Cooperation of aquaporin 5 and the adrenergic system in the initiation of birth in rat model.

Aquaporins (AQPs) are involved in the process of implantation, regulate myometrial contractions and cervical ripening, and maintain appropriate placental functioning. The molecular mechanism of these functions is not fully understood. Our study aimed to investigate the physiological significance of AQP5 during pregnancy and to determine the cooperation between the adrenergic system and the AQP5 in uterine contraction in the late-pregnant rat uterus. After administering AQP5 siRNA intraperitoneally to Sprague-Dawley rats, the length of the gestational period was determined and the changes in uterine contractions were measured in an isolated organ bath system. Pharmacological influence on AQP5 expression and uterine contraction was investigated by treatment with terbutaline (10 mg/kg, subcutaneously) and doxazosin (5 mg/kg, orally) in vivo; and mercuric chloride (HgCl2), in vitro. Moreover, the levels of cAMP response element binding protein (CREB) were measured in the uterus by an ELISA kit. The gestational period became shorter, AQP5 expression significantly decreased and rat uterus contraction increased after AQP5 siRNA treatment compared to the control. Treatment with terbutaline significantly increased AQP5 mRNA and protein expression after 30 min and continuously reduced it until 90 min, whereas doxazosin treatment did not significantly alter AQP5 expression. Treatment with the AQP5 antagonist HgCl2 increased spontaneous uterus contraction and decreased norepinephrine-induced uterus contraction with decreasing AQP5 expression in pregnant rat uterus. Moreover, the tocolytic effect through the adrenergic system was amplified in the presence of an AQP5 antagonist, presumably via the changes in cAMP level. In conclusion, our findings elucidate the collaborative role of aquaporin 5 (AQP5) and adrenergic systems in the regulation of uterine contractions in late-pregnant rats. Our findings suggest this may be a good starting point for developing a new tocolytic therapy.

5ß-Dihydrosteroids: Formation and Properties.

5ß-Dihydrosteroids are produced by the reduction of Δ4-3-ketosteroids catalyzed by steroid 5ß-reductase (AKR1D1). By analogy with steroid 5α-reductase, genetic deficiency exists in AKR1D1 which leads to errors in newborn metabolism and in this case to bile acid deficiency. Also, like the 5α-dihydrosteroids (e.g., 5α-dihydrotestosterone), the 5ß-dihydrosteroids produced by AKR1D1 are not inactive but regulate ligand access to nuclear receptors, can act as ligands for nuclear and membrane-bound receptors, and regulate ion-channel opening. For example, 5ß-reduction of cortisol and cortisone yields the corresponding 5ß-dihydroglucocorticoids which are inactive on the glucocorticoid receptor (GR) and provides an additional mechanism of pre-receptor regulation of ligands for the GR in liver cells. By contrast, 5ß-pregnanes can act as neuroactive steroids at the GABAA and NMDA receptors and at low-voltage-activated calcium channels, act as tocolytic agents, have analgesic activity and act as ligands for PXR, while bile acids act as ligands for FXR and thereby control cholesterol homeostasis. The 5ß-androstanes also have potent vasodilatory properties and work through blockade of Ca2+ channels. Thus, a preference for 5ß-dihydrosteroids to work at the membrane level exists via a variety of mechanisms. This article reviews the field and identifies gaps in knowledge to be addressed in future research.

Preterm birth in low-middle income Countries.

Preterm birth (PTB), remains a major cause of significant morbidity and mortality world-wide with about 12-15million preterm births occurring every year. Although the overall trend is decreasing, this is mainly in high-income countries (HIC). The rate remains high in low-and middle-income countries (LMIC) varying on average between 10 and 12% compared to 9% in HIC. The pathogenesis of PTB is complex and multifactorial. Attempts to reduce rates that have focused on PTB as a single condition have in general been unsuccessful. However, more recent attempts to phenotype PTB have resulted in targeted preventative approaches which are yielding better results. Prevention (primary or secondary) is the only approach that has been shown to make a difference to rates of PTB. These include identifying risk factors pre-pregnancy and during pregnancy and instituting appropriate measures to address these. In LMIC, although some approaches that have been shown to be effective in some HIC are adaptable, there is a need to involve stakeholders at all levels in utilizing evidence preferrably generated in LMIC to implement strategies that are likely to reduce the rate of PTB. In this review, we focus on prevention and how to involve policy makers in the process of applying evidence into policy that would reduce PTB in LMIC.

