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International Journal of Gynaecology... Oct 2023Preterm labor occurs in around 10% of pregnancies worldwide. Once diagnosed, significant efforts must be made to reduce the likelihood of morbidity and mortality...
Preterm labor occurs in around 10% of pregnancies worldwide. Once diagnosed, significant efforts must be made to reduce the likelihood of morbidity and mortality associated with preterm birth. In high-resource settings, access to hospitals with a neonatal intensive care unit (NICU) is readily available, whereas access to NICU care is limited in low- and middle-income countries (LMICs) and many rural settings. Use of FIGO's Prep-for-Labor triage method rapidly identifies low- and high-risk patients with preterm labor to enable clinicians to decide whether the patient can be managed on site or if transfer to a level II-IV facility is needed. The management steps described in this paper aim to minimize the morbidity and mortality associated with preterm labor and in the setting of preterm labor with preterm premature rupture of membranes (PPROM). The methods for accurate diagnosis of PPROM and chorioamnionitis are described. When the risk of preterm birth is high, antenatal corticosteroids should be administered for lung maturation combined with limited tocolysis for 48 hours to permit the corticosteroid course to be completed. Magnesium sulfate is also administered for fetal neuroprotection. Implementation of FIGO's Prep-for-Labor triage method in an LMIC setting will help improve maternal and neonatal outcomes.
Topics: Pregnancy; Infant, Newborn; Humans; Female; Premature Birth; Triage; Obstetric Labor, Premature; Fetal Membranes, Premature Rupture; Adrenal Cortex Hormones
PubMed: 37807588
DOI: 10.1002/ijgo.15113 -
Biomolecules Jun 2023Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. At the present time, nothing can reliably halt labor once it begins. The... (Review)
Review
Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. At the present time, nothing can reliably halt labor once it begins. The knowledge that agonists of the β2 adrenergic receptor relax airway smooth muscle and are effective in the treatment of asthma led to the notion that β2 mimetics would prevent preterm birth by relaxing uterine smooth muscle. The activation of cAMP-dependent protein kinase by β2 receptors is unable to provide meaningful tocolysis. The failure of β2 agonists such as ritodrine and terbutaline to prevent preterm birth suggests that the regulation of uterine smooth muscle is disparate from that of airway. Other smooth muscle quiescent-mediating molecules, such as nitric oxide, relax vascular smooth muscle in a cGMP-protein kinase G-dependent manner; however, nitric oxide activation of protein kinase G fails to explain the relaxation of the myometrium to nitric oxide. Moreover, nitric oxide-mediated relaxation is blunted in preterm labor, and thus, for this reason and because of the fall in maternal blood pressure, nitric oxide cannot be employed as a tocolytic. The β3 adrenergic receptor-mediated relaxation of the human myometrium is claimed to be cAMP-dependent protein kinase-dependent. This is scientifically displeasing given the failure of β2 agonists as tocolytics and suggests a non-canonical signaling role for β3AR in myometrium. The addition of the β3 agonist mirabegron to pregnant human myometrial strips in the tissue bath relaxes oxytocin-induced contractions. Mirabegron stimulates nitric oxide production in myometrial microvascular endothelial cells, and the relaxation of uterine tissue in vitro is partially blocked by the addition of the endothelial nitric oxide synthase blocker Nω-Nitro-L-arginine. Recent data suggest that both endothelial and smooth muscle cells respond to β3 stimulation and contribute to relaxation through disparate signaling pathways. The repurposing of approved medications such as mirabegron (Mybetriq™) tested in human myometrium as uterine tocolytics can advance the prevention of preterm birth.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Myometrium; Tocolytic Agents; Premature Birth; Nitric Oxide; Endothelial Cells; Obstetric Labor, Premature; Cyclic AMP-Dependent Protein Kinases; Receptors, Adrenergic
PubMed: 37371585
DOI: 10.3390/biom13061005 -
Expert Opinion on Investigational Drugs May 2020Preterm birth is the leading cause of neonatal morbidity and mortality globally and poses a substantial economic burden. Consequently, there is a need for the... (Review)
Review
INTRODUCTION
Preterm birth is the leading cause of neonatal morbidity and mortality globally and poses a substantial economic burden. Consequently, there is a need for the identification of therapeutic targets and novel experimental drugs for the inhibition of preterm labor to improve neonatal outcomes.
