Vaginal Progesterone for Pregnancy Prolongation After Arrested Preterm Labor: A Randomized Clinical Trial.

Importance: Women with arrested preterm labor (APTL) are at very high risk for spontaneous preterm delivery (SPTD), the leading cause of neonatal mortality and morbidity. To date, no maintenance therapy has been found to be effective for pregnancy prolongation. A few clinical trials with considerable methodological limitations have demonstrated some efficacy for 400 mg vaginal micronized progesterone (VMP) in women with APTL. Objective: To investigate the effectiveness of daily 400 mg VMP for the prolongation of pregnancy after APTL. Design, Setting, and Participants: This randomized clinical trial was conducted between December 19, 2018, and February 27, 2023, in 3 university-affiliated medical centers in Israel. Participants included women with singleton and twin pregnancies after APTL following tocolysis at 24 weeks 0 days to 34 weeks 0 days' gestation. Women with a history of preterm delivery or asymptomatic cervical shortening in the current pregnancy were excluded. Interventions: Participants were randomly allocated to receive VMP 200 mg twice a day or no treatment until 36 weeks 6 days' gestation. Main Outcomes and Measures: The primary end points were mean number of days from study enrollment to delivery and the rate of SPTD prior to 37 weeks' gestation. Results: A total of 129 participants were enrolled (65 in the VMP group and 64 in the no-treatment group). Mean (SD) age was 27.6 (5.1) years. Between the VMP and no-treatment groups, there was no difference in pregnancy prolongation (mean [SD], 40.0 [17.8] vs 37.4 [20.3] days; P = .44) and the rate of SPTD (16 [25%] vs 19 [30%]; relative risk, 0.8; 95% CI, 0.5-1.5; P = .52). In twin pregnancies, including 12 and 15 pairs in the VMP and no-treatment groups, respectively, VMP prolonged pregnancy (mean [SD], 43.7 [18.1] vs 26.1 [15.2] days; P = .02), postponed the delivery week (36.5 [1.4] vs 34.7 [2.2] weeks; P = .01), shortened the length of stay in the neonatal intensive care unit (4.9 [10.6] vs 13.2 [18.5] days; P = .03) and overall hospital stay (8.3 [9.6] vs 15.1 [17.2] days; P = .03), and was associated with a higher birth weight (2444 [528] vs 2018 [430] g; P = .01). Conclusions and Relevance: These findings show that VMP given in a dosage of 200 mg twice a day following APTL is not an effective treatment to prolong pregnancy or prevent SPTD. However, VMP demonstrated beneficial effects in twin pregnancies, warranting further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT02430233.

Implications of maternal vitamin D administration for the neonatal respiratory distress syndrome: A randomized clinical trial.

BACKGROUND: Vitamin D deficiency has been suggested to be a risk factor for neonatal respiratory distress syndrome (RDS). This study aimed to evaluate the effect of 25 (OH) D administrations in pregnant women with findings of preterm labor on the incidence of RDS in their preterm neonates. MATERIALS AND METHODS: A randomized controlled clinical trial was conducted on pregnant mothers with gestational age (GA) of less than 34 weeks at risk of preterm delivery. 175 subjects were randomly assigned into two groups, including intervention (intramuscular injection of 50,000 units of 25(OH) D during 72 hours before delivery) and control (no injections). Serum concentrations of 25(OH) D were measured shortly after birth in both mothers and neonates. Then, clinical and laboratory results of mothers and their offspring were recorded (in a checklist). Short-term outcomes and the need for respiratory support were also assessed. Data were analyzed by independent t-test, Mann-Whitney U test, Fisher's exact test, and chi-square test. RESULTS: Even though gestational age, birth weight, delivery method, and serum vitamin D levels are consistent among both groups, 45% of neonates in the control group and 20% in the intervention group developed respiratory distress syndrome (P = 0.05). The mean 25(OH) D level in neonates was 17.7±10.5 and 19.29±9.94 ng/mL in the intervention and control groups, respectively (P > 0.05). CONCLUSION: A single dose of 50,000 units of intramuscular 25(OH)D in pregnant women at risk of preterm labor can lower the risk of RDS in the infant.

