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.

Fetal echocardiographic evaluation before and after nifedipine treatment in preterm labor.

OBJECTIVE: To assess the effect of nifedipine used for tocolysis on cardiac morphology and functions. METHODS: The study included 47 pregnant women diagnosed with preterm labor at 32-33 weeks. Fetal echocardiographic evaluation was performed with two-dimensional (2D) imaging, M-mode, pulsed wave (PW) Doppler, and tissue Doppler imaging (TDI) before and after the 48th hour of nifedipine treatment. RESULTS: No significant change was observed in Doppler parameters (pulsatility indices of the umbilical artery, middle cerebral artery, ductus venosus) and cardiac morphology (cardiothoracic ratio, end-diastolic longitudinal diameters, sphericity indices, wall thickness) after nifedipine treatment. The parameters obtained with TDI (e', a', s', e'/a', E/e' of mitral and tricuspid valves), M- mode (TAPSE, MAPSE), pulsed Doppler (myocardial performance index, left cardiac output, right cardiac output, tricuspid E, A waves, tricuspid E/A ratio, mitral E, A waves, mitral E/A ratio) did not change after nifedipine treatment. CONCLUSION: To date, this is the first study to examine the effects of nifedipine on the fetal heart using the TDI. Since nifedipine is a drug that is frequently used and well-tolerated in the prevention of preterm labor, it is crucial that it does not cause changes in fetal cardiac parameters during tocolysis. Therefore, we used TDI in addition to conventional methods to evaluate the effect of nifedipine, which is frequently used in obstetrics, on cardiac functions in the early period. Nifedipine treatment seems not to affect systolic or diastolic functions. This indicates that nifedipine is reliable on cardiac functions and morphology in pregnancies treated for preterm labor.

Four kinds of tocolytic therapy for preterm delivery: Systematic review and network meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Premature birth affects more than 15 million infants, as well as mothers and families around the world. With the relaxation of the two-child policy, the problem of premature birth has become relatively prominent in China. According to statistics, China had a birth population of 15.23 million in 2018, with a considerably large number of premature births. This study aims to evaluate the efficacy and safety of tocolysis in the treatment of preterm delivery, provide clinical evidence for medical staff and promote the self-management of patients with premature births. METHODS: Four English databases (PubMed, Embase, Cochrane Library and Web of Science) were retrieved by computer, the retrieval time was from the establishment of each database to November 2021, and the randomized controlled trials for the treatment of preterm delivery were screened according to the pre-set natriuretic exclusion criteria. After literature screening, data selection and risk of bias evaluation were independently conducted by two researchers. R 4.1.1 and Stata 17.0 software were used for statistical analysis. RESULTS AND DISCUSSION: A total of 44 RCTs were included, including 6939 patients. The results of network meta-analysis reveal that in terms of effectiveness, indomethacin was the most effective intervention measure, followed by nifedipine, and the difference was statistically significant; regarding safety, nifedipine was the safest intervention measure, followed by indomethacin, and the difference was statistically significant; and in respect of adverse reactions, ritodrine had the highest probability, and the difference was statistically significant. WHAT IS NEW AND CONCLUSION: Nifedipine may be better for delayed delivery and less likely to produce adverse pregnancy outcomes, followed by indomethacin. Limited by the number and quality of recipient studies, the aforementioned conclusions need to be verified through more high-quality studies. At the same time, the focus should be on patients with twin pregnancy and patients with clinical manifestations of extreme preterm delivery.

Nifedipine for Acute Tocolysis of Preterm Labor: A Placebo-Controlled Randomized Trial.

