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BMC Pregnancy and Childbirth Jul 2023There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product...
BACKGROUND
There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product profiles (TPPs) for medicines to prevent spontaneous preterm birth and manage preterm labor. The objectives of this study were to 1) analyse the research and development pipeline of medicines for preterm birth and 2) compare these medicines to target product profiles for spontaneous preterm birth to identify the most promising candidates.
METHODS
Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched to identify candidate medicines (including drugs, dietary supplements and biologics) and populate the Accelerating Innovations for Mothers (AIM) database. This database was screened for all candidates that have been investigated for preterm birth. Candidates in clinical development were ranked against criteria from TPPs, and classified as high, medium or low potential. Preclinical candidates were categorised by product type, archetype and medicine subclass.
RESULTS
The AIM database identified 178 candidates. Of the 71 candidates in clinical development, ten were deemed high potential (Prevention: Omega-3 fatty acid, aspirin, vaginal progesterone, oral progesterone, L-arginine, and selenium; Treatment: nicorandil, isosorbide dinitrate, nicardipine and celecoxib) and seven were medium potential (Prevention: pravastatin and lactoferrin; Treatment: glyceryl trinitrate, retosiban, relcovaptan, human chorionic gonadotropin and Bryophyllum pinnatum extract). 107 candidates were in preclinical development.
CONCLUSIONS
This analysis provides a drug-agnostic approach to assessing the potential of candidate medicines for spontaneous preterm birth. Research should be prioritised for high-potential candidates that are most likely to meet the real world needs of women, babies, and health care professionals.
Topics: Infant, Newborn; Female; Humans; Premature Birth; Progesterone; Obstetric Labor, Premature; Fatty Acids, Omega-3
PubMed: 37464260
DOI: 10.1186/s12884-023-05842-9 -
Scientific Reports Oct 2020Preterm labor (PTL) and Preterm Premature Rupture of Membranes (PPROM) impose substantial morbimortality on mothers and newborns. Exosomes act in intercellular...
Preterm labor (PTL) and Preterm Premature Rupture of Membranes (PPROM) impose substantial morbimortality on mothers and newborns. Exosomes act in intercellular communication carrying molecules involved in physiopathological processes. Little is known about exosomal proteins in prematurity. Our aim was to evaluate the protein expression of hemopexin, C1 inhibitor (C1INH) and alpha-2-macroglobulin (A2M) from circulating exosomes of women with PTL and PPROM. Plasma was obtained from PTL, PPROM, Term in labor and Term out of labor (T) patients, exosomes were isolated by ultracentrifugation, then lysed and the proteins quantified. Western Blot (WB) and Nanoparticle Tracking Analysis (NTA) were performed. Data were compared by Kruskal-Wallis, unpaired T-test and one-way ANOVA. WB and NTA confirmed exosome isolation (concentration: 4.3 × 10 particles/ml ± 1.9 × 10). There was no difference regarding hemopexin or C1INH expression between the groups. For A2M, the fold change was significantly higher on preterm groups when compared to term groups (1.07 ± 0.30 vs. 0.42 ± 0.17, p < 0.0001). Higher levels of A2M in circulating exosomes are linked to preterm pregnancies. sEV are strong candidates to intermediate maternal-fetal communication, carrying preterm labor-related immunomodulatory proteins.
Topics: Adult; Complement C1 Inhibitor Protein; Exosomes; Female; Fetal Membranes, Premature Rupture; Hemopexin; Humans; Maternal-Fetal Exchange; Obstetric Labor, Premature; Pregnancy; Pregnancy-Associated alpha 2-Macroglobulins; Pregnant Women; Young Adult
PubMed: 33046786
DOI: 10.1038/s41598-020-73772-z -
European Review For Medical and... Jul 2017To investigate changes in the peripheral blood mRNA levels of oxytocin receptor (OXTR) and Zinc finger E-box-binding homeobox 1 (ZEB1) before and after progesterone...
OBJECTIVE
To investigate changes in the peripheral blood mRNA levels of oxytocin receptor (OXTR) and Zinc finger E-box-binding homeobox 1 (ZEB1) before and after progesterone dosing in pregnant women with threatened premature labor.
PATIENTS AND METHODS
Blood samples were collected from 30 healthy pregnant women with 28- to 33+6-week gestational age and singleton pregnancy (group A) and from 30 pregnant women with singleton pregnancy and threatened premature labor before and 48 hours after progesterone dosing (groups B and C, respectively) for quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assay to assess the OXTR and ZEB1 mRNA levels.
RESULTS
The OXTR mRNA level was higher in the group B than in the groups A and C, and the ZEB1 mRNA level was lower in the group B than in the groups A and C. Notably, no significant difference was found in the mRNA level of OXTR or ZEB1 between group A and group C.
