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Molecular Pathogenesis and Treatment of Pregnancy Complications

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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: 15 December 2024 | Viewed by 12625

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Dr. Radzisław Mierzyński

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Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-954 Lublin, Poland
Interests: maternal and fetal medicine; obesity; metabolic syndrome; adipokines; maternal nutrition; hypertension; preeclampsia; ultrasound in obstetrics; perinatal outcome

Dr. Elżbieta Poniedziałek-Czajkowska

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Guest Editor

Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-954 Lublin, Poland
Interests: maternal and fetal medicine; obesity; metabolic syndrome; adipokines; hypertension; preeclampsia; preterm labor; obstetric emergency; perinatal outcome
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Dear Colleagues,

We are honored to present this Special Issue entitled "Molecular Pathogenesis and Treatment of Pregnancy Complications". It aims to present high-quality scientific articles (original research articles or comprehensive/systematic review papers) presenting the latest achievements and research directions in the field of pregnancy complications.

Pregnancy is a unique period in which attention is focused simultaneously on two people: the mother and the developing baby. The health of the pregnant mother during the pre-pregnancy period is one of the necessary conditions for the proper development of the fetus and affects the further development of the child after birth. An understanding of the molecular mechanisms associated with the initiation and onset of severe pregnancy-related complications enables for the identification of potential biomarkers for early stratification of at-risk patients. Pregnancy-related complications may also affect the occurrence of metabolic, cardiovascular, cerebrovascular, renal and other diseases in the later life of mothers and their offspring. The currently observed progress in perinatal medicine in the field of basic sciences has allowed us to understand to a greater degree the impact of maternal factors on the development of the fetus. Additionally, the development of trials has meant that we can now create the optimal conditions for the development of the fetus through the prevention and treatment of diseases in the mother.

The aim of this Special Issue is to provide an overview of the latest research on the molecular mechanisms involved in pregnancy-related complications. In the hope of creating a multidisciplinary platform for scientific exchange, we invite all researchers interested in maternal health to share their research results.

Dr. Radzisław Mierzyński
Dr. Elżbieta Poniedziałek-Czajkowska
Guest Editors

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Keywords

preterm delivery
intraamniotic infection
preeclampsia
hypertension
metabolic syndrome
maternal health
prematurity

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Published Papers (10 papers)

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24 pages, 6053 KiB

Open AccessArticle

Gestational Diabetes-like Fuels Impair Mitochondrial Function and Long-Chain Fatty Acid Uptake in Human Trophoblasts

by Kyle M. Siemers, Lisa A. Joss-Moore and Michelle L. Baack

Int. J. Mol. Sci. 2024, 25(21), 11534; https://doi.org/10.3390/ijms252111534 - 27 Oct 2024

Viewed by 1312

Abstract

In the parent, gestational diabetes mellitus (GDM) causes both hyperglycemia and hyperlipidemia. Despite excess lipid availability, infants exposed to GDM are at risk for essential long-chain polyunsaturated fatty acid (LCPUFA) deficiency. Isotope studies have confirmed less LCPUFA transfer from the parent to the fetus, but how diabetic fuels impact placental fatty acid (FA) uptake and lipid droplet partitioning is not well-understood. We evaluated the effects of high glucose conditions, high lipid conditions, and their combination on trophoblast growth, viability, mitochondrial bioenergetics, BODIPY-labeled fatty acid (FA) uptake, and lipid droplet dynamics. The addition of four carbons or one double bond to FA acyl chains dramatically affected the uptake in both BeWo and primary isolated cytotrophoblasts (CTBs). The uptake was further impacted by media exposure. The combination-exposed trophoblasts had more mitochondrial protein (p = 0.01), but impaired maximal and spare respiratory capacities (p < 0.001 and p < 0.0001), as well as lower viability (p = 0.004), due to apoptosis. The combination-exposed trophoblasts had unimpaired uptake of BODIPY C12 but had significantly less whole-cell and lipid droplet uptake of BODIPY C16, with an altered lipid droplet count, area, and subcellular localization, whereas these differences were not seen with individual high glucose or lipid exposure. These findings bring us closer to understanding how GDM perturbs active FA transport to increase the risk of adverse outcomes from placental and neonatal lipid accumulation alongside LCPUFA deficiency. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Treatment of Pregnancy Complications)