AREAS COVERED
The authors review the pathophysiology of labor and the inflammatory pathways underpinning it. The interruption of these pathways forms the basis of therapeutic targets to inhibit preterm labor. Current drugs available for the treatment of preterm labor are reviewed, followed by experimental drugs including toll-like receptor 4 (TLR-4) antagonists, cytokine suppressive anti-inflammatory drugs (CSAIDs), N-acetyl cysteine (NAC), Sulfasalazine (SSZ), tumor necrosis factor-alpha (TNF-α) antagonists, interleukin-1 receptor (IL-1) inhibitors, omega-3 polyunsaturated fatty acids and lipid metabolites, and the polyphenols.
EXPERT OPINION
A number of new therapeutic strategies for the prevention of preterm labor are being investigated. These have the potential to improve neurodevelopmental outcomes and survival in babies born preterm, reducing the economic and healthcare costs of caring for the complex needs of these children in the immediate and long term. It is likely that over the next decade there will be a new treatment option that targets the pathological inflammatory processes involved in preterm labor.
Topics: Animals; Anti-Inflammatory Agents; Drug Development; Drugs, Investigational; Female; Humans; Infant, Newborn; Obstetric Labor, Premature; Pregnancy; Premature Birth
PubMed: 32290715
DOI: 10.1080/13543784.2020.1752661 -
American Journal of Perinatology Aug 2022While antenatal corticosteroids (ACS) administered in the late preterm period have been shown to reduce respiratory morbidity, this finding was demonstrated in a... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
While antenatal corticosteroids (ACS) administered in the late preterm period have been shown to reduce respiratory morbidity, this finding was demonstrated in a well-designed randomized controlled trial (the Antenatal Betamethasone for Women at Risk for Late Preterm Delivery [ALPS]) with strict inclusion/exclusion criteria that may differ from clinical practice. The aim of this study was to investigate whether there has been indication creep since use of late preterm ACS became standard of care.
STUDY DESIGN
Retrospective cohort study of pregnant women who received late preterm ACS between 2016 and 2019 were identified and separated into epochs of 2016 to 2017 and 2018 to 2019 based on year of exposure. The primary outcome was rate of inappropriate ACS exposure, defined as nonadherence to the inclusion/exclusion criteria of the ALPS trial. Secondary outcomes were rates of nonoptimal ACS exposure (delivery >7 days from ACS or term delivery). Logistic regression was used to generate adjusted odds ratios (aORs) between epochs for the primary outcome adjusting for confounders.
RESULTS
There were 660 women who received late preterm ACS during the study period with 229 (34.6 %) deemed inappropriate exposures. The most common reason for inappropriate treatment was preterm premature rupture of membrane (PPROM; 29.0%) with exclusionary cervical examination or contraction frequency. No difference was observed in inappropriate ACS exposure between epochs (aOR = 0.83, 95% confidence interval [CI]: 0.59-1.2). However, there was a reduction in nonoptimal exposure over time (aOR = 0.67, 95% CI: 0.47-0.97) . Women receiving inappropriate ACS were more likely to deliver at term if indicated for maternal/fetal status (50.0 vs. 19.5%, < 0.001) and preterm labor (66.0 vs. 41.9%; = 0.015). Further, inappropriate exposure in preterm labor had higher rates of exposure latency >7 days (62.3 vs. 39.1%, = 0.006) with a longer latency to delivery (3 vs. 16 days; < 0.001).
CONCLUSION
Over one-third of women received late preterm ACS for an indication that could be classified as indication creep. Depending on indication, inappropriate administration is associated with higher rates of nonoptimal exposure.
KEY POINTS
· There is potential for indication creep of ACS administration.. · One third of late preterm ACS exposures in our study were inappropriate.. · Utilizing clinical criteria can aid in identifying patients who best benefit from late preterm ACS..