Relationship between maternal mortality and ritodrine hydrochloride as a tocolytic agent in Japan.

AIM: In Japan, unlike Western countries, tocolytic agents are administered in long-term protocols to treat threatened preterm labor. Evaluating the side effects of this practice is crucial. We examined whether ritodrine hydrochloride had been administered in cases of maternal death, aiming to investigate any relationship between ritodrine administration and maternal death. METHODS: This retrospective cohort study used reports of maternal deaths from multiple institutions in Japan between 2010 and 2020. Data on the reported cases were retrospectively analyzed, and data on the route of administration, administered dose, and clinical findings, including causes of maternal death, were extracted. The amount of tocolytic agents was compared between maternal deaths with ritodrine administration and those without. RESULTS: A total of 390 maternal deaths were reported to the Maternal Death Exploratory Committee in Japan during the study period. Ritodrine hydrochloride was administered in 32 of these cases. The frequencies (n) and median doses (range) of oral or intravenous ritodrine hydrochloride were 34.4% (11) and 945 (5-2100) mg and 84.4% (27) and 4032 (50-18 680) mg, respectively. Frequencies of perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema as causes of maternal death were significantly higher with ritodrine administration than without it. CONCLUSIONS: Our results suggest a relationship between long-term administration of ritodrine hydrochloride and an increased risk of maternal death due to perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema. In cases where ritodrine should be administered to prevent preterm labor, careful management and monitoring of maternal symptoms are required.

Comparison of the efficacy of nifedipine with ritodrine, nitroglycerine and magnesium sulfate for the management of preterm labor: a systematic review and meta-analysis.

BACKGROUND: Some studies have compared the efficacy of nifedipine with that of other tocolytic drugs in the treatment of preterm labor, but the reported results are conflicting. OBJECTIVE: To compare the efficacy of nifedipine with that of ritodrine, nitroglycerine and magnesium sulfate for the management of preterm labor. METHODS: In this systematic review and meta-analysis, PubMed/MEDLINE, Scopus, Clarivate Analytics Web of Science, and Google Scholar were searched until April 3,2024 using predefined keywords. Randomized controlled trials (RCTs) and clinical trials that compared the efficacy of nifedipine with that of ritodrine, nitroglycerine and magnesium sulfate for the management of preterm labor were included. Two authors independently reviewed the articles, assessed their quality and extracted the data. The quality of the included RCTs based on the Cochrane Risk of Bias Tool 1 for clinical trial studies. The risk difference (RD) with the associated 95% confidence interval (CI) was calculated. A forest plot diagram was used to show the comparative point estimates of nifedipine and other tocolytic drugs on the prevention of preterm labor and their associated 95% confidence intervals based on the duration of pregnancy prolongation. Study heterogeneity was evaluated by the I2 index, and publication bias was evaluated by Egger's test. RESULTS: Forty studies enrolling 4336 women were included. According to our meta-analysis, there was a significant difference in the prolongation of preterm labor within the first 48 h between the nifedipine group and the nitroglycerine group (RD, -0.04; 95% CI, -0.08 to -0.00; I2: 32.3%). Additionally, there were significant differences between nifedipine and ritodrine (RD, 0.11; 95% CI, 0.02 to 0.21; I2, 51.2%) for more than one week RD, 0.10; 95% CI, 0.03 to 0.19; I2, 33.2%) and for 34 weeks and more. The difference between nifedipine and magnesium sulfate was not significant in any of the four time points. CONCLUSIONS: Considering the superiority of nifedipine over ritodrine and nitroglycerine and its similar efficacy to magnesium sulfate for tocolysis, it seems that the side effects of these options determine the first drug line.

A singleton pregnancy with placental chorioangioma and hydrops fetalis complicated with mirror syndrome and ritodrine-induced side effects: a case report.

