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Diagnostic or Therapeutic Strategies for Pregnancy Complications
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Diagnostic or Therapeutic Strategies for Pregnancy Complications

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Obstetrics & Gynecology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 46108

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

Special Issue Editors

Prof. Dr. Alex Heazell

E-Mail Website
Guest Editor
1. Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9WL, UK
2. St Mary’s Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre; Manchester M13 9WL, UK
Interests: pregnancy complications; stillbirth; reduced fetal movements; growth restriction
Dr. Sylvie Girard

E-Mail Website
Guest Editor
Department of Obstetrics & Gynecology, Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
Interests: placenta; inflammation; infection; preeclampsia; preterm birth; cytokines; alarmins

Special Issue Information

Dear Colleagues,

As many of you know, pregnancy complications including preeclampsia, preterm birth, stillbirth, and intrauterine growth restriction affect over 12% of all pregnancies worldwide. These complications negatively impact both maternal and neonatal health and have short- and long-term effects such as increased risk of neurodevelopmental and cardiovascular diseases. Over the past decade, numerous groups have investigated the use of new and/or existing drugs to either prolong gestation, such as in cases of threatened preterm labour; alleviate hypertension  in preeclampsia; or promote adequate blood flow and nutrient delivery to the placenta to facilitate growth in IUGR. The overarching goal has been to promote healthier pregnancies and neonatal health, but the work has been difficult to translate into the clinical setting with problems in terms of drug delivery, specificity, and importantly, the early diagnostic capacities for the complications of pregnancy. Our goal with this Special Issue is to encourage submissions of papers that discuss current advances in prenatal diagnostics, knowledge gaps in the development of novel therapeutic strategies, uses of artificial intelligence to understand the placental impact of pregnancy complications, as well as recent advances in targeted drug delivery.

Prof. Dr. Alex Heazell
Dr. Sylvie Girard
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Pregnancy complications
  • Prenatal diagnostic
  • Placenta
  • Therapies
  • Drug development
  • Targeted drug delivery

Published Papers (15 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 171 KiB  
Editorial
Diagnostic or Therapeutic Strategies for Pregnancy Complications
by Camille Couture and Sylvie Girard
J. Clin. Med. 2022, 11(11), 3144; https://doi.org/10.3390/jcm11113144 - 31 May 2022
Viewed by 1620
Abstract
Pregnancy complications including preeclampsia, preterm birth, recurrent pregnancy loss, and fetal growth restriction affect over 12% of all pregnancies worldwide [...] Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)