Topics: Adrenal Cortex Hormones; Betamethasone; Female; Humans; Infant, Newborn; Obstetric Labor, Premature; Pregnancy; Premature Birth; Respiratory Distress Syndrome, Newborn; Retrospective Studies
PubMed: 35235958
DOI: 10.1055/a-1785-9290 -
The Journal of Maternal-fetal &... Oct 2022Fetal therapy term has been described for any therapeutic intervention either invasive or noninvasive for the purpose of correcting or treating any fetal malformation or... (Review)
Review
Fetal therapy term has been described for any therapeutic intervention either invasive or noninvasive for the purpose of correcting or treating any fetal malformation or condition. Fetal therapy is a rapidly evolving specialty and has gained pace in last two decades and now fetal intervention is being tried in many malformations with rate of success varying with the type of different fetal conditions. The advances in imaging techniques have allowed fetal medicine persons to make earlier and accurate diagnosis of numerous fetal anomalies. Still many fetal anomalies are managed postnatally because the fetal outcomes have not changed significantly with the use of fetal therapy and this approach avoids unnecessary maternal risk secondary to intervention. The short-term maternal risk associated with fetal surgery includes preterm labor, premature rupture of membranes, uterine wall bleeding, chorioamniotic separation, placental abruption, chorioamnionitis, and anesthesia risk. Whereas, maternal long-term complications include risk of infertility, uterine rupture, and need for cesarean section in future pregnancies. The decision for invasive fetal therapy should be taken after discussion with parents about the various aspects like postnatal fetal outcome without fetal intervention, possible outcome if the fetal intervention is done, available postnatal intervention for the fetal condition, and possible short-term and long-term maternal complications. The center where fetal intervention is done should have facility of multi-disciplinary team to manage both maternal and fetal complications. The major issues in the development of fetal surgery include selection of patient for intervention, crafting effective fetal surgical skills, requirement of regular fetal and uterine monitoring, effective tocolysis, and minimizing fetal and maternal fetal risks. This review will cover the surgical or invasive aspect of fetal therapy with available evidence and will highlight the progress made in the management of fetal malformations in last two decades.
Topics: Cesarean Section; Female; Fetal Diseases; Fetal Therapies; Humans; Infant, Newborn; Obstetric Labor, Premature; Placenta; Pregnancy; Premature Birth
PubMed: 33135508
DOI: 10.1080/14767058.2020.1839880 -
Frontiers in Immunology 2023Given the important roles of immune tolerance and inflammation in both preterm and term labor, some inflammation-related genes could be related to the initiation of...
INTRODUCTION
Given the important roles of immune tolerance and inflammation in both preterm and term labor, some inflammation-related genes could be related to the initiation of labor, even preterm labor. Inspection of cell-free RNA (cfRNA) engaged in inflammation in maternal blood may represent the varied gestational age and may have significant implications for the development of noninvasive diagnostics for preterm birth.
METHODS
To identify potential biomarkers of preterm birth, we investigated the cfRNA and exosomal miRNA in the peripheral blood of pregnant women at different gestational ages that undergo term labor or preterm labor. 17 inflammatory initiation-related cfRNAs were screened by overlapping with the targets of decreasing miRNAs during gestation and highly expressed cfRNAs at late gestation in maternal blood. To reveal the origins and mechanisms of these screened cfRNAs, the datasets of single-cell RNA sequencing from peripheral blood mononuclear cells of pregnant women, the fetal lung, and the placenta across different gestational ages were analyzed.
RESULTS
During late gestation, TNFSF4 expression increased exclusively in pro-inflammatory macrophages of maternal blood, whereas its receptor, TNFRSF4, increased expression in T cells from the decidua, which suggested the potential cell-cell communication of maternally-originated pro-inflammatory macrophages with the decidual T cells and contributed to the initiation of labor. Additionally, the cfRNA of TNFSF4 was also increased in preterm labor compared to term labor in the validation cohorts. The EIF2AK2 and TLR4 transcripts were increased in pro-inflammatory macrophages from both fetal lung and placenta but not in those from maternal mononuclear cells at late gestation, suggesting these cfRNAs are possibly derived from fetal tissues exclusively. Moreover, EIF2AK2 and TLR4 transcripts were found highly expressed in the pro-inflammatory macrophages from decidua as well, which suggested these specific fetal-origin macrophages may function at the maternal-fetal interface to stimulate uterine contractions, which have been implicated as the trigger of parturition and preterm labor.