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13 pages, 648 KiB

Open AccessArticle

Polymorphism rs259983 of the Zinc Finger Protein 831 Gene Increases Risk of Superimposed Preeclampsia in Women with Gestational Diabetes Mellitus

by Nataliia Karpova, Olga Dmitrenko and Malik Nurbekov

Int. J. Mol. Sci. 2024, 25(20), 11108; https://doi.org/10.3390/ijms252011108 - 16 Oct 2024

Viewed by 599

Abstract

Hypertensive disorders of pregnancy (HDP) are a great danger. A previous GWAS found a relationship between rs259983 of the ZNF831 gene and HDP, such as for chronic hypertension (CHTN) and preeclampsia (PE). We conducted the case-control study to determine the association between rs259983 of the ZNF831 gene and HDP in women with Gestational Diabetes Mellitus (GDM). For target genotyping, we developed primers and TaqMan probes. In analyzing the population, we did not manage to find a relationship between PE and rs259983 of the ZNF831 gene. Additional study of women with PE and PE superimposed on CHTN (SIPE) establishes an association between rs259983 of the ZNF831 gene only with SIPE. Carriers of CC genotypes have been discovered to have a 5.05 times higher risk of SIPE development in women with GDM. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Treatment of Pregnancy Complications)

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14 pages, 5396 KiB

Open AccessArticle

Impaired Endothelium-Dependent Vasodilation and Increased Levels of Soluble Fms-like Tyrosine Kinase-1 Induced by Reduced Uterine Perfusion Pressure in Pregnant Rats: Evidence of Protective Effects with Sodium Nitrite Treatment in Preeclampsia

by Maria Luiza Santos Da Silva, Sáskia Estela Biasotti Gomes, Laisla Zanetoni Martins, Serginara David Rodrigues, Cristal de Jesus Toghi and Carlos Alan Dias-Junior

Int. J. Mol. Sci. 2024, 25(20), 11051; https://doi.org/10.3390/ijms252011051 - 15 Oct 2024

Viewed by 654

Abstract

Preeclampsia (PE) is a hypertensive disorder of pregnancy and is associated with increases in soluble fms-like tyrosine kinase-1 (sFlt-1) and reductions in nitric oxide (NO) levels. Placental ischemia and hypoxia are hypothesized as initial pathophysiological events of PE. Nitrite (NO metabolite) may be recycled back to NO in ischemic and hypoxic tissues. Therefore, this study examined the sodium nitrite effects in an experimental model of PE. Pregnant rats received saline (Preg group) or sodium nitrite (Preg + Na-Nitrite group). Pregnant rats submitted to the placental ischemia received saline (RUPP group) or sodium nitrite (RUPP + Na-Nitrite group). Blood pressure, placental and fetal weights, and the number of pups were recorded. Plasma levels of NO metabolites and sFlt-1 were also determined. Vascular and endothelial functions were also measured. Blood pressure, placental and fetal weights, the number of pups, NO metabolites, sFlt-1 levels, vascular contraction, and endothelium-dependent vasodilation in the RUPP + Na-Nitrite rats were brought to levels comparable to those in Preg rats. In conclusion, sodium nitrite may counteract the reductions in NO and increases in sFlt-1 levels induced by the placental ischemia model of PE, thus suggesting that increased blood pressure and vascular and endothelial dysfunctions may be attenuated by sodium nitrite-derived NO. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Treatment of Pregnancy Complications)

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16 pages, 5664 KiB

Open AccessArticle

Maternal Plasma miRNAs as Early Biomarkers of Moderate-to-Late-Preterm Birth

by Farha Ramzan, Jing Rong, Claire T. Roberts, Justin M. O’Sullivan, Jo K. Perry, Rennae Taylor, Lesley McCowan and Mark H. Vickers

Int. J. Mol. Sci. 2024, 25(17), 9536; https://doi.org/10.3390/ijms25179536 - 2 Sep 2024