BACKGROUND: Ritodrine hydrochloride is a widely used beta-adrenergic agonist used to stop preterm labor in Taiwan. Many side effects causing maternal morbidity and mortality have been reported. We report a case complicated with ritodrine-induced side effects and mirror syndrome that was associated with placental chorioangioma. CASE PRESENTATION: A 36-year-old singleton pregnant woman at 25 6/7 weeks of gestation, with an undiagnosed placental chorioangioma, underwent tocolysis due to preterm uterine contractions. Her clinical condition deteriorated, attributed to mirror syndrome and adverse events induced by ritodrine. An emergency cesarean section was performed at 27 1/7 weeks of gestation, delivering an infant with generalized subcutaneous edema. A placental tumor measuring 8.5 cm was discovered during the operation, and pathology confirmed chorioangioma. Gradual improvement in her symptoms and laboratory data was observed during the postpartum period. Identifying mirror syndrome and ritodrine-induced side effects poses challenges. Therefore, this case is educational and warrants discussion. CONCLUSION: Our case demonstrates mirror syndrome induced by chorioangioma, which is rare, and ritodrine-induced side effects. The cessation of intravenous ritodrine and delivery are the best methods to treat maternal critical status due to fluid overload.

Efficient administration of a combination of nifedipine and sildenafil citrate versus only nifedipine on clinical outcomes in women with threatened preterm labor: a systematic review and meta-analysis.

BACKGROUND: Preterm labor (PTL) is a common and serious pregnancy disorder that can cause long-term neurological issues in the infant. There are conflicting studies concerning whether sildenafil citrate (SC) reduces preterm labor complications. Therefore, the meta-analysis aimed to examine the clinical outcomes in women with threatened PTL who received nifedipine plus SC therapy versus only nifedipine. METHODS: For the original articles, six databases were searched using relevant keywords without restriction on time or language until January 13, 2024. The Cochrane risk-of-bias tool for randomized trials (RoB) and the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) were both used to assess the risk of bias in randomized and non-randomized studies, and GRADE determined the quality of our evidence. Meta-analysis of all data was carried out using Review Manager (RevMan) version 5.1. RESULTS: Seven studies with mixed quality were included in the meta-analysis. The study found that combining nifedipine and SC resulted in more prolongation of pregnancy (MD = 6.99, 95% CI: 5.32, 8.65, p < 0.00001), a lower rate of delivery in the 1st to 3rd days after hospitalization (RR = 0.62, 95% CI: 0.50, 0.76, p < 0.00001), a higher birth weight (252.48 g vs. nifedipine alone, p = 0.02), and the risk ratio of admission to the neonatal intensive care unit (NICU) was significantly lower (RR = 0.62, 95% CI: 0.50, 0.76, p < 0.00001) compared to nifidepine alone. The evidence was high for prolongation of pregnancy, delivery rate 24-72 h after admission, and NICU admission, but low for newborn birth weight. CONCLUSIONS: Given the effectiveness of SC plus nifedipine in increased prolongation of pregnancy and birth weight, lower delivery in the 1st to 3rd days after hospitalization, and NICU admission, Gynecologists and obstetricians are suggested to consider this strategy for PTL management, although additional article rigor is required to improve the quality of the evidence.

Indomethacin Pharmacokinetics and Pharmacodynamics in Pregnancies With Preterm Labor: The Need for Dose-Ranging Trials.

The use of indomethacin to delay delivery in preterm labor (PTL) is widely accepted; however, the optimal dosage of indomethacin in pregnancy is unknown. Here, we perform population pharmacokinetic (PK) and pharmacodynamic (PD) analyses, characterize the plasma disposition of indomethacin in pregnant women with PTL, and relate indomethacin exposure to delayed delivery and maternal/neonatal safety. We analyzed plasma and urine samples collected from a multicenter, prospective, opportunistic PK/PD study of indomethacin in pregnant women 12-32 weeks gestation admitted with PTL. Ninety-four participants with 639 plasma concentrations for indomethacin were included in the analysis. The final population PK (popPK) model for indomethacin was a 2-compartment structural model with first-order absorption and elimination and a covariate effect of body mass index on apparent oral clearance. We observed a 21%-60% increase in apparent oral clearance observed during pregnancy. There was no clear association between indomethacin exposure and maternal or neonatal safety outcomes, or with the magnitude of delayed delivery; however, 96.7% of women treated with indomethacin had a delivery that was delayed at least 48 hours. Given the changes to indomethacin apparent oral clearance during pregnancy, and the lack of relationship between indomethacin exposure and safety, dose-finding studies of indomethacin in pregnant women with PTL may help clarify the most safe and efficacious dosage and duration of indomethacin.