A historical narrative review through the field of tocolysis in threatened preterm birth.

Preterm birth presents a significant challenge in clinical obstetrics, requiring effective strategies to reduce associated mortality and morbidity risks. Tocolytic drugs, aimed at inhibiting uterine contractions, are a key aspect of addressing this challenge. Despite extensive research over many years, determining the most effective tocolytic agents remains a complex task, prompting better understanding of the underlying mechanisms of spontaneous preterm birth and recording meaningful outcome measures. This paper provides a comprehensive review of various obsolete and current tocolytic drug regimens that were instituted over the past century, examining both historical contexts and contemporary challenges in their development and adoption. The examination of historical debates and advancements highlights the complexity of introducing new therapies. While the search for effective tocolytics continues, questions arise regarding their actual benefits in obstetric care and the necessity for ongoing exploration. The presence of methodological limitations in current research emphasizes the importance of well-designed randomized controlled trials with robust endpoints and extended follow-up periods.In response to these complexities, the consideration of shifting towards prevention strategies aimed at addressing the root causes of preterm labor becomes more and more evident. This potential shift may offer a more effective approach than relying solely on tocolytics to delay labor initiation.Ultimately, effectively managing threatened preterm birth necessitates ongoing investigation, innovation, and a willingness to reassess strategies in pursuit of optimal outcomes for mothers, neonates, and long-term child health.

Risks of maternal cardiopulmonary events associated with ritodrine for tocolysis: A national database linkage study in 1 831 564 pregnant women.

OBJECTIVE: Real-world data on cardiopulmonary events among pregnant women receiving ß-agonist therapy are scarce. In the present study, we aimed to examine the absolute and relative risks of maternal cardiopulmonary events associated with the use of ß-agonist ritodrine during pregnancy. METHODS: By linking Taiwan's National Birth Certificate Application Database with National Health Insurance data, 1 831 564 pregnancies at ≥20 weeks' gestation were identified. Age-standardized incidence rates of cardiopulmonary events among pregnant women exposed to ritodrine were estimated. Nested case-control analyses were conducted to evaluate the relative risk of pulmonary edema, heart failure, and arrhythmia associated with prior ritodrine use. Cases and controls were matched using risk set sampling, and adjusted odds ratios were estimated using conditional logistic regression models. RESULTS: A total of 189 cases of pulmonary edema, 126 cases of heart failure, and 162 cases of arrhythmia were identified (corresponding age-standardized incidence rates: 20.90, 8.35, and 16.63 per 100 000 among pregnant women only exposed to oral ritodrine; 91.28, 36.01, and 14.61 per 100 000 among those ever exposed to intravenous ritodrine). Exposure to oral ritodrine was associated with a lower increased risk of pulmonary edema (aOR 1.76; 95% CI: 1.12-2.76) and arrhythmia (2.21; 1.47-3.32) whereas exposure to ritodrine injection was associated with a significantly higher risk of pulmonary edema (10.56; 6.39-17.45), arrhythmia (4.15; 1.99-8.64), and heart failure (5.58; 2.27-13.74). CONCLUSIONS: Pregnant women receiving intravenous ritodrine therapy had higher cardiopulmonary risks and should be intensively monitored. While the relative risk associated with oral ritodrine is not pronounced, it should be used judiciously among pregnant women as well.

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.

An unusual case of severe asphyxia with the fetal position unexpectedly inverted in a malformed uterus: a case report.

BACKGROUND: We present a severe neonatal consequence due to the unexpected and crucial inversion of the fetal position after sudden termination of tocolysis during early labor of a woman with congenital uterine anomaly. It has been reported that congenital uterine anomalies latently affect the fetal position. The clinical pitfalls in childbirth with uterine anomalies are discussed here on the basis of clinical evidence. CASE PRESENTATION: At a perinatal medical center in Japan, a 29-year-old Japanese mother who had a history of bicornuate uterus, received tocolysis to prolong her pregnancy for 5 days during the late preterm period after preterm-premature rupture of the membrane. She gave birth to a 2304 g male neonate of the gestational age of 35 weeks and 5 days with severe asphyxia by means of crash cesarean section for fetal sustained bradycardia after sudden termination of tocolysis. We found the fetal position to reverse from cephalic to breech position during early labor. He ended up having severe cerebral palsy after brain cooling against hypoxic-ischemic encephalopathy for 3 days. The mechanism of inversion from cephalic to breech position without amnionic fluid remains unclear, although women with a known diagnosis of a uterine anomaly have higher risk of adverse outcomes such as malpresentation. CONCLUSIONS: When considering the clinical course of this case on the basis of the medical reports, we suspected that uterine anomalies and changes in intrauterine pressure could cause fetal malpresentation and adverse neonatal outcomes.