CONCLUSIONS
The peripheral blood mRNA level of OXTR was increased, and that of ZEB1 was decreased in pregnant women with threatened premature labor. Progesterone helped to maintain pregnancy by readjusting the mRNA levels of OXTR and ZEB1.
Topics: Adult; Female; Gestational Age; Humans; Obstetric Labor, Premature; Pregnancy; Progesterone; RNA, Messenger; Real-Time Polymerase Chain Reaction; Receptors, Oxytocin; Zinc Finger E-box-Binding Homeobox 1
PubMed: 28770970
DOI: No ID Found -
Obstetrics and Gynecology Oct 2019To examine inflammatory mediators in three fetomaternal biological compartments to inform theory related to the fetal and maternal inflammatory contributions to...
OBJECTIVE
To examine inflammatory mediators in three fetomaternal biological compartments to inform theory related to the fetal and maternal inflammatory contributions to parturition at term and preterm.
METHODS
We conducted a cross-sectional study of amniotic fluid, cord blood, and maternal plasma from women with singleton pregnancies. Women had one of four conditions: term labor (n=11), term not in labor (n=13), spontaneous preterm birth with intact membranes (preterm birth; n=13), or preterm prelabor rupture of membranes (PROM; n=8). We measured two damage-associated molecular pattern markers (high-mobility group box-1 [HMGB1] and uric acid) and two acute phase response markers (interleukin [IL]-6 and C-reactive protein [CRP]) using enzyme-linked immunosorbent assay. The distribution of each analyte within amniotic fluid, cord blood, and maternal plasma across the four conditions (term not in labor, term labor, preterm birth, and preterm PROM) were calculated. To explore whether there were distributional differences in each analyte across each of the four labor conditions, we used a nonparametric Kruskal-Wallis test. For analytes that differed across groups, we further compared distributions by labor group (term labor vs term not in labor, and preterm PROM vs preterm birth).
RESULTS
Fetal compartments (amniotic fluid and cord blood) showed higher HMGB1 in term labor vs term not in labor and preterm PROM vs preterm birth. Amniotic fluid IL-6, cord blood CRP and cord blood uric acid were higher in term vs term not in labor. Cord blood uric acid was higher in preterm PROM vs preterm birth. Only maternal plasma IL-6 was higher in term labor vs term not in labor.
CONCLUSION
Accumulation of HMGB1 and an overall increase in inflammation observed on the fetal side, but not the maternal side, may be signals of parturition. Understanding fetal-derived proparturition inflammatory signals at term and preterm, especially in preterm PROM, might provide fetal-specific biomarkers and identify underlying mechanisms and targets for interventions to reduce the risk of preterm birth and preterm PROM.
Topics: Adult; Amniotic Fluid; Cross-Sectional Studies; Female; Fetal Blood; Fetal Membranes, Premature Rupture; Humans; Inflammation Mediators; Labor, Obstetric; Obstetric Labor, Premature; Parturition; Pregnancy; Term Birth
PubMed: 31503157
DOI: 10.1097/AOG.0000000000003470 -
Taiwanese Journal of Obstetrics &... May 2023To assess the incidence of threatened preterm labor and preterm labor admissions and treatment of women with singleton gestations and no prior preterm birth before and...
OBJECTIVE
To assess the incidence of threatened preterm labor and preterm labor admissions and treatment of women with singleton gestations and no prior preterm birth before and after implementation of the universal mid-trimester transvaginal ultrasound cervical length screening.
MATERIALS AND METHODS
A retrospective cohort study included of singleton gestations without a history of preterm birth presenting with threatened preterm labor between 24 0/7 and 36 6/7 gestational week in two study periods: before and after the implementation of the universal cervical length screening. Women with cervical length <25 mm were considered being at high risk for preterm birth and were prescribed a treatment with vaginal progesterone daily. The primary outcome was the incidence of threatened preterm labor. Secondary outcomes were the incidence of preterm labor.
RESULTS
We have found a significant increase in the incidence of threatened preterm labor from 6.42% (410/6378) in 2011 to 11.61% (483/4158) in 2018 (p < 0.0001). Gestational age at triage consult was lower in than in 2011, although the rate of admission for threatened preterm labor was similar in both periods. There was a significant decrease in the incidence of preterm delivery <37 weeks from 25.60% in 2011 to 15.94% in 2018 (p < 0.0004). Although there was a reduction in preterm delivery ≤34 weeks, this reduction was not significant.