Research

Jump to: Editorial, Review, Other

13 pages, 853 KiB  
Article
Placental Pathology as a Tool to Identify Women for Postpartum Cardiovascular Risk Screening following Preeclampsia: A Preliminary Investigation
by Samantha J. Benton, Erika E. Mery, David Grynspan, Laura M. Gaudet, Graeme N. Smith and Shannon A. Bainbridge
J. Clin. Med. 2022, 11(6), 1576; https://doi.org/10.3390/jcm11061576 - 13 Mar 2022
Cited by 6 | Viewed by 2117
Abstract
Preeclampsia (PE) is associated with an increased risk of cardiovascular disease (CVD) in later life. Postpartum cardiovascular risk screening could identify patients who would benefit most from early intervention and lifestyle modification. However, there are no readily available methods to identify these high-risk [...] Read more.
Preeclampsia (PE) is associated with an increased risk of cardiovascular disease (CVD) in later life. Postpartum cardiovascular risk screening could identify patients who would benefit most from early intervention and lifestyle modification. However, there are no readily available methods to identify these high-risk women. We propose that placental lesions may be useful in this regard. Here, we determine the association between placental lesions and lifetime CVD risk assessed 6 months following PE. Placentas from 85 PE women were evaluated for histopathological lesions. At 6 months postpartum, a lifetime cardiovascular risk score was calculated. Placental lesions were compared between CVD risk groups and the association was assessed using odds ratios. Multivariable logistic regression was used to develop prediction models for CVD risk with placental pathology. Placentas from high-risk women had more severe lesions of maternal vascular malperfusion (MVM) and resulted in a 3-fold increased risk of screening as high-risk for CVD (OR 3.10 (1.20–7.92)) compared to women without these lesions. MVM lesion severity was moderately predictive of high-risk screening (AUC 0.63 (0.51, 0.75); sensitivity 71.8% (54.6, 84.4); specificity 54.7% (41.5, 67.3)). When clinical parameters were added, the model’s predictive performance improved (AUC 0.73 (0.62, 0.84); sensitivity 78.4% (65.4, 87.5); specificity 51.6% (34.8, 68.0)). The results suggest that placenta pathology may provide a unique modality to identify women for cardiovascular screening. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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10 pages, 1277 KiB  
Article
Circulating SPINT1 Is Reduced in a Preeclamptic Cohort with Co-Existing Fetal Growth Restriction
by Ciara N. Murphy, Catherine A. Cluver, Susan P. Walker, Emerson Keenan, Roxanne Hastie, Teresa M. MacDonald, Natalie J. Hannan, Fiona C. Brownfoot, Ping Cannon, Stephen Tong and Tu’uhevaha J. Kaitu’u-Lino
J. Clin. Med. 2022, 11(4), 901; https://doi.org/10.3390/jcm11040901 - 9 Feb 2022
Cited by 4 | Viewed by 1717
Abstract
Fetal growth restriction (FGR), when undetected antenatally, is the biggest risk factor for preventable stillbirth. Maternal circulating SPINT1 is reduced in pregnancies, which ultimately deliver small for gestational age (SGA) infants at term (birthweight < 10th centile), compared to appropriate for gestational age [...] Read more.
Fetal growth restriction (FGR), when undetected antenatally, is the biggest risk factor for preventable stillbirth. Maternal circulating SPINT1 is reduced in pregnancies, which ultimately deliver small for gestational age (SGA) infants at term (birthweight < 10th centile), compared to appropriate for gestational age (AGA) infants (birthweight ≥ 10th centile). SPINT1 is also reduced in FGR diagnosed before 34 weeks’ gestation. We hypothesised that circulating SPINT1 would be decreased in co-existing preterm preeclampsia and FGR. Plasma SPINT1 was measured in samples obtained from two double-blind, randomised therapeutic trials. In the Preeclampsia Intervention with Esomeprazole trial, circulating SPINT1 was decreased in women with preeclampsia who delivered SGA infants (n = 75, median = 18,857 pg/mL, IQR 10,782–29,890 pg/mL, p < 0.0001), relative to those delivering AGA (n = 22, median = 40,168 pg/mL, IQR 22,342–75,172 pg/mL). This was confirmed in the Preeclampsia Intervention 2 with metformin trial where levels of SPINT1 in maternal circulation were reduced in SGA pregnancies (n = 95, median = 57,764 pg/mL, IQR 42,212–91,356 pg/mL, p < 0.0001) compared to AGA controls (n = 40, median = 107,062 pg/mL, IQR 70,183–176,532 pg/mL). Placental Growth Factor (PlGF) and sFlt-1 were also measured. PlGF was significantly reduced in the SGA pregnancies, while ratios of sFlt-1/SPINT1 and sFlt1/PlGF were significantly increased. This is the first study to demonstrate significantly reduced SPINT1 in co-existing FGR and preeclamptic pregnancies. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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10 pages, 523 KiB  