Parturition at term: induction, second and third stages of labor, and optimal management of life-threatening complications-hemorrhage, infection, and uterine rupture.

Childbirth is a defining moment in anyone's life, and it occurs 140 million times per year. Largely a physiologic process, parturition does come with risks; one mother dies every two minutes. These deaths occur mostly among healthy women, and many are considered preventable. For each death, 20 to 30 mothers experience complications that compromise their short- and long-term health. The risk of birth extends to the newborn, and, in 2020, 2.4 million neonates died, 25% in the first day of life. Hence, intrapartum care is an important priority for society. The American Journal of Obstetrics & Gynecology has devoted two special Supplements in 2023 and 2024 to the clinical aspects of labor at term. This article describes the content of the Supplements and highlights new developments in the induction of labor (a comparison of methods, definition of failed induction, new pharmacologic agents), management of the second stage, the value of intrapartum sonography, new concepts on soft tissue dystocia, optimal care during the third stage, and common complications that account for maternal death, such as infection, hemorrhage, and uterine rupture. All articles are available to subscribers and non-subscribers and have supporting video content to enhance dissemination and improve intrapartum care. Our hope is that no mother suffers because of lack of information.

Comparison of terbutaline and atosiban as tocolytic agents in intrauterine repair of myelomeningocele: a retrospective cohort study.

BACKGROUND: Myelomeningocele (MMC) is a neural tube defect disease. Antenatal repair of fetal MMC is an alternative to postnatal repair. Many agents can be used as tocolytics during the in utero fetal repair such as ß2-agonists and oxytocin receptor antagonists, with possible maternal and fetal repercussions. This study aims to compare maternal arterial blood gas analysis between terbutaline or atosiban, as tocolytic agents, during intrauterine MMC repair. METHODS: Retrospective cohort study. Patients were divided into two groups depending on the main tocolytic agent used during intrauterine MMC repair: atosiban (16) or terbutaline (9). Maternal arterial blood gas samples were analyzed on three moments: post induction (baseline, before the start of tocolysis), before extubation, and two hours after the end of the surgery. RESULTS: Twenty-five patients were included and assessed. Before extubation, the terbutaline group showed lower arterial pH (7.347 ± 0.05 vs. 7.396 ± 0.02 for atosiban, p = 0.006) and higher arterial lactate (28.33 ± 12.76 mg.dL-1 vs. 13.06 ± 6.35 mg.dL-1, for atosiban, p = 0.001) levels. CONCLUSIONS: Patients who received terbutaline had more acidosis and higher levels of lactate, compared to those who received atosiban, during intrauterine fetal MMC repair.

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.

Comparison of terbutaline and atosiban as tocolytic agents in intrauterine repair of myelomeningocele: a retrospective cohort study

Abstract Background: Myelomeningocele (MMC) is a neural tube defect disease. Antenatal repair of fetal MMC is an alternative to postnatal repair. Many agents can be used as tocolytics during the in utero fetal repair such as β2-agonists and oxytocin receptor antagonists, with possible maternal and fetal repercussions. This study aims to compare maternal arterial blood gas analysis between terbutaline or atosiban, as tocolytic agents, during intrauterine MMC repair. Methods: Retrospective cohort study. Patients were divided into two groups depending on the main tocolytic agent used during intrauterine MMC repair: atosiban (16) or terbutaline (9). Maternal arterial blood gas samples were analyzed on three moments: post induction (baseline, before the start of tocolysis), before extubation, and two hours after the end of the surgery. Results: Twenty-five patients were included and assessed. Before extubation, the terbutaline group showed lower arterial pH (7.347 ± 0.05 vs. 7.396 ± 0.02 for atosiban, p = 0.006) and higher arterial lactate (28.33 ± 12.76 mg.dL-1 vs. 13.06 ± 6.35 mg.dL-1, for atosiban, p = 0.001) levels. Conclusions: Patients who received terbutaline had more acidosis and higher levels of lactate, compared to those who received atosiban, during intrauterine fetal MMC repair.