CONCLUSION
The universal mid-trimester cervical length screening in asymptomatic women is not associated with a reduction in the frequency of threatened preterm labor or the admission rate for preterm labor, but reduces the rate of preterm births.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Premature Birth; Retrospective Studies; Obstetric Labor, Premature; Pregnancy Trimester, Second; Cervix Uteri; Cervical Length Measurement
PubMed: 37188445
DOI: 10.1016/j.tjog.2022.09.014 -
Clinical Microbiology Reviews Jan 2017The human Ureaplasma species are the most frequently isolated microorganisms from the amniotic fluid and placentae of women who deliver preterm and are also associated... (Review)
Review
The human Ureaplasma species are the most frequently isolated microorganisms from the amniotic fluid and placentae of women who deliver preterm and are also associated with spontaneous abortions or miscarriages, neonatal respiratory diseases, and chorioamnionitis. Despite the fact that these microorganisms have been habitually found within placentae of pregnancies with chorioamnionitis, the role of Ureaplasma species as a causative agent has not been satisfactorily explained. There is also controversy surrounding their role in disease, particularly as not all women infected with Ureaplasma spp. develop chorioamnionitis. In this review, we provide evidence that Ureaplasma spp. are associated with diseases of pregnancy and discuss recent findings which demonstrate that Ureaplasma spp. are associated with chorioamnionitis, regardless of gestational age at the time of delivery. Here, we also discuss the proposed major virulence factors of Ureaplasma spp., with a focus on the multiple-banded antigen (MBA), which may facilitate modulation/alteration of the host immune response and potentially explain why only subpopulations of infected women experience adverse pregnancy outcomes. The information presented within this review confirms that Ureaplasma spp. are not simply "innocent bystanders" in disease and highlights that these microorganisms are an often underestimated pathogen of pregnancy.
Topics: Chorioamnionitis; Female; Humans; Infant, Newborn; Obstetric Labor, Premature; Pregnancy; Ureaplasma; Ureaplasma Infections; Virulence Factors
PubMed: 27974410
DOI: 10.1128/CMR.00091-16 -
Inflammation Research : Official... Sep 2020The purpose of the review was to gather information on the role and possibilities of using lipoxin in the treatment of infertility and maintaining a normal pregnancy.... (Review)
Review
OBJECTIVE AND DESIGN
The purpose of the review was to gather information on the role and possibilities of using lipoxin in the treatment of infertility and maintaining a normal pregnancy. Ovulation, menstruation, embryo implantation, and childbirth are reactions representing short-term inflammatory events involving lipoxin activities. Lipoxin A4 (LXA4) is an arachidonic acid metabolite, and in cooperation with its positional isomer lipoxin B4 (LXB4), it is a major lipoxin in mammals. Biosynthesis process occurs in two stages: in the first step, the donor cell releases the eicosanoid intermediate; secondarily, the acceptor cell gets and converts the intermediate product into LXA4 (leukocyte/platelet interaction).
RESULTS
Generating lipoxin synthesis may also be triggered by salicylic acid, which acetylates cyclooxygenase-2. Lipoxin A4 and its analogues are considered as specialized pro-resolving mediators. LXA4 is an important component for a proper menstrual cycle, embryo implantation, pregnancy, and delivery. Its level in the luteal phase is high, while in the follicular phase, it decreases, which coincides with an increase in estradiol concentration with which it competes for the receptor. LXA4 inhibits the progression of endometriosis. However, during the peri-implantation period, before pregnancy is confirmed clinically, high levels of LXA4 can contribute to early pregnancy loss and may cause miscarriage. After implantation, insufficient LXA4 levels contribute to incorrect maternal vessel remodeling; decreased, shallow trophoblastic invasion; and the immuno-energetic abnormality of the placenta, which negatively affects fetal growth and the maintenance of pregnancy. Moreover, the level of LXA4 increases in the final stages of pregnancy, allowing vessel remodeling and placental separation.
METHODS
The review evaluates the literature published in the PubMed and Embase database up to 31 December 2019. The passwords were checked on terms: lipoxin and pregnancy with combined endometriosis, menstrual cycle, implantation, pre-eclampsia, fetal growth restriction, and preterm labor.
CONCLUSIONS
Although no human studies have been performed so far, the cell and animal model study results suggest that LXA4 will be used in obstetrics and gynecology soon.
Topics: Animals; Embryo Implantation; Endometriosis; Female; Fetal Growth Retardation; Humans; Lipoxins; Menstruation; Obstetric Labor, Premature; Pregnancy
PubMed: 32488315
DOI: 10.1007/s00011-020-01358-6 -
Reproductive Sciences (Thousand Oaks,... Sep 2016The human placenta is a source of hematopoietic stem and progenitor cells (HSPCs). The RUNX1 transcription factor is required for the formation of functional HSPCs. The...
BACKGROUND
The human placenta is a source of hematopoietic stem and progenitor cells (HSPCs). The RUNX1 transcription factor is required for the formation of functional HSPCs. The impact of preeclampsia (PE) and preterm labor (PTL, spontaneous preterm labor [sPTL] and inflammatory preterm labor [iPTL]) on HSPC localization and RUNX1 expression in the human placenta is unknown.