Article
Impact of Co-Existing Placental Pathologies in Pregnancies Complicated by Placental Abruption and Acute Neonatal Outcomes
by Dorsa Mavedatnia, Jason Tran, Irina Oltean, Vid Bijelić, Felipe Moretti, Sarah Lawrence and Dina El Demellawy
J. Clin. Med. 2021, 10(23), 5693; https://doi.org/10.3390/jcm10235693 - 3 Dec 2021
Cited by 5 | Viewed by 1999
Abstract
Placental abruption (PA) is a concern for maternal and neonatal morbidity. Adverse neonatal outcomes in the setting of PA include higher risk of prematurity. Placental pathologies include maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), acute chorioamnionitis, and villitis of unknown etiology (VUE). [...] Read more.
Placental abruption (PA) is a concern for maternal and neonatal morbidity. Adverse neonatal outcomes in the setting of PA include higher risk of prematurity. Placental pathologies include maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), acute chorioamnionitis, and villitis of unknown etiology (VUE). We aimed to investigate how placental pathology contributes to acute neonatal outcome in PA. A retrospective cohort study of all placentas with PA were identified. Exposures were MVM, FVM, acute chorioamnionitis and VUE. The primary outcome was NICU admission and the secondary outcomes included adverse base deficit and Apgar scores, need for resuscitation, and small-for-gestational age. A total of 287 placentas were identified. There were 160 (59.9%) of placentas with PA alone vs 107 (40.1%) with PA and additional placental pathologies. Odds of NICU admission were more than two times higher in pregnancies with placental pathologies (OR = 2.37, 95% CI 1.28–4.52). These estimates were in large part mediated by prematurity and birthweight, indirect effect acting through prematurity was OR 1.79 (95% CI 1.12–2.75) and through birthweight OR 2.12 (95% CI 1.40–3.18). Odds of Apgar score ≤ 5 was more than four times higher among pregnancies with placental pathologies (OR = 4.56, 95% CI 1.28–21.26). Coexisting placental pathology may impact Apgar scores in pregnancies complicated by PA. This knowledge could be used by neonatal teams to mobilize resources in anticipation of the need for neonatal resuscitation. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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10 pages, 6263 KiB  
Article
Clinical Validation of a Proteomic Biomarker Threshold for Increased Risk of Spontaneous Preterm Birth and Associated Clinical Outcomes: A Replication Study
by Julja Burchard, Ashoka D. Polpitiya, Angela C. Fox, Todd L. Randolph, Tracey C. Fleischer, Max T. Dufford, Thomas J. Garite, Gregory C. Critchfield, J. Jay Boniface, George R. Saade and Paul E. Kearney
J. Clin. Med. 2021, 10(21), 5088; https://doi.org/10.3390/jcm10215088 - 29 Oct 2021
Cited by 5 | Viewed by 2850
Abstract
Preterm births are the leading cause of neonatal death in the United States. Previously, a spontaneous preterm birth (sPTB) predictor based on the ratio of two proteins, IBP4/SHBG, was validated as a predictor of sPTB in the Proteomic Assessment of Preterm Risk (PAPR) [...] Read more.
Preterm births are the leading cause of neonatal death in the United States. Previously, a spontaneous preterm birth (sPTB) predictor based on the ratio of two proteins, IBP4/SHBG, was validated as a predictor of sPTB in the Proteomic Assessment of Preterm Risk (PAPR) study. In particular, a proteomic biomarker threshold of −1.37, corresponding to a ~two-fold increase or ~15% risk of sPTB, significantly stratified earlier deliveries. Guidelines for molecular tests advise replication in a second independent study. Here we tested whether the significant association between proteomic biomarker scores above the threshold and sPTB, and associated adverse outcomes, was replicated in a second independent study, the Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor (TREETOP). The threshold significantly stratified subjects in PAPR and TREETOP for sPTB (p = 0.041, p = 0.041, respectively). Application of the threshold in a Kaplan–Meier analysis demonstrated significant stratification in each study, respectively, for gestational age at birth (p < 001, p = 0.0016) and rate of hospital discharge for both neonate (p < 0.001, p = 0.005) and mother (p < 0.001, p < 0.001). Above the threshold, severe neonatal morbidity/mortality and mortality alone were 2.2 (p = 0.0083,) and 7.4-fold higher (p = 0.018), respectively, in both studies combined. Thus, higher predictor scores were associated with multiple adverse pregnancy outcomes. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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12 pages, 1187 KiB  
Article
Sildenafil Citrate Downregulates PDE5A mRNA Expression in Women with Recurrent Pregnancy Loss without Altering Angiogenic Factors—A Preliminary Study
by Monika Kniotek, Aleksander Roszczyk, Michał Zych, Małgorzata Wrzosek, Monika Szafarowska, Radosław Zagożdżon and Małgorzata Jerzak
J. Clin. Med. 2021, 10(21), 5086; https://doi.org/10.3390/jcm10215086 - 29 Oct 2021
Cited by 3 | Viewed by 1805
Abstract
In our previous study, we showed that sildenafil citrate (SC), a selective PDE5A blocker, modulated NK cell activity in patients with recurrent pregnancy loss, which correlated with positive pregnancy outcomes. It was found that NK cells had a pivotal role in decidualization, angiogenesis, [...] Read more.
In our previous study, we showed that sildenafil citrate (SC), a selective PDE5A blocker, modulated NK cell activity in patients with recurrent pregnancy loss, which correlated with positive pregnancy outcomes. It was found that NK cells had a pivotal role in decidualization, angiogenesis, spiral artery remodeling, and the regulation of trophoblast invasion. Thus, in the current study, we determined the effects of SC on angiogenic factor expression and production, as well as idNK cell activity in the presence of nitric synthase blocker L-NMMA. Methods: NK cells (CD56+) were isolated from the peripheral blood of 15 patients and 15 fertile women on MACS columns and cultured in transformation media containing IL-15, TGF-β, and AZA—a methylation agent—for 7 days in hypoxia (94% N2, 1% O2, 5% CO2). Cultures were set up in four variants: (1) with SC, (2) without SC, (3) with NO, a synthase blocker, and (4) with SC and NO synthase blocker. NK cell activity was determined after 7 days of culturing as CD107a expression after an additional 4h of stimulation with K562 erythroleukemia cells. The expression of the PDE5A, VEGF-A, PIGF, IL-8, and RENBP genes was determined with quantitative real-time PCR (qRT-PCR) using TaqMan probes and ELISA was used to measure the concentrations of VEGF-A, PLGF, IL-8, Ang-I, Ang-II, IFN–γ proteins in culture supernatants after SC supplementation. Results: SC downregulated PDE5A expression and had no effect on other studied angiogenic factors. VEGF-A expression was increased in RPL patients compared with fertile women. Similarly, VEGF production was enhanced in RPL patients’ supernatants and SC increased the concentration of PIGF in culture supernatants. SC did not affect the expression or concentration of other studied factors, nor idNK cell activity, regardless of NO synthase blockade. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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13 pages, 1935 KiB  
Article
Proteomic Analysis of Maternal Urine for the Early Detection of Preeclampsia and Fetal Growth Restriction
by Emmanuel Bujold, Alexandre Fillion, Florence Roux-Dalvai, Marie Pier Scott-Boyer, Yves Giguère, Jean-Claude Forest, Clarisse Gotti, Geneviève Laforest, Paul Guerby and Arnaud Droit
J. Clin. Med. 2021, 10(20), 4679; https://doi.org/10.3390/jcm10204679 - 13 Oct 2021
Cited by 4 | Viewed by 1901
Abstract
Background: To explore the use of maternal urine proteome for the identification of preeclampsia biomarkers. Methods: Maternal urine samples from women with and without preeclampsia were used for protein discovery followed by a validation study. The targeted proteins of interest were then measured [...] Read more.