Viewed by 1144

Abstract

Globally, preterm birth (PTB) is a primary cause of mortality and morbidity in infants, with PTB rates increasing worldwide over the last two decades. Biomarkers for accurate early prediction of PTB before the clinical event do not currently exist. Given their roles in the development and progression of many disease states, there has been increasing interest in the utility of microRNAs (miRNAs) as early biomarkers for pregnancy-related disorders, including PTB. The present study was designed to examine potential differences in miRNA abundances in maternal plasma from mothers with infants born following a moderate to late (28–36 weeks’ gestation, n = 54) spontaneous PTB (SPTB) compared to mothers with matched term infants (n = 54). Maternal plasma collected at 15 weeks’ gestation were utilised from the Auckland and Adelaide cohorts from the Screening for Pregnancy Endpoints (SCOPE) study. miRNAs in plasma were quantified using the NanoString nCounter expression panel (800 miRNAs). The top four most abundant miRNAs were significantly decreased in the plasma of mothers in the SPTB group with results consistent across both cohorts and pathway analysis was undertaken to examine the biological processes linked to the dysregulated miRNAs. The top candidate miRNAs (miRs-451a, −223-3p, let-7a-5p, and -126-3p) were linked to gene pathways associated with inflammation, apoptosis, and mitochondrial biogenesis. Moreover, miRNAs were consistently less abundant in the plasma of mothers of preterm infants across both sites, suggesting potential global dysregulation in miRNA biogenesis. This was supported by a significant downregulation in expression of key genes that are involved in miRNA biogenesis (DROSHA, DICER, and AGO2) across both sites in the SPTB group. In summary, the present study has identified miRNAs in maternal plasma that may provide predictive utility as early biomarkers for the risk of later SPTB. Importantly, these observations were conserved across two independent cohorts. Further, our data provide evidence for a persistent decrease in miRNA abundance in mothers who later experienced an SPTB, which is likely to have widespread consequences for gene regulation and epigenetic processes. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Treatment of Pregnancy Complications)

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19 pages, 4020 KiB

Open AccessArticle

Impact of Maternal Pre-Pregnancy Underweight on Cord Blood Metabolome: An Analysis of the Population-Based Survey of Neonates in Pomerania (SNiP)

by Alexander Lichtwald, Till Ittermann, Nele Friedrich, Anja Erika Lange, Theresa Winter, Claudia Kolbe, Heike Allenberg, Matthias Nauck and Matthias Heckmann

Int. J. Mol. Sci. 2024, 25(14), 7552; https://doi.org/10.3390/ijms25147552 - 10 Jul 2024

Viewed by 910

Abstract

Intrauterine growth restriction leads to an altered lipid and amino acid profile in the cord blood at the end of pregnancy. Pre-pregnancy underweight is an early risk factor for impaired fetal growth. The aim of this study was to investigate whether a pre-pregnancy body mass index (ppBMI) of <18.5 kg/m², as early as at the beginning of pregnancy, is associated with changes in the umbilical cord metabolome. In a sample of the Survey of Neonates in Pomerania (SNIP) birth cohort, the cord blood metabolome of n = 240 newborns of mothers with a ppBMI of <18.5 kg/m² with n = 208 controls (ppBMI of 18.5–24.9 kg/m²) was measured by NMR spectrometry. A maternal ppBMI of <18.5 kg/m² was associated with increased concentrations of HDL4 cholesterol, HDL4 phospholipids, VLDL5 cholesterol, HDL 2, and HDL4 Apo-A1, as well as decreased VLDL triglycerides and HDL2 free cholesterol. A ppBMI of <18.5 kg/m² combined with poor intrauterine growth (a gestational weight gain (GWG) < 25th percentile) was associated with decreased concentrations of total cholesterol; cholesterol transporting lipoproteins (LDL4, LDL6, LDL free cholesterol, and HDL2 free cholesterol); LDL4 Apo-B; total Apo-A2; and HDL3 Apo-A2. In conclusion, maternal underweight at the beginning of pregnancy already results in metabolic changes in the lipid profile in the cord blood, but the pattern changes when poor GWG is followed by pre-pregnancy underweight. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Treatment of Pregnancy Complications)

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14 pages, 279 KiB

Open AccessArticle

The Effects of Pregestational Overweight and Obesity on Maternal Lipidome in Pregnancy: Implications for Newborns’ Characteristics

by Minja Derikonjic, Marija Saric Matutinovic, Sandra Vladimirov Sopic, Tamara Antonic, Aleksandra Stefanovic, Jelena Vekic, Daniela Ardalic, Milica Miljkovic-Trailovic, Marko Stankovic, Tamara Gojkovic, Jasmina Ivanisevic, Jelena Munjas, Snezana Jovicic, Zeljko Mikovic and Aleksandra Zeljkovic

Int. J. Mol. Sci. 2024, 25(13), 7449; https://doi.org/10.3390/ijms25137449 - 7 Jul 2024