The combined uterorelaxant effect of sildenafil and terbutalin in the rat: The potential benefit of co-administration of low doses.

Aims: Our aims were to investigate the uterus relaxant effect of sildenafil alone and co-administered with ß2-mimetic terbutaline in an isolated organ bath and to perform in vivo smooth muscle electromyographic studies in pregnant rats. The modifications in uterine cAMP/cGMP levels were also detected. Main methods: Contractions of non-pregnant and 5/15/18/20/22-day pregnant uterine rings were measured in an isolated organ bath system in the presence of sildenafil alone or with terbutaline. The uterine levels of cAMP and cGMP were determined by commercial ELISA assays. The in vivo efficacy of the combination was measured by smooth muscle electromyography. Key findings: Sildenafil reduced uterine contractions in vitro and in vivo; additionally, terbutaline significantly increased the uterorelaxant effect of sildenafil in the lower concentration or dose ranges. Terbutaline enhanced the cGMP level increasing effect of sildenafil. Significance: The co-administration of sildenafil and terbutaline could be a promising tocolytic combination to reduce maternal and foetal adverse events and increase efficacy.

Management of preterm labor: Clinical practice guideline and recommendation by the WAPM-World Association of Perinatal Medicine and the PMF-Perinatal Medicine Foundation.

This practice guideline follows the mission of the World Association of Perinatal Medicine in collaboration with the Perinatal Medicine Foundation, bringing together groups and individuals throughout the world, with the goal of improving the management of preterm labor. In fact, this document provides further guidance for healthcare practitioners on the appropriate use of examinations with the aim to improve the accuracy in diagnosing preterm labor and allow timely and appropriate administration of tocolytics, antenatal corticosteroids and magnesium sulphate and avoid unnecessary or excessive interventions. Therefore, it is not intended to establish a legal standard of care. This document is based on consensus among perinatal experts throughout the world in the light of scientific literature and serves as a guideline for use in clinical practice.

Tocolysis after preterm prelabor rupture of membranes and 5-year outcomes: a population-based cohort study.

BACKGROUND: The administration of tocolytics after preterm prelabor rupture of membranes remains a controversial practice. In theory, reducing uterine contractility should delay delivery and allow for optimal antenatal management, thereby reducing the risks for prematurity and adverse consequences over the life course. However, tocolysis may be associated with neonatal death or long-term adverse neurodevelopmental outcomes, mainly related to prolonged fetal exposure to intrauterine infection or inflammation. In a previous study, we showed that tocolysis administration was not associated with short-term benefits. There are currently no data available to evaluate the impact of tocolysis on neurodevelopmental outcomes in school-aged children born prematurely in this clinical setting. OBJECTIVE: This study aimed to investigate whether tocolysis administered after preterm prelabor rupture of membranes is associated with neurodevelopmental outcomes at 5.5 years of age. STUDY DESIGN: We used data from a prospective, population-based cohort study of preterm births recruited in 2011 (referred to as the EPIPAGE-2 study) and for whom the results of a comprehensive medical and neurodevelopmental assessment of the infant at age 5.5 years were available. We included pregnant individuals with preterm prelabor rupture of membranes at 24 to 32 weeks' gestation in singleton pregnancies with a live fetus at the time of rupture, birth at 24 to 34 weeks' gestation, and participation of the infant in an assessment at 5.5 years of age. Exposure was the administration of any tocolytic treatment after preterm prelabor rupture of membranes. The main outcome was survival without moderate to severe neurodevelopmental disabilities at 5.5 years of age. Secondary outcomes included survival without any neurodevelopmental disabilities, cerebral palsy, full-scale intelligence quotient, developmental coordination disorders, and behavioral difficulties. A propensity-score analysis was used to minimize the indication bias in the estimation of the treatment effect on outcomes. RESULTS: Overall, 596 of 803 pregnant individuals (73.4%) received tocolytics after preterm prelabor rupture of membranes. At the 5.5-year follow-up, 82.7% and 82.5% of the children in the tocolysis and no tocolysis groups, respectively, were alive without moderate to severe neurodevelopmental disabilities; 52.7% and 51.1%, respectively, were alive without any neurodevelopmental disabilities. After applying multiple imputations and inverse probability of treatment weighting, we found no association between the exposure to tocolytics and survival without moderate to severe neurodevelopmental disabilities (odds ratio, 0.93; 95% confidence interval, 0.55-1.60), survival without any neurodevelopmental disabilities (odds ratio, 1.02; 95% confidence interval, 0.65-1.61), or any of the other outcomes. CONCLUSION: There was no difference in the neurodevelopmental outcomes at age 5.5 years among children with and without antenatal exposure to tocolysis after preterm prelabor rupture of membranes. To date, the health benefits of tocolytics remain unproven, both in the short- and long-term.