Background: To explore the use of maternal urine proteome for the identification of preeclampsia biomarkers. Methods: Maternal urine samples from women with and without preeclampsia were used for protein discovery followed by a validation study. The targeted proteins of interest were then measured in urine samples collected at 20–24 and 30–34 weeks among nine women who developed preeclampsia, one woman with fetal growth restriction, and 20 women with uncomplicated pregnancies from a longitudinal study. Protein identification and quantification was obtained using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results: Among the 1108 urine proteins quantified in the discovery study, 21 were upregulated in preeclampsia and selected for validation. Nineteen (90%) proteins were confirmed as upregulated in preeclampsia cases. Among them, two proteins, ceruloplasmin and serpin A7, were upregulated at 20–24 weeks and 30–34 weeks of gestation (p < 0.05) in cases of preeclampsia, and could have served to identify 60% of women who subsequently developed preeclampsia and/or fetal growth restriction at 20–24 weeks of gestation, and 78% at 30–34 weeks, for a false-positive rate of 10%. Conclusions: Proteomic profiling of maternal urine can differentiate women with and without preeclampsia. Several proteins including ceruloplasmin and serpin A7 are upregulated in maternal urine before the diagnosis of preeclampsia and potentially fetal growth restriction. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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12 pages, 1782 KiB  
Article
Evaluating Markers of Immune Tolerance and Angiogenesis in Maternal Blood for an Association with Risk of Pregnancy Loss
by Michelle A. Wyatt, Sarah C. Baumgarten, Amy L. Weaver, Chelsie C. Van Oort, Bohdana Fedyshyn, Rodrigo Ruano, Chandra C. Shenoy and Elizabeth Ann L. Enninga
J. Clin. Med. 2021, 10(16), 3579; https://doi.org/10.3390/jcm10163579 - 14 Aug 2021
Cited by 7 | Viewed by 1947
Abstract
Pregnancy loss affects approximately 20% of couples. The lack of a clear cause complicates half of all miscarriages. Early evidence indicates the maternal immune system and angiogenesis regulation are both key players in implantation success or failure. Therefore, this prospective study recruited women [...] Read more.
Pregnancy loss affects approximately 20% of couples. The lack of a clear cause complicates half of all miscarriages. Early evidence indicates the maternal immune system and angiogenesis regulation are both key players in implantation success or failure. Therefore, this prospective study recruited women in the first trimester with known viable intrauterine pregnancy and measured blood levels of immune tolerance proteins galectin-9 (Gal-9) and interleukin (IL)-4, and angiogenesis proteins (vascular endothelial growth factors (VEGF) A, C, and D) between 5 and 9 weeks gestation. Plasma concentrations were compared between groups defined based on (a) pregnancy outcome and (b) maternal history of miscarriage, respectively. In total, 56 women were recruited with 10 experiencing a miscarriage or pregnancy loss in the 2nd or 3rd trimester and 11 having a maternal history or miscarriage. VEGF-C was significantly lower among women with a miscarriage or pregnancy loss. Gal-9 and VEGF-A concentrations were decreased in women with a prior miscarriage. Identification of early changes in maternal immune and angiogenic factors during pregnancy may be a tool to improve patient counseling on pregnancy loss risk and future interventions to reduce miscarriage in a subset of women. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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17 pages, 4523 KiB  
Article
Pre-Clinical Investigation of Cardioprotective Beta-Blockers as a Therapeutic Strategy for Preeclampsia
by Natalie K. Binder, Teresa M. MacDonald, Sally A. Beard, Natasha de Alwis, Stephen Tong, Tu’uhevaha J. Kaitu’u-Lino and Natalie J. Hannan
J. Clin. Med. 2021, 10(15), 3384; https://doi.org/10.3390/jcm10153384 - 30 Jul 2021
Cited by 5 | Viewed by 2016
Abstract
Despite significant maternal and fetal morbidity, a treatment for preeclampsia currently remains an unmet need in clinical care. As too does the lifelong cardiovascular risks imparted on preeclampsia sufferers. Endothelial dysfunction and end-organ injury are synonymous with both preeclampsia and cardiovascular disease, including [...] Read more.