Viewed by 977

Abstract

Obesity is an important risk factor for the development of pregnancy complications. We investigated the effects of pregestational overweight and obesity on maternal lipidome during pregnancy and on newborns’ characteristics. The study encompassed 131 pregnant women, 99 with pre-pregnancy body mass index (BMI) < 25 kg/m² and 32 with BMI ≥ 25 kg/m². Maternal lipid status parameters, plasma markers of cholesterol synthesis and absorption and sphingolipids were determined in each trimester. Data on neonatal height, weight and APGAR scores were assessed. The results showed a higher prevalence (p < 0.05) of pregnancy and childbirth complications among the participants with elevated pregestational BMI. Levels of total cholesterol, HDL-cholesterol (p < 0.05) and LDL-cholesterol (p < 0.01) were significantly lower, and concentrations of triglycerides were higher (p < 0.05) in women with increased pre-gestational BMI. Lower concentrations of the cholesterol synthesis marker, desmosterol, in the 2nd trimester (p < 0.01) and the cholesterol absorption marker, campesterol, in each trimester (p < 0.01, p < 0.05, p < 0.01, respectively) were also found in this group. Markers of maternal cholesterol synthesis were in positive correlation with neonatal APGAR scores in the group of mothers with healthy pre-pregnancy weight but in negative correlation in the overweight/obese group. Our results indicate that gestational adaptations of maternal lipidome depend on her pregestational nutritional status and that such changes may affect neonatal outcomes. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Treatment of Pregnancy Complications)

14 pages, 1652 KiB

Open AccessArticle

Fetal Hypoglycemia Induced by Placental SLC2A3-RNA Interference Alters Fetal Pancreas Development and Transcriptome at Mid-Gestation

by Victoria C. Kennedy, Cameron S. Lynch, Amelia R. Tanner, Quinton A. Winger, Ahmed Gad, Paul J. Rozance and Russell V. Anthony

Int. J. Mol. Sci. 2024, 25(9), 4780; https://doi.org/10.3390/ijms25094780 - 27 Apr 2024

Viewed by 1102

Abstract

Glucose, the primary energy substrate for fetal oxidative processes and growth, is transferred from maternal to fetal circulation down a concentration gradient by placental facilitative glucose transporters. In sheep, SLC2A1 and SLC2A3 are the primary transporters available in the placental epithelium, with SLC2A3 located on the maternal-facing apical trophoblast membrane and SLC2A1 located on the fetal-facing basolateral trophoblast membrane. We have previously reported that impaired placental SLC2A3 glucose transport resulted in smaller, hypoglycemic fetuses with reduced umbilical artery insulin and glucagon concentrations, in addition to diminished pancreas weights. These findings led us to subject RNA derived from SLC2A3-RNAi (RNA interference) and NTS-RNAi (non-targeting sequence) fetal pancreases to qPCR followed by transcriptomic analysis. We identified a total of 771 differentially expressed genes (DEGs). Upregulated pathways were associated with fat digestion and absorption, particularly fatty acid transport, lipid metabolism, and cholesterol biosynthesis, suggesting a potential switch in energetic substrates due to hypoglycemia. Pathways related to molecular transport and cell signaling in addition to pathways influencing growth and metabolism of the developing pancreas were also impacted. A few genes directly related to gluconeogenesis were also differentially expressed. Our results suggest that fetal hypoglycemia during the first half of gestation impacts fetal pancreas development and function that is not limited to β cell activity. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Treatment of Pregnancy Complications)

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11 pages, 1290 KiB

Open AccessArticle

Identification of Short-Chain Fatty Acids for Predicting Preterm Birth in Cervicovaginal Fluid Using Mass Spectrometry

by Young-Min Hur, Eun-Jin Kwon, Young-Ah You, Sunwha Park, Soo-Min Kim, Gain Lee, Yoon-Young Go and Young-Ju Kim

Int. J. Mol. Sci. 2024, 25(6), 3396; https://doi.org/10.3390/ijms25063396 - 17 Mar 2024

Viewed by 1147

Abstract

Preterm birth (PTB) refers to delivery before 37 weeks of gestation. Premature neonates exhibit higher neonatal morbidity and mortality rates than term neonates; therefore, predicting and preventing PTB are important. In this study, we investigated the potential of using short-chain fatty acid (SCFA) levels, specific vaginal microbiota-derived metabolites, as a biomarker in predicting PTB using gas chromatography/mass spectrometry. Cervicovaginal fluid (CVF) was collected from 89 pregnant women (29 cases of PTB vs. 60 controls) without evidence of other clinical infections, and SCFA levels were measured. Furthermore, the PTB group was divided into two subgroups based on birth timing after CVF sampling: delivery ≤ 2 days after sampling (n = 10) and ≥2 days after sampling (n = 19). The concentrations of propionic acid, isobutyric acid, butyric acid, valeric acid, hexanoic acid, and heptanoic acid were significantly higher in the PTB group than in the term birth (TB) group (p < 0.05). In particular, the concentrations of propionic acid, isobutyric acid, hexanoic acid, and heptanoic acid were continuously higher in the PTB group than in the TB group (p < 0.05). In the delivery ≤ 2 days after sampling group, the propionic acid, isobutyric acid, hexanoic acid, and heptanoic acid levels were significantly higher than those in the other groups (p < 0.05). This study demonstrated a significant association between specific SCFAs and PTB. We propose these SCFAs as potential biomarkers for the prediction of PTB. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Treatment of Pregnancy Complications)