Prenatal use of indomethacin for preterm labor and renal function among very low birth weight infants.

BACKGROUND: Indomethacin is administered as a tocolytic agent for threatening preterm labor <28weeks of gestation. Only a few, not conclusive, studies have investigated its nephrotoxicity in very low birth weight (VLBW) infants. We investigated whether indomethacin increases the incidence of acute kidney injury (AKI) among VLBW infants. METHODS: This is a retrospective study including all VLBW infants born at our center between January 1, 2005, and December 31, 2013. Indomethacin was administered to women with preterm labor and intact membranes. Neonatal AKI was defined according to KDIGO classification. Univariate analyses were performed comparing VLBW infants exposed to and not exposed to indomethacin. In the multivariable model, the association of indomethacin and AKI was adjusted for patent ductus arteriosus, use of nephrotoxic medications, birth weight, and gestational age. RESULTS: Five hundred seventy-five VLBW infants were included, 49 (8.5%) of whom were exposed to indomethacin in utero. The univariate analysis showed that infants exposed to indomethacin had lower birth weight, lower gestational age, and higher incidence of AKI than infants not exposed. The multivariable model adjusted for confounding factors confirmed an increased risk of AKI in relation to gestational age at birth <27 weeks, but not to indomethacin. CONCLUSIONS: Our data suggest that extreme prematurity, but not the use of indomethacin, is associated with AKI.

Relationship between prolonged gestation and nifedipine pharmacokinetics in long-term tocolysis.

In this study, we examined the pharmacokinetics of nifedipine and investigated the maternal and foetal background factors that prolong pregnancy in pregnant women undergoing long-term tocolysis. This prospective observational study included 38 pregnant women hospitalised for threatened preterm labour and treated with nifedipine extended-release tablets in combination with an intravenous ritodrine infusion. Maternal plasma nifedipine concentrations were determined using high-performance liquid chromatography. All patients were administered 20 or 40 mg/dose of nifedipine every 6 h at the time of blood sampling. The plasma trough concentration (Ctrough ) was 22.6 ± 17.3 ng/mL, the maximum plasma concentration (Cmax ) was 30.9 ± 15.3 ng/mL and the time to maximum concentration (Tmax ) was 1.70 ± 1.10 h, as determined using noncompartmental analysis (NCA). The area under the curve for drug concentration (AUCtau ) was 152.3 ± 91.8 mg/L・h, and oral clearance (CL/F) was 0.17 ± 0.08 L/h. Using logistic regression analyses, we identified the factors that predicted term delivery from 37 weeks to <42 weeks of gestation. Gestational age at admission and the AUCtau of nifedipine can predict term delivery. The AUCtau of nifedipine is a valuable regulatory predictor of term delivery in pregnant women undergoing long-term tocolysis.

Progressive multiple organ dysfunction syndrome in adolescent pregnancy: Case report. / Síndrome de disfunción orgánica múltiple progresiva en embarazo adolescente: reporte de caso clínico.

