunology. Recently, the discovery that galectins are highly expressed at the maternal–fetal interface has garnerd the interest of experts in human reproduction. Galectins are involved in a variety of functions such as maternal–fetal immune tolerance, angiogenesis, trophoblast invasion and placental development and are considered to be important mediators of successful embryo implantation and during pregnancy. Dysregulation of these galectins is associated with abnormal and pathological pregnancies (e.g., preeclampsia, gestational diabetes mellitus, fetal growth restriction, preterm birth). Our work reviews the regulatory mechanisms of galectins in normal and pathological pregnancies and has implications for clinicians in the prevention, diagnosis and treatment of pregnancy-related diseases. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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Other

8 pages, 4448 KiB  
Case Report
A Fatal Case of Metastatic Pulmonary Calcification during the Puerperium
by Alberto Chighine, Andrea Corona, Gualtiero Catani, Celeste Conte, Roberto Demontis and Matteo Nioi
Int. J. Mol. Sci. 2022, 23(23), 15131; https://doi.org/10.3390/ijms232315131 - 01 Dec 2022
Cited by 1 | Viewed by 1080
Abstract
We present an unusual case of a fatal respiratory failure in a young woman developed two weeks after she gave birth at home. Circumstantial and clinical features of the case were strongly suggestive for a ‘classical’ septic origin of the respiratory symptoms. Autopsy, [...] Read more.
We present an unusual case of a fatal respiratory failure in a young woman developed two weeks after she gave birth at home. Circumstantial and clinical features of the case were strongly suggestive for a ‘classical’ septic origin of the respiratory symptoms. Autopsy, together with histopathological and immunohistochemical analyses allowed demonstrating a massive calcium redistribution consisting of an important osteolysis, especially from cranial bones and abnormal accumulation in lungs and other organs. Such physiopathology was driven by a primary hyperparathyroidism secondary to a parathyroid carcinoma as demonstrated by immunohistochemistry. This very rare case is furthermore characterised by a regular pregnancy course, ended with the birth of a healthy new-born. A complex interaction between pregnancy physiology and hyperparathyroidism might be hypothesised, determining the discrepancy between the relative long period of wellness and the tumultuous cascade occurred in the puerperium. Full article
(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complication)
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