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28 pages, 1298 KiB

Open AccessReview

Neurodevelopmental Disruptions in Children of Preeclamptic Mothers: Pathophysiological Mechanisms and Consequences

by Andrea González-Rojas and Martina Valencia-Narbona

Int. J. Mol. Sci. 2024, 25(7), 3632; https://doi.org/10.3390/ijms25073632 - 24 Mar 2024

Cited by 1 | Viewed by 2008

Abstract

Preeclampsia (PE) is a multisystem disorder characterized by elevated blood pressure in the mother, typically occurring after 20 weeks of gestation and posing risks to both maternal and fetal health. PE causes placental changes that can affect the fetus, particularly neurodevelopment. Its key pathophysiological mechanisms encompass hypoxia, vascular and angiogenic dysregulation, inflammation, neuronal and glial alterations, and disruptions in neuronal signaling. Animal models indicate that PE is correlated with neurodevelopmental alterations and cognitive dysfunctions in offspring and in humans, an association between PE and conditions such as cerebral palsy, autism spectrum disorder, attention deficit hyperactivity disorder, and sexual dimorphism has been observed. Considering the relevance for mothers and children, we conducted a narrative literature review to describe the relationships between the pathophysiological mechanisms behind neurodevelopmental alterations in the offspring of PE mothers, along with their potential consequences. Furthermore, we emphasize aspects pertinent to the prevention/treatment of PE in pregnant mothers and alterations observed in their offspring. The present narrative review offers a current, complete, and exhaustive analysis of (i) the pathophysiological mechanisms that can affect neurodevelopment in the children of PE mothers, (ii) the relationship between PE and neurological alterations in offspring, and (iii) the prevention/treatment of PE. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Treatment of Pregnancy Complications)

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20 pages, 1368 KiB

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The Role of the FGF19 Family in the Pathogenesis of Gestational Diabetes: A Narrative Review

by Agata Sadowska, Elżbieta Poniedziałek-Czajkowska and Radzisław Mierzyński

Int. J. Mol. Sci. 2023, 24(24), 17298; https://doi.org/10.3390/ijms242417298 - 9 Dec 2023

Viewed by 1744

Abstract

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. Understanding the pathogenesis and appropriate diagnosis of GDM enables the implementation of early interventions during pregnancy that reduce the risk of maternal and fetal complications. At the same time, it provides opportunities to prevent diabetes, metabolic syndrome, and cardiovascular diseases in women with GDM and their offspring in the future. Fibroblast growth factors (FGFs) represent a heterogeneous family of signaling proteins which play a vital role in cell proliferation and differentiation, repair of damaged tissues, wound healing, angiogenesis, and mitogenesis and also affect the regulation of carbohydrate, lipid, and hormone metabolism. Abnormalities in the signaling function of FGFs may lead to numerous pathological conditions, including metabolic diseases. The FGF19 subfamily, also known as atypical FGFs, which includes FGF19, FGF21, and FGF23, is essential in regulating metabolic homeostasis and acts as a hormone while entering the systemic circulation. Many studies have pointed to the involvement of the FGF19 subfamily in the pathogenesis of metabolic diseases, including GDM, although the results are inconclusive. FGF19 and FGF21 are thought to be associated with insulin resistance, an essential element in the pathogenesis of GDM. FGF21 may influence placental metabolism and thus contribute to fetal growth and metabolism regulation. The observed relationship between FGF21 and increased birth weight could suggest a potential role for FGF21 in predicting future metabolic abnormalities in children born to women with GDM. In this group of patients, different mechanisms may contribute to an increased risk of cardiovascular diseases in women in later life, and FGF23 appears to be their promising early predictor. This study aims to present a comprehensive review of the FGF19 subfamily, emphasizing its role in GDM and predicting its long-term metabolic consequences for mothers and their offspring. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Treatment of Pregnancy Complications)

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