DISCUSSION
Taken together, our findings not only revealed the potential of peripheral TNFSF4 as a novel cfRNA biomarker for noninvasive testing of preterm labor but further illustrated how maternal and fetal signals coordinately modulate the inflammatory process at the maternal-fetal interface, causing the initiation of term or preterm labor.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Premature Birth; Leukocytes, Mononuclear; Toll-Like Receptor 4; Decidua; Obstetric Labor, Premature; Parturition; Inflammation; Biomarkers; OX40 Ligand
PubMed: 37275889
DOI: 10.3389/fimmu.2023.1154025 -
The Journal of Obstetrics and... May 2022This study examined the maternal experience of threatened abortion, threatened premature labor, or preterm birth before, during, and after the first state of emergency...
AIM
This study examined the maternal experience of threatened abortion, threatened premature labor, or preterm birth before, during, and after the first state of emergency for COVID-19 in 2020 in Japan.
METHODS
This was a cross-sectional, internet-based questionnaire survey. We recruited 600 postpartum women and divided them into three groups by date of delivery: before (October 2019-March 2020), during (April-May 2020), and after (June-October 2020) the first state of emergency. The outcome was the presence of at least one of the following complications: threatened abortion, threatened premature labor, and/or preterm birth. The prevalence ratios (PRs) of the outcome were calculated and compared among the three groups using a multivariable Poisson regression model with adjustment for potential confounders.
RESULTS
Of the 553 women eligible for analysis, those who delivered during (PR 0.69, 95% confidence interval [CI] 0.47-0.99) and after (PR 0.62, 95% CI 0.42-0.90) the state of emergency were less likely to have experienced either threatened abortion, threatened premature labor, or preterm birth than those who delivered before the state of emergency. Among the adjustment variables, smoking at the time of survey (PR 1.68, 95% CI 1.01-2.80) and living in the prefectures with a population of >5 million (PR 0.71, 95% CI 0.51-0.97) were associated with the study outcome.
CONCLUSION
Threatened abortion, threatened premature labor, or preterm birth appeared to decrease during and after the first state of emergency in 2020. The longitudinal effects of coronavirus disease on maternal and newborn health should be monitored continuously.
Topics: Abortion, Threatened; COVID-19; Cross-Sectional Studies; Female; Humans; Infant, Newborn; Japan; Male; Obstetric Labor, Premature; Pregnancy; Premature Birth
PubMed: 35218103
DOI: 10.1111/jog.15203 -
Translational Research : the Journal of... Sep 2023Preterm birth remains the leading cause of neonatal morbidity and mortality worldwide. A substantial number of spontaneous preterm births occur in the context of sterile...
Preterm birth remains the leading cause of neonatal morbidity and mortality worldwide. A substantial number of spontaneous preterm births occur in the context of sterile intra-amniotic inflammation, a condition that has been mechanistically proven to be triggered by alarmins. However, sterile intra-amniotic inflammation still lacks treatment. The NLRP3 inflammasome has been implicated in sterile intra-amniotic inflammation; yet, its underlying mechanisms, as well as the maternal and fetal contributions to this signaling pathway, are unclear. Herein, by utilizing a translational and clinically relevant model of alarmin-induced preterm labor and birth in Nlrp3 mice, we investigated the role of NLRP3 signaling by using imaging and molecular biology approaches. Nlrp3 deficiency abrogated preterm birth and the resulting neonatal mortality induced by the alarmin S100B by impeding the premature activation of the common pathway of labor as well as by dampening intra-amniotic and fetal inflammation. Moreover, Nlrp3 deficiency altered leukocyte infiltration and functionality in the uterus and decidua. Last, embryo transfer revealed that maternal and fetal Nlrp3 signaling contribute to alarmin-induced preterm birth and neonatal mortality, further strengthening the concept that both individuals participate in the complex process of preterm parturition. These findings provide novel insights into sterile intra-amniotic inflammation, a common etiology of preterm labor and birth, suggesting that the adverse perinatal outcomes resulting from prematurity can be prevented by targeting NLRP3 signaling.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Animals; Mice; Premature Birth; Alarmins; NLR Family, Pyrin Domain-Containing 3 Protein; Obstetric Labor, Premature; Inflammation; Amniotic Fluid; S100 Calcium Binding Protein beta Subunit
PubMed: 37121539
DOI: 10.1016/j.trsl.2023.04.004 -
Frontiers in Immunology 2022The maternal-fetal immune disorder is considered to be an important factor of preterm birth (PTB); however, the underlying mechanism is still not fully understood. This...