Despite significant maternal and fetal morbidity, a treatment for preeclampsia currently remains an unmet need in clinical care. As too does the lifelong cardiovascular risks imparted on preeclampsia sufferers. Endothelial dysfunction and end-organ injury are synonymous with both preeclampsia and cardiovascular disease, including heart failure. We propose that beta-blockers, known to improve endothelial dysfunction in the treatment of cardiovascular disease, and specifically known to reduce mortality in the treatment of heart failure, may be beneficial in the treatment of preeclampsia. Here, we assessed whether the beta-blockers carvedilol, bisoprolol, and metoprolol could quench the release of anti-angiogenic factors, promote production of pro-angiogenic factors, reduce markers of inflammation, and reduce endothelial dysfunction using our in vitro pre-clinical preeclampsia models encompassing primary placental tissue and endothelial cells. Here, we show beta-blockers effected a modest reduction in secretion of anti-angiogenic soluble fms-like tyrosine kinase-1 and soluble endoglin and increased expression of pro-angiogenic placental growth factor, vascular endothelial growth factor and adrenomedullin in endothelial cells. Beta-blocker treatment mitigated inflammatory changes occurring after endothelial dysfunction and promoted cytoprotective antioxidant heme oxygenase-1. The positive effects of the beta-blockers were predominantly seen in endothelial cells, with a less consistent response seen in placental cells/tissue. In conclusion, beta-blockers show potential as a novel therapeutic approach in the treatment of preeclampsia and warrant further investigation. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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14 pages, 3084 KiB  
Article
The Inflammatory Milieu of Amniotic Fluid Increases with Chorio-Deciduitis Grade in Inflammation-Restricted to Choriodecidua, but Not Amnionitis, of Extra-Placental Membranes
by Joon Hyung Lee, Chan-Wook Park, Kyung Chul Moon, Joong Shin Park and Jong Kwan Jun
J. Clin. Med. 2021, 10(14), 3041; https://doi.org/10.3390/jcm10143041 - 8 Jul 2021
Cited by 1 | Viewed by 1876
Abstract
No information exists about whether intra-amniotic inflammatory response increases with a chorio-deciduitis grade in the context of both inflammation-restricted to chorio-decidua and amnionitis of extra-placental membranes among spontaneous preterm births. The objective of current study is to examine this issue. A study population [...] Read more.
No information exists about whether intra-amniotic inflammatory response increases with a chorio-deciduitis grade in the context of both inflammation-restricted to chorio-decidua and amnionitis of extra-placental membranes among spontaneous preterm births. The objective of current study is to examine this issue. A study population included 195 singleton pregnant women with chorio-deciduitis, and who spontaneously delivered at preterm (21.6~35.7 weeks) within 7 days of amniocentesis. We examined intra-amniotic inflammatory response according to the chorio-deciduitis grade in the context of inflammation restricted to chorio-decidua and amnionitis of extra-placental membranes. Intra-amniotic inflammatory response was measured by MMP-8 concentration (ng/mL) and WBC-count (cells/mm3) in amniotic-fluid (AF). Inflammation restricted to chorio-decidua and amnionitis were present in 47.7% (93/195) and 52.3% (102/195) of cases, respectively. Median AF MMP-8 concentration and WBC-count significantly increased with chorio-deciduitis grade in the context of inflammation restricted to chorio-decidua. However, there was no significant difference in median AF MMP-8 concentration and WBC-count between chorio-deciduitis grade-1 and grade-2 in the context of amnionitis. The inflammatory milieu of AF increases with chorio-deciduitis grade in inflammation-restricted to chorio-decidua, but not amnionitis, of extra-placental membranes. This finding suggests that a chorio-deciduitis grade may have little effect on the intensification of intra-amniotic inflammatory response in the context of amnionitis of extra-placental membranes. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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9 pages, 262 KiB  
Article
MMP-2 and MMP-9 Polymorphisms and Preeclampsia Risk in Tunisian Arabs: A Case-Control Study
by Marwa Ben Ali Gannoun, Nozha Raguema, Hedia Zitouni, Meriem Mehdi, Ondrej Seda, Touhami Mahjoub and Julie L. Lavoie
J. Clin. Med. 2021, 10(12), 2647; https://doi.org/10.3390/jcm10122647 - 16 Jun 2021