FIGO good practice recommendations for preterm labor and preterm prelabor rupture of membranes: Prep-for-Labor triage to minimize risks and maximize favorable outcomes.

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.

Tocolytic treatment and maternal characteristics, obstetric outcomes, and offspring childhood outcomes among births at and after 37 weeks of gestation: the Japan environment and children's study.

PURPOSE: To evaluate differences in maternal characteristics and obstetric and offspring childhood outcomes between births at and after 37 weeks of gestation (referred to as term and post-term births) according to the use of tocolytic treatment. METHODS: Data for 63,409 women with singleton births at and after 37 weeks of gestation were analyzed using data from the Japan Environment and Children's Study (JECS). We compared maternal characteristics, obstetric outcomes, and offspring childhood outcomes between term and post-term births exposed and not exposed to tocolytic treatment. Additionally, multivariable logistic regression models were used to calculate adjusted odds ratios for offspring childhood outcomes with significant between-group differences in the univariable analysis, with term and post-term births without tocolytic agents as the reference group. RESULTS: We observed differences in maternal characteristics and obstetric outcomes between term and post-term births exposed and not exposed to tocolytic treatment. The incidence of offspring childhood developmental disorders showed no significant between-group differences. However, participants exposed to tocolytic agents had higher incidence of offspring childhood allergic disorders. The adjusted odds ratio for any of the offspring childhood allergic disorders in term and post-term births with tocolytic agents was 1.08 (95% confidence interval, 1.03-1.13). CONCLUSION: This study found no significant difference in the incidence of offspring developmental disorders between term and post-term births exposed and not exposed to tocolytic treatment. However, tocolytic treatment was associated with differences in maternal characteristics and obstetric outcomes, along with a marginal increase in the incidence of childhood allergic disorders in offspring.

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.

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.

A Comparative Study of the Effectiveness of Transdermal Nitroglycerine Patches and Oral Nifedipine in Prolongation of Pregnancy in Women With Preterm Labour.

Backgrounds A significant contributor to newborn morbidity and mortality is preterm birth. Several techniques have been employed to identify patients at risk of premature labour. However, these predictors are not always effective because of their multifactorial aetiology. Preterm labour can be suppressed largely through tocolysis. This study compared the effectiveness and safety of transdermal nitroglycerine and oral nifedipine in preventing premature labour. Methods This study was done at Acharya Vinoba Bhave Rural Hospital, Sawangi, Wardha, Maharashtra, from December 2020 to November 2022, on 130 women presenting with preterm labour pains between 28 and 37 weeks of gestational age. All the women selected were randomized into two equal groups by using the envelope method. Sixty-five women were given a nitroglycerine patch (Group A), and the rest (65 women) were given an oral nifedipine tablet (group B). The variables studied were mean days of prolongation of pregnancy, treatment outcome, steroid coverage, along with feto-maternal outcomes among both groups. Results The percentage of women whose pregnancy was prolonged for at least 48 hours in the nitroglycerine group was 75.3%, and in the nifedipine group it was 93.8%. Failure to achieve tocolysis, defined as delivery within 48 hours, was seen significantly more in the nitroglycerine group (24.6%) than in the nifedipine group (6.1%). The overall foetal outcomes were comparable in both groups. Conclusion Oral nifedipine was found to be superior to transdermal nifedipine patches in terms of efficacy and safety in the management of preterm labour, with a better side effect profile.