Introduction: Adolescent pregnancy is a physiological process, but it can evolve with premature delivery, severe obstetric or clinical pathologies, mortality, or sequelae for mother and child. We aim to report the progressive multiple organ dysfunction syndrome secondary to pyelonephritis and sepsis during prepartum, delivery, and puerperium of adolescent pregnancy and its sequelae. Case report: A 14-year-old adolescent with a pregnancy of 27 weeks of gestation controlled from 8 to 25 weeks. She was urgently admitted to the high-risk obstetric unit due to signs of preterm labor, pyelonephritis, and acute renal injury. Treatment was started with intravenous cefazolin and betamethasone for lung maturation, oral nifedipine, and magnesium sulfate to prevent preterm labor and fetal neuronal protection, evolving with sustained hypotension and septic shock. At 13 hours after admission, she was transferred to the intensive care unit, where she evolved with persistent and progressive multiple organ failure for 28 days, progressively affecting the cardiovascular, hematologic, respiratory, and gastrointestinal systems. She was treated with vasoactive drugs, antibiotics, invasive mechanical ventilation, ultrafiltration, hemodialysis, pleural drainage, and cholecystectomy. Twenty-four hours after admission to intensive care, preterm vaginal delivery occurred. She developed chronic kidney disease stage KDIGO 5 (Kidney Disease Improving Global Outcomes V) and is awaiting renal transplantation. On the other hand, the preterm newborn presented severe neonatal asphyxia, bronchopulmonary dysplasia, and hypoxic-ischemic encephalopathy. Conclusion: Complicated adolescent pregnancy is a health emergency. Avoiding delays in the diagnosis and treatment of pyelonephritis, septic shock and the progressive multiple organ dysfunction syndrome can prevent mortality and permanent sequelae, both maternal and neonatal.

Introducción: El embarazo adolescente es un proceso fisiológico, pero puede evolucionar con parto prematuro, patologías obstétricas o médicas graves, mortalidad o secuelas para madre e hijo/a. Nuestro objetivo es reportar el síndrome de disfunción orgánica múltiple progresiva secundario a pielonefritis y sepsis ocurrido durante el preparto, parto y puerperio de embarazo adolescente y sus secuelas. Caso clínico: Adolescente de 14 años, con embarazo de 27 semanas de gestación controlado desde las 8 hasta 25 semanas. Ingresó de urgencia en unidad de alto riesgo obstétrico por signos de parto prematuro, pielonefritis e injuria renal aguda. Se inició tratamiento con cefazolina intravenosa y betametasona para maduración pulmonar, nifedipino oral y sulfato de magnesio para prevención del parto prematuro y protección neuronal fetal, evolucionando con hipotensión sostenida y shock séptico. A las 13 horas después del ingreso, fue trasladada a unidad de paciente crítico donde evolucionó con falla orgánica múltiple persistente y progresiva durante 28 días, afectando sucesivamente los sistemas cardiovascular, hematológico, respiratorio y gastrointestinal. Se trató con drogas vasoactivas, antibióticos, ventilación mecánica invasiva, ultrafiltración, hemodiálisis, drenaje pleural y colecistectomía. A las 24 horas de ingreso a cuidado intensivo, ocurrió el parto prematuro vaginal. La embarazada desarrolló enfermedad renal crónica etapa KDIGO 5 ( V) y se encuentra en espera de trasplante renal. Por su parte, la recién nacida prematura viva presentó asfixia neonatal severa, displasia broncopulmonar y encefalopatía hipóxico-isquémica.El embarazo adolescente complicado es una emergencia sanitaria. El diagnóstico y manejo oportuno de la pielonefritis, shock séptico y disfunción orgánica asociada a la sepsis pueden evitar mortalidad y secuelas permanentes materna y/o neonatal.

A multicenter, retrospective comparison of pregnancy outcomes between groups of preterm labor nulliparous mothers treated with atosiban vs. ritodrine in singleton and multiple pregnancies.