Cited by 11 | Viewed by 1919
Abstract
The abnormal production of matrix metalloproteinases (MMPs), especially MMP-9 and MMP-2, plays a pivotal role in hypertensive disorders of pregnancy, and as such, can influence the development of preeclampsia. These alterations may result from functional genetic polymorphisms in the promoter region of MMP-9 [...] Read more.
The abnormal production of matrix metalloproteinases (MMPs), especially MMP-9 and MMP-2, plays a pivotal role in hypertensive disorders of pregnancy, and as such, can influence the development of preeclampsia. These alterations may result from functional genetic polymorphisms in the promoter region of MMP-9 and MMP-2 genes, which modify MMP-9 and MMP-2 expression. We investigated the association of MMP-9 polymorphism rs3918242 (-1562 C>T) and MMP-2 polymorphism rs2285053 (-735 C>T) with the risk of preeclampsia. This case–control study was conducted on 345 women with preeclampsia and 281 age-matched women with normal pregnancies from Tunisian hospitals. Genomic DNA was extracted from whole blood collected at delivery. Genotypes for -1562 C>T and -735 C>T polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). An increased frequency of heterozygous MMP-9 -1562 C/T genotype carriers was observed in women with preeclampsia compared to healthy controls (p = 0.03). In contrast, the MMP-2 -735 C>T polymorphism was not significantly different regarding frequency distribution of the allele and genotype between healthy pregnant women and women with preeclampsia. Our study suggests that the MMP-9 -1562 C/T variant, associated with high MMP-9 production, could be a genetic risk factor for preeclampsia in Tunisian women. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
12 pages, 3056 KiB  
Article
Uterine Cervical Change at Term Examined Using Ultrasound Elastography: A Longitudinal Study
by Hyun Soo Park, Hayan Kwon, Ja-Young Kwon, Yun Ji Jung, Hyun-Joo Seol, Won Joon Seong, Hyun Mi Kim, Han-Sung Hwang, Ji-Hee Sung and Soo-young Oh
J. Clin. Med. 2021, 10(1), 75; https://doi.org/10.3390/jcm10010075 - 28 Dec 2020
Cited by 6 | Viewed by 1993
Abstract
The aim of the study was to investigate if there are changes in elastographic parameters in the cervix at term around the time of delivery and if there are differences in the parameters between women with spontaneous labor and those without labor (labor [...] Read more.
The aim of the study was to investigate if there are changes in elastographic parameters in the cervix at term around the time of delivery and if there are differences in the parameters between women with spontaneous labor and those without labor (labor induction). Nulliparous women at 36 weeks of gestation eligible for vaginal delivery were enrolled. Cervical elastography was performed and cervical length were measured using the E-CervixTM system (WS80A Ultrasound System, Samsung Medison, Seoul, Korea) at each weekly antenatal visit until admission for spontaneous labor or labor induction. E-Cervix parameters of interest included elasticity contrast index (ECI), internal os strain mean level (IOS), external os strain mean level (EOS), IOS/EOS strain mean ratio, strain mean level, and hardness ratio. Regression analysis was performed using days from elastographic measurement at each visit to admission for delivery and the presence or absence of labor against cervical length, and each E-Cervix parameter fitted to a linear model for longitudinal data measured repeatedly. A total of 96 women were included in the analysis, (spontaneous labor, n = 39; labor induction, n = 57). Baseline characteristics were not different between the two groups except for cesarean delivery rate. Cervical length decreased with advancing gestation and was different between the two groups. Most elastographic parameters including ECI, IOS, EOS, strain mean, and hardness ratio were significantly different between the two groups. In addition, ECI, IOS, and strain mean values significantly increased with advancing gestation. Our longitudinal study using ultrasound elastography indicated that E-cervix parameters tended to change linearly at term near the time of admission for delivery and that there were differences in E-Cervix parameters according to the presence or absence of labor. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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Review