OBJECTIVE: To evaluate the effectiveness of acute nifedipine tocolysis in preventing preterm birth in women in preterm labor. METHOD: This was a randomized, double-blind, placebo-controlled trial of nifedipine in women with a singleton pregnancy between 28 0/7 and 33 6/7 weeks of gestation who were admitted with uterine activity, intact membranes, and cervical dilatation from 2 to 4 cm. Women were randomized to receive nifedipine 20 mg or placebo orally, followed by a repeat dose after 90 minutes if contractions persisted. The study drug was continued every 4 hours to complete a 48-hour regimen. The primary outcome was birth before 37 weeks of gestation. A total of 150 women were necessary to detect a one-third reduction in this outcome. After treating 88 patients, a preplanned interim analysis of blinded outcomes by the Data Safety Monitoring Committee recommended discontinuation of the trial due to futility. RESULTS: A total of 90 women were enrolled between May 2014 and November 2017. After two women withdrew, 88 were analyzed: 46 in the nifedipine group and 42 in the placebo group. There was no significant difference in the primary outcome of delivery before 37 weeks of gestation in the nifedipine group compared with the placebo group (52% vs 48%, relative risk [RR] 1.1, 95% CI 0.7-1.7), nor in the secondary outcome of delivery at least 48 hours from randomization (78% vs 71%, respectively, RR 1.1, 95% CI 0.9-1.4). There were also no significant differences between groups in neonatal outcomes. CONCLUSION: Acute tocolysis of preterm labor with nifedipine did not affect preterm birth rates, delivery within 48 hours, or neonatal outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02132533.

Vaginal Progesterone Supplementation in the Management of Preterm Labor: A Randomized Controlled Trial.

OBJECTIVES: The primary objective in this study was to evaluate the effects of vaginal progesterone supplementation for the prolongation of the latency period in preterm labor. The secondary objectives were to evaluate gestational age at delivery, rates of preterm birth less than 34 and 37 weeks, obstetric outcomes, maternal compliance with medication use, and side effects. METHODS: A randomized controlled, unblinded trial was performed. Ninety women with preterm labor occurring at 24 to 34 weeks were either randomized to a vaginal progesterone group (44 women) receiving tocolytic and antenatal corticosteroids treatment combined with vaginal micronized progesterone (400 mg everyday) or to the no-progesterone group (46 women) receiving tocolytic and antenatal corticosteroids treatment only. RESULTS: Latency periods were more prolonged in the vaginal progesterone group than in the no-progesterone group (32.8 ± 18.7 vs. 25.8 ± 22.7 days, p = 0.045). Gestational age at delivery in the vaginal progesterone group was also higher than in the no-progesterone group (37 vs. 35 weeks, p = 0.027). There were significant reduction rates of preterm birth less than 34 weeks (13.6% vs. 39.1%, p = 0.012), low birth weight (29.5% vs. 50%, p = 0.048), neonatal respiratory distress syndrome (13.6% vs. 37%, p = 0.021), and neonatal intensive care unit admission (6.8% vs. 28.3%, p = 0.017). CONCLUSIONS: Combined treatment with vaginal progesterone 400 mg could prolong the latency period in preterm labor when compared with no progesterone.

A comparative study of transdermal nitroglycerine patch and oral nifedipine in preterm labor.

Background: Currently, the main goal for the use of tocolytic therapy is to delay the birth so as to allow the use of corticosteroids for accelerating fetal lung maturity and maternal transfer to a tertiary care center and thereby reducing neonatal morbidity and mortality. Aims and Objectives: The aims amd objectives were to compare the safety and efficacy of transdermal nitroglycerine patch with oral nifedipine as a tocolytic agent to arrest preterm labor and prevent preterm birth. Materials and Methods: Based on the selection criteria, 50 patients were selected randomly in Group A and Group B. Group A women were given transdermal nitroglycerin patch, which delivered 10 mg Nitroglycerin (NTG) over 24 h and it was applied to the woman's abdomen followed by another patch of 10 mg after 1 h if contractions persisted. After 24 h, it was replaced by a fresh patch. Group B women were given an oral loading dose of nifedipine 20 mg followed by a similar dose if contractions persisted after 1 h. A maintenance dose of 10 mg thrice daily was given if contractions were suppressed. Patients were monitored from the time of admission to the time of discharge. Results: The mean duration of prolongation of pregnancy in Group B (3.68 ± 1.91 days) was significantly more than Group A (2.78 ± 1.39 days). Headache was seen significantly more in Group A (42%) than group B (6%). Tachycardia, hypotension, and palpitation showed no statistically significant difference between them. There was no statistically significant difference in the birth weight of the babies in both the groups. Conclusion: Nifedipine is a safe and effective drug in prolonging preterm labor and has minimal maternal and neonatal side effects.