METHODS
We compared the frequency and density of HSPC in control samples from sPTL (n = 6) versus PE (n = 6) and iPTL (n = 6). We examined RUNX1 protein and RNA expression in placentas from normal pregnancies (5-22 weeks, n = 8 total) and in placentas from the aforementioned pregnancy complications (n = 5/group).
RESULTS
Hematopoietic stem and progenitor cells were rare cell types, associated predominantly with the vasculature of placental villi. The HSPC density was greater in the chorionic plate (CP) compared to the villi (P < .001) and greater in PE and iPTL samples as compared to controls within the CP (not significant) and overall (P < .05). During the fetal period, RUNX1 was expressed in the mesenchyme of the CP and villi. Inflammatory PTL samples were more likely to exhibit intraluminal RUNX1(+) cell populations (P < .001) and RUNX1(+) cell clusters attached to arterial endothelial cells.
CONCLUSION
Placental HSPCs likely arise from hematopoietic niches comprised RUNX1(+) mesenchyme and vascular endothelium. Pregnancy complications that result in preterm birth differentially affect placental HSPC localization and RUNX1 expression. Our results support previous findings that inflammation positively regulates hematopoiesis. We present new evidence that hemogenic endothelium may be active at later stages of human fetal development in the context of inflammation.
Topics: Cell Count; Core Binding Factor Alpha 2 Subunit; Female; Hematopoietic Stem Cells; Humans; Inflammation; Obstetric Labor, Premature; Placenta; Pre-Eclampsia; Pregnancy; RNA, Messenger
PubMed: 26944948
DOI: 10.1177/1933719116632926 -
Sensors (Basel, Switzerland) Apr 2022Electrohysterogram (EHG) is a promising method for noninvasive monitoring of uterine electrical activity. The main purpose of this study was to characterize the...
Electrohysterogram (EHG) is a promising method for noninvasive monitoring of uterine electrical activity. The main purpose of this study was to characterize the multichannel EHG signals to distinguish between term delivery and preterm birth, as well as deliveries within and beyond 24 h. A total of 219 pregnant women were grouped in two ways: (1) term delivery (TD), threatened preterm labor (TPL) with the outcome of preterm birth (TPL_PB), and TPL with the outcome of term delivery (TPL_TD); (2) EHG recording time to delivery (TTD) ≤ 24 h and TTD > 24 h. Three bipolar EHG signals were analyzed for the 30 min recording. Six EHG features between multiple channels, including multivariate sample entropy, mutual information, correlation coefficient, coherence, direct partial Granger causality, and direct transfer entropy, were extracted to characterize the coupling and information flow between channels. Significant differences were found for these six features between TPL and TD, and between TTD ≤ 24 h and TTD > 24 h. No significant difference was found between TPL_PB and TPL_TD. The results indicated that EHG signals of TD were more regular and synchronized than TPL, and stronger coupling between multichannel EHG signals was exhibited as delivery approaches. In addition, EHG signals propagate downward for the majority of pregnant women regardless of different labors. In conclusion, the coupling and propagation features extracted from multichannel EHG signals could be used to differentiate term delivery and preterm birth and may predict delivery within and beyond 24 h.
Topics: Electromyography; Female; Humans; Infant, Newborn; Labor, Obstetric; Obstetric Labor, Premature; Pregnancy; Premature Birth; Uterine Contraction
PubMed: 35591042
DOI: 10.3390/s22093352 -
Fetal Diagnosis and Therapy 2018Spontaneous preterm birth has enormous consequences for newborns, children, and families. Intra-amniotic inflammation (IAI) is the leading cause of spontaneous preterm... (Review)
Review
Spontaneous preterm birth has enormous consequences for newborns, children, and families. Intra-amniotic inflammation (IAI) is the leading cause of spontaneous preterm delivery, mainly at earlier gestational ages. Amniocentesis is the only method used to identify IAI in clinical practice. Although it is an invasive procedure with a very low risk of complications, many women and physicians are hesitant about amniocentesis on this indication. This has been an incentive to explore IAI and the intra-amniotic environment through noninvasive techniques, such as sampling cervical mucus, vaginal fluid, or maternal blood. With this overview, we aim to provide a concise update on the state of the art of the noninvasive sampling of the intrauterine environment in women with preterm labor and intact membranes. So far, it is unknown whether this screening helps improve our knowledge about the impact of IAI on the neonatal and long-term outcome, but we believe it merits this review.
Topics: Amniocentesis; Amniotic Fluid; Chorioamnionitis; Female; Humans; Obstetric Labor, Premature; Pregnancy; Premature Birth
PubMed: 29080890
DOI: 10.1159/000480232