OBJECTIVE: To evaluate the safety and efficacy of atosiban and ritodrine in pregnant women who were hospitalized for threatened preterm labor (TPL). MATERIALS AND METHODS: Diagnosis records of preterm labor and subsequent pregnancy-related records and medical records of newborns were extracted from the Clinical Data Warehouse of the Catholic Medical Center's affiliated hospital. Since 2009, cases of preterm labor diagnosed before 34 weeks of pregnancy for first-time mothers who delivered at any one of three hospitals and who received drug treatment for more than 2 days to delay delivery were included in the dataset. Based on characteristics of Korea's national health insurance system, the drug treatment after diagnosis of preterm labor could be classified into cases using only ritodrine (571 women), cases using only atosiban (244 women), and cases where ritodrine treatment was started and then changed to atosiban (275 women). Demographic factors, obstetric outcomes, neonatal outcomes of the two groups were analyzed. RESULTS: The duration and maintenance of pregnancy were found to be similar between the two groups, although the initial cervical length was significantly shorter in the atosiban cohort (AC). Only in multifetal pregnancies, the maintenance of pregnancy was significantly longer in the AC. The total duration of pregnancy did not show any significant difference between the two groups regardless of singleton or multiple pregnancy. However, the distribution graph showed non-responders in the ritodrine cohort (RC). Our study showed a difference in neonatal birth weight of singleton between the two groups. The length of hospitalization and the NICU admission rate were also significantly higher in the RC for singleton. Although not significant, the proportion of numbers with an Apgar score less than 7 was higher in the RC. Neonatal death was more common in the RG (8 cases in AC and 18 cases in RC). CONCLUSIONS: Using atosiban for TPL is more effective than using ritodrine for maintaining pregnancy in the case of a multifetal pregnancy. In singleton pregnancies, neonatal outcomes of the atosiban group were superior to those of the ritodrine group. There seems to be a non-responder group when using ritodrine for TPL. Further studies are needed to determine causes of non-responders of ritodrine and effects of ritodrine on the fetus.

Prevention of Preterm Labor by Isosorbide Dinitrate and Nitroglycerin Patch.

BACKGROUND: Preterm labor is one of the most important causes of hospitalization during pregnancy and can lead to serious complications in neonates. OBJECTIVE: This study aims to compare the effect of transdermal nitroglycerin (TNG) patches and sublingual tablets of Isosorbide dinitrate (ISD) for the prevention of preterm delivery. METHODS: A total of 110 healthy pregnant women aged 18-35 years with a healthy and alive fetus and gestational age between 24-34 weeks who had at least 8 regular uterine contractions per hour were included in this single-blinded clinical trial. After exclusion, the women were randomly divided into TNG (n = 50) and ISD (n = 49) groups. After the first dose of medication (TNG or ISD), patients who developed complications such as hypotension, headache, or both, were also excluded from the study. RESULTS: A total of 58 patients completed the treatment course (29 patients in each group). A significant difference in delayed preterm labor and recovery time was reported between the TNG and ISD groups. CONCLUSION: Complications and the number of contractions were not statistically different in the two groups. We concluded that the TNG patch is more effective than ISD in delaying labor. Both drugs are likely to have a similar incidence of side effects.

Arrest of mouse preterm labor until term delivery by combination therapy with atosiban and mundulone, a natural product with tocolytic efficacy.

There is a lack of FDA-approved tocolytics for the management of preterm labor (PL). In prior drug discovery efforts, we identified mundulone and mundulone acetate (MA) as inhibitors of in vitro intracellular Ca2+-regulated myometrial contractility. In this study, we probed the tocolytic potential of these compounds using human myometrial samples and a mouse model of preterm birth. In a phenotypic assay, mundulone displayed greater efficacy, while MA showed greater potency and uterine-selectivity in the inhibition of intracellular-Ca2+ mobilization. Cell viability assays revealed that MA was significantly less cytotoxic. Organ bath and vessel myography studies showed that only mundulone exerted inhibition of myometrial contractions and that neither compounds affected vasoreactivity of ductus arteriosus. A high-throughput combination screen identified that mundulone exhibits synergism with two clinical-tocolytics (atosiban and nifedipine), and MA displayed synergistic efficacy with nifedipine. Of these combinations, mundulone+atosiban demonstrated a significant improvement in the in vitro therapeutic index compared to mundulone alone. The ex vivo and in vivo synergism of mundulone+atosiban was substantiated, yielding greater tocolytic efficacy and potency on myometrial tissue and reduced preterm birth rates in a mouse model of PL compared to each single agent. Treatment with mundulone after mifepristone administration dose-dependently delayed the timing of delivery. Importantly, mundulone+atosiban permitted long-term management of PL, allowing 71% dams to deliver viable pups at term (>day 19, 4-5 days post-mifepristone exposure) without visible maternal and fetal consequences. Collectively, these studies provide a strong foundation for the development of mundulone as a single or combination tocolytic for management of PL.