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21 pages, 788 KiB  
Review
Sex Differences Are Here to Stay: Relevance to Prenatal Care
by Amy M. Inkster, Icíar Fernández-Boyano and Wendy P. Robinson
J. Clin. Med. 2021, 10(13), 3000; https://doi.org/10.3390/jcm10133000 - 5 Jul 2021
Cited by 21 | Viewed by 9354
Abstract
Sex differences exist in the incidence and presentation of many pregnancy complications, including but not limited to pregnancy loss, spontaneous preterm birth, and fetal growth restriction. Sex differences arise very early in development due to differential gene expression from the X and Y [...] Read more.
Sex differences exist in the incidence and presentation of many pregnancy complications, including but not limited to pregnancy loss, spontaneous preterm birth, and fetal growth restriction. Sex differences arise very early in development due to differential gene expression from the X and Y chromosomes, and later may also be influenced by the action of gonadal steroid hormones. Though offspring sex is not considered in most prenatal diagnostic or therapeutic strategies currently in use, it may be beneficial to consider sex differences and the associated mechanisms underlying pregnancy complications. This review will cover (i) the prevalence and presentation of sex differences that occur in perinatal complications, particularly with a focus on the placenta; (ii) possible mechanisms underlying the development of sex differences in placental function and pregnancy phenotypes; and (iii) knowledge gaps that should be addressed in the development of diagnostic or risk prediction tools for such complications, with an emphasis on those for which it would be important to consider sex. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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34 pages, 23966 KiB  
Review
Landscape of Preterm Birth Therapeutics and a Path Forward
by Brahm Seymour Coler, Oksana Shynlova, Adam Boros-Rausch, Stephen Lye, Stephen McCartney, Kelycia B. Leimert, Wendy Xu, Sylvain Chemtob, David Olson, Miranda Li, Emily Huebner, Anna Curtin, Alisa Kachikis, Leah Savitsky, Jonathan W. Paul, Roger Smith and Kristina M. Adams Waldorf
J. Clin. Med. 2021, 10(13), 2912; https://doi.org/10.3390/jcm10132912 - 29 Jun 2021
Cited by 23 | Viewed by 8266
Abstract
Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear efficacy. Tocolytic agents are drugs that briefly delay PTB, typically to allow antenatal corticosteroid administration for accelerating fetal [...] Read more.
Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear efficacy. Tocolytic agents are drugs that briefly delay PTB, typically to allow antenatal corticosteroid administration for accelerating fetal lung maturity or to transfer patients to high-level care facilities. Globally, there is an unmet need for better tocolytic agents, particularly in low- and middle-income countries. Although most tocolytics, such as betamimetics and indomethacin, suppress downstream mediators of the parturition pathway, newer therapeutics are being designed to selectively target inflammatory checkpoints with the goal of providing broader and more effective tocolysis. However, the relatively small market for new PTB therapeutics and formidable regulatory hurdles have led to minimal pharmaceutical interest and a stagnant drug pipeline. In this review, we present the current landscape of PTB therapeutics, assessing the history of drug development, mechanisms of action, adverse effects, and the updated literature on drug efficacy. We also review the regulatory hurdles and other obstacles impairing novel tocolytic development. Ultimately, we present possible steps to expedite drug development and meet the growing need for effective preterm birth therapeutics. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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22 pages, 893 KiB  
Systematic Review
A Systematic Review of the Safety of Blocking the IL-1 System in Human Pregnancy
by Marie-Eve Brien, Virginie Gaudreault, Katia Hughes, Dexter J. L. Hayes, Alexander E. P. Heazell and Sylvie Girard
J. Clin. Med. 2022, 11(1), 225; https://doi.org/10.3390/jcm11010225 - 31 Dec 2021
Cited by 18 | Viewed by 3065
Abstract
Blockade of the interleukin-1 (IL-1) pathway has been used therapeutically in several inflammatory diseases including arthritis and cryopyrin-associated periodic syndrome (CAPS). These conditions frequently affect women of childbearing age and continued usage of IL-1 specific treatments throughout pregnancy has been reported. IL-1 is [...] Read more.
Blockade of the interleukin-1 (IL-1) pathway has been used therapeutically in several inflammatory diseases including arthritis and cryopyrin-associated periodic syndrome (CAPS). These conditions frequently affect women of childbearing age and continued usage of IL-1 specific treatments throughout pregnancy has been reported. IL-1 is involved in pregnancy complications and its blockade could have therapeutic potential. We systematically reviewed all reported cases of IL-1 blockade in human pregnancy to assess safety and perinatal outcomes. We searched several databases to find reports of specific blockade of the IL-1 pathway at any stage of pregnancy, excluding broad spectrum or non-specific anti-inflammatory intervention. Our literature search generated 2439 references of which 22 studies included, following extensive review. From these, 88 different pregnancies were assessed. Most (64.8%) resulted in healthy term deliveries without any obstetrical/neonatal complications. Including pregnancy exposed to Anakinra or Canakinumab, 12 (15.0%) resulted in preterm birth and one stillbirth occurred. Regarding neonatal complications, 2 cases of renal agenesis (2.5%) were observed, and 6 infants were diagnosed with CAPS (7.5%). In conclusion, this systematic review describes that IL-1 blockade during pregnancy is not associated with increased adverse perinatal outcomes, considering that treated women all presented an inflammatory disease associated with elevated risk of pregnancy complications. Full article
(This article belongs to the Special Issue Diagnostic or Therapeutic Strategies for Pregnancy Complications)
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