The maternal-fetal immune disorder is considered to be an important factor of preterm birth (PTB); however, the underlying mechanism is still not fully understood. This study was designed to explore the innate and adaptive immune features in the decidua during term and preterm labor. Women delivered at term or preterm were classified into four groups: term not in labor (TNL, N=19), term in labor (TL, N=17), preterm not in labor (PNL, N=10), and preterm in labor (PIL, N=10). Decidua basalis and parietalis were collected and analyzed for macrophage subtypes (M1 and M2) as well as T helper 1 (Th1), Th2, Th17 and regulatory T (Treg) cells by flow cytometry and immunohistochemistry. Our results demonstrated significantly decreased frequencies of M2 cells and elevated M1/M2 ratio in the PIL group compared to that in the PNL group in both decidua basalis and parietalis, whereas no significant differences were found between the above two groups in both sites in terms of the polarization status of Th cells. On the contrary, macrophage subsets were comparable in the TL and TNL groups, whereas elevated Th1 percentages and Th1/Th2 ratio were observed in TL women compared to that in TNL women in the decidua. Interestingly, although the frequencies and ratios of Th17 and Treg were comparable among the four groups, the Th17/Treg ratios of these groups were significantly increased in decidua basalis than that in decidua parietalis. Collectively, the M1/M2 imbalance is associated with the breakdown of maternal-fetal immune tolerance during PTB, whereas the aberrant Th1/Th2 profile plays an important role in immune disorder during term labor. Moreover, Th17/Treg deviation is more remarkable in decidua basalis than in decidua parietalis.
Topics: Decidua; Female; Flow Cytometry; Humans; Infant, Newborn; Labor, Obstetric; Obstetric Labor, Premature; Pregnancy; Premature Birth
PubMed: 35757768
DOI: 10.3389/fimmu.2022.877314 -
American Journal of Obstetrics &... Apr 2023Cervical cerclage is an effective intervention to prevent preterm birth among individuals with a history of cervical insufficiency, individuals with a short cervix and...
BACKGROUND
Cervical cerclage is an effective intervention to prevent preterm birth among individuals with a history of cervical insufficiency, individuals with a short cervix and history of preterm birth, or individuals with second-trimester painless dilation. Although cerclage reduces the mechanical stress on the cervix by reinforcing it with sutures, cerclage could also cause scarring of the cervix, which may affect the progress of labor.
OBJECTIVE
This study aimed to compare the labor curves between individuals who underwent cerclage and those who did not undergo cerclage.
STUDY DESIGN
This was a retrospective cohort study of individuals with singleton term pregnancy, vertex presentation, and vaginal delivery, using the data from the Consortium on Safe Labor. We excluded individuals with fetal anomalies, stillbirth, or abnormal perinatal outcomes, including 5-minute Apgar score of <7, birth injury, and neonatal intensive care unit admission. We modeled the course of cervical dilation using repeated-measures analysis with a polynomial function and generated smoothed labor curves. An interval-censored regression analysis was performed to estimate traverse times (the elapsed time between 2 cervical dilation measures). The traverse times were compared between individuals who underwent cerclage and those who did not undergo cerclage, controlling for induction of labor and parity.
RESULTS
There were 245 individuals who underwent cerclage and 110,080 individuals who did not undergo cerclage. Individuals who underwent cerclage compared with those who did not undergo cerclage had a similar traverse time from 1 to 6 cm (median, 9.1 vs 10.3 hours; adjusted P=.37) and from 6 to 10 cm (median, 1.5 vs 1.5 hours; adjusted P=.23). Individuals who underwent cerclage compared with those who did not undergo cerclage had a longer traverse time from rupture of membranes to delivery (median, 4.0 vs 3.0 hours; adjusted P<.01).
CONCLUSION
Cervical cerclage did not affect the overall progress of labor.
Topics: Female; Pregnancy; Infant, Newborn; Humans; Cerclage, Cervical; Premature Birth; Retrospective Studies; Labor, Obstetric; Cervix Uteri
PubMed: 36592821
DOI: 10.1016/j.ajogmf.2022.100858