New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline.

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.

Genomic analysis of Enterococcus faecium strain RAOG174 associated with acute chorioamnionitis carried antibiotic resistance gene: is it time for precise microbiological identification for appropriate antibiotic use?

BACKGROUND: Preterm labor syndrome is associated with high perinatal morbidity and mortality, and intra-amniotic infection is a cause of preterm labor. The standard identification of causative microorganisms is based on the use of biochemical phenotypes, together with broth dilution-based antibiotic susceptibility from organisms grown in culture. However, such methods could not provide an accurate epidemiological aspect and a genetic basis of antimicrobial resistance leading to an inappropriate antibiotic administration. Hybrid genome assembly is a combination of short- and long-read sequencing, which provides better genomic resolution and completeness for genotypic identification and characterization. Herein, we performed a hybrid whole genome assembly sequencing of a pathogen associated with acute histologic chorioamnionitis in women presenting with PPROM. RESULTS: We identified Enterococcus faecium, namely E. faecium strain RAOG174, with several antibiotic resistance genes, including vancomycin and aminoglycoside. Virulence-associated genes and potential bacteriophage were also identified in this genome. CONCLUSION: We report herein the first study demonstrating the use of hybrid genome assembly and genomic analysis to identify E. faecium ST17 as a pathogen associated with acute histologic chorioamnionitis. The analysis provided several antibiotic resistance-associated genes/mutations and mobile genetic elements. The occurrence of E. faecium ST17 raised the awareness of the colonization of clinically relevant E. faecium and the carrying of antibiotic resistance. This finding has brought the advantages of genomic approach in the identification of the bacterial species and antibiotic resistance gene for E. faecium for appropriate antibiotic use to improve maternal and neonatal care.

ß3 Receptor Signaling in Pregnant Human Myometrium Suggests a Role for ß3 Agonists as Tocolytics.

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 ß2 adrenergic receptor relax airway smooth muscle and are effective in the treatment of asthma led to the notion that ß2 mimetics would prevent preterm birth by relaxing uterine smooth muscle. The activation of cAMP-dependent protein kinase by ß2 receptors is unable to provide meaningful tocolysis. The failure of ß2 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 ß3 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 ß2 agonists as tocolytics and suggests a non-canonical signaling role for ß3AR in myometrium. The addition of the ß3 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 ß3 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.

Use, misuse, and overuse of antenatal corticosteroids. A retrospective cohort study.

OBJECTIVES: To evaluate the timing of antenatal corticosteroids (ACS) administration in relation to the delivery timing based on indications and risk factors for preterm delivery. METHODS: We conducted a retrospective cohort study to understand what factors predict the optimal timing of ACS administration (ACS administration within seven days). We reviewed consecutive charts of adult pregnant women receiving ACS from January 1, 2011, to December 31, 2019. We excluded pregnancies under 23 weeks, incomplete and duplicate records, and patients delivered outside our health system. The timing of ACS administration was categorized as optimal or suboptimal. These groups were analyzed regarding demographics, indications for ACS administration, risk factors for preterm delivery, and signs and symptoms of preterm labor. RESULTS: We identified 25,776 deliveries. ACS were administered to 531 pregnancies, of which 478 met the inclusion criteria. Of the 478 pregnancies included in the study, 266 (55.6 %) were delivered in the optimal timeframe. There was a higher proportion of patients receiving ACS for the indication of threatened preterm labor in the suboptimal group as compared to the optimal group (85.4 % vs. 63.5 %, p<0.001). In addition, patients who delivered in the suboptimal timeframe had a higher proportion of short cervix (33 % vs. 6.4 %, p<0.001) and positive fetal fibronectin (19.8 % vs. 1.1 %, p<0.001) compared to those who delivered in the optimal timeframe. CONCLUSIONS: More emphasis should be placed on the judicious use of ACS. Emphasis should be placed on clinical assessment rather than relying solely on imaging and laboratory tests. Re-appraisal of institutional practices and thoughtful ACS administration based on the risk-benefit ratio is warranted.

A nomogram to optimize the timing of antenatal corticosteroids in threatened preterm delivery.

BACKGROUND: Recent observational studies reported a high rate of suboptimal use of antenatal corticosteroids (too anticipated or retrospectively not indicated) for women at risk of preterm delivery despite a recommended use within 7 days before delivery. OBJECTIVE: This study aimed to elaborate a nomogram aiming at optimizing the timing of administration of antenatal corticosteroids in case of threatened preterm labor, asymptomatic short cervix, or uterine contractions. STUDY DESIGN: This was an observational retrospective study conducted in a tertiary hospital. All women between 24 and 34 weeks of gestation who received corticosteroids during hospitalization for threatened preterm delivery, asymptomatic short cervix, or uterine contractions requiring tocolysis between 2015 and 2019 were included. Clinical, biological, and sonographic data of women were used to construct logistic regression models for predicting delivery within 7 days. The model was validated on an independent series of women hospitalized in 2020. RESULTS: Among the 1343 women included in this study, the risk factors independently associated with a delivery within 7 days in multivariate analysis were vaginal bleeding (odds ratio, 14.47; 95% confidence interval, 7.81-26.81; P<.001); need for a second-line tocolysis, such as atosiban (odds ratio, 5.66; 95% confidence interval, 3.39-9.45; P<.001); C-reactive protein level (per 1 mg/L increase; odds ratio, 1.03; 95% confidence interval, 1.02-1.04; P<.001); cervical length (per 1 mm increase; odds ratio, 0.84; 95% confidence interval, 0.82-0.87; P<.001); uterine scar (odds ratio, 2.98; 95% confidence interval, 1.33-6.65; P=.008), and gestational age at admission (per week of amenorrhea increase; odds ratio, 1.10; 95% confidence interval, 1.00-1.20; P=.041). Based on these results, a nomogram was developed that, in retrospect, would have allowed physicians to avoid or delay antenatal corticosteroids in 57% of cases in our population. The discrimination of the predictive model was good when applied to the validation set of 232 women hospitalized in 2020. It would have enabled physicians to avoid or delay antenatal corticosteroids in 52% of cases. CONCLUSION: This study developed a simple use, accurate prognostic score to identify women at risk of delivery within 7 days in cases of threatened preterm delivery, asymptomatic short cervix, or uterine contractions and thereby optimized the use of antenatal corticosteroids.

Progestogen maintenance therapy for prolongation of pregnancy after an episode of preterm labour: A systematic review and meta-analysis.

BACKGROUND: Evidence for progestogen maintenance therapy after an episode of preterm labour (PTL) is contradictory. OBJECTIVES: To assess effectiveness of progestogen maintenance therapy after an episode of PTL. SEARCH STRATEGY: An electronic search in Central Cochrane, Ovid Embase, Ovid Medline and clinical trial databases was performed. SELECTION CRITERIA: Randomised controlled trials (RCT) investigating women between 16+0 and 37+0 weeks of gestation with an episode of PTL who were treated with progestogen maintenance therapy compared with a control group. DATA COLLECTION AND ANALYSIS: Systematic review and meta-analysis were conducted. The primary outcome was latency time in days. Secondary neonatal and maternal outcomes are consistent with the core outcome set for preterm birth studies. Studies were extensively assessed for data trustworthiness (integrity) and risk of bias. MAIN RESULTS: Thirteen RCT (1722 women) were included. Progestogen maintenance therapy demonstrated a longer latency time of 4.32 days compared with controls (mean difference [MD] 4.32, 95% CI 0.40-8.24) and neonates were born with a higher birthweight (MD 124.25 g, 95% CI 8.99-239.51). No differences were found for other perinatal outcomes. However, when analysing studies with low risk of bias only (five RCT, 591 women), a significantly longer latency time could not be shown (MD 2.44 days; 95% CI -4.55 to 9.42). CONCLUSIONS: Progestogen maintenance therapy after PTL might have a modest effect on prolongation of latency time. When analysing low risk of bias studies only, this effect was not demonstrated. Validation through further research, preferably by an individual patient data meta-analysis is highly recommended.