RésuméContexte: Actuellement, le principal objectif de l'utilisation de la thérapie tocolytique est de retarder la naissance afin de permettre l'utilisation de corticostéroïdes pour accélérer la maturité pulmonaire fœtale et le transfert maternel vers un centre de soins tertiaires et ainsi réduire la morbidité et la mortalité néonatales. Buts et objectifs: Les buts et objectifs étaient de comparer l'innocuité et l'efficacité du timbre transdermique de nitroglycérine avec la nifédipine par voie orale comme agent tocolytique pour arrêter le travail prématuré et prévenir l'accouchement prématuré. Matériel et méthodes: Sur la base des critères de sélection, 50 patientes ont été sélectionnées au hasard dans les groupes A et B.Les femmes du groupe A ont reçu un patch transdermique de nitroglycérine, qui a administré 10 mg de NTG en 24 h et appliqué sur l'abdomen de la femme suivi d'un autre patch de 10 mg après 1 h si les contractions ont persisté. Après 24 h, il a été remplacé par un nouveau patch. Les femmes du groupe B ont reçu une dose de charge orale de 20 mg de nifédipine suivie d'une dose similaire si les contractions persistaient après 1 h. Une dose d'entretien de 10 mg trois fois par jour était administrée si les contractions étaient supprimées. Les patients ont été suivis du moment de l'admission au moment de la sortie. Résultats: La durée moyenne de prolongation de la grossesse dans le groupe B (3,68 ± 1,91 jours) était significativement plus élevée que dans le groupe A (2,78 ± 1,39 jours). Les céphalées étaient significativement plus observées dans le groupe A (42%) que dans le groupe B (6%). La tachycardie, l'hypotension et les palpitations n'ont montré aucune différence statistiquement significative entre elles. Il n'y avait pas de différence statistiquement significative du poids à la naissance des bébés dans les deux groupes. Conclusion: La nifédipine est un médicament sûr et efficace pour prolonger le travail prématuré et a des effets secondaires maternels et néonatals minimes.

Preterm Labor and Birth: A Clinical Review.

When caring for women experiencing preterm labor and birth, nurses play a significant role as bedside experts, advocates, patient educators, and key members of the maternity care team. Enhanced expertise on clinical and professional knowledge of preterm labor and birth is crucial in prevention and treatment. As preterm birth rates continue to rise, perinatal nurses as well-informed clinical experts have the opportunity to offer innovative education, holistic assessments, and communication through shared decision-making models. Educating pregnant women about early recognition of preterm labor warning signs and symptoms allows for timely diagnosis, interventions, and treatment. Informed and collaborative nursing practice improves quality of clinical care based on individualized interactions. A clinical review of preterm labor and preterm birth is presented for perinatal nurses.

A comparative study on the efficacy of nifedipine and indomethacin for prevention of preterm birth as monotherapy and combination therapy: a randomized clinical trial.

Introduction: Preterm delivery is an important issue in obstetrics, which is the most common cause of neonatal mortality and morbidity. Therefore, finding a way to prevent it is always under serious concern.Objective: The study aimed to compare the efficacy of two tocolytic agents, nifedipine and indomethacin, for inhibiting preterm uterine contractions as monotherapy and combination therapy.Materials and methods: A double-blind randomized clinical trial was performed on pregnant women with gestational age of 26-34 weeks of pregnancy who referred to hospital for preterm labor. They were randomly assigned to three groups. Indomethacin plus placebo, nifedipine plus placebo, and a combination of indomethacin and nifedipine were administered to the three groups. Inhibiting contractions for 2 hours and prevention of delivery for 48 hours and 7 days were evaluated. Also, duration of pregnancy, the number of preterm births, and the interval between entering the study and delivery were compared between three groups.Results: One hundred fifty women were eligible for the study. Two women in the nifedipine group and one woman in the combined group were excluded from the study because of hypotension. The women of the three groups did not have significant difference according to age, BMI, gravidity, parity, Bishop score, gestational age, and the number of contractions at entering the study. Thirty-six women (72%) in the indomethacin group, 36 women (72%) in the nifedipine group, and 41 women (89.4%) in the combination group had stopped contractions within the first 2 hours of intervention (p = .002). Inhibiting contractions for 48 hours (p = .003), inhibiting contractions for 7 days (p = .021), gestational age at birth (p = .001), number of pregnancies more than 37 weeks (p = .007), and neonatal weight (p = .020) were significantly more in the combination group.Conclusion: Combination therapy with nifedipine and indomethacin was more effective than monotherapy with either of these two medications for inhibiting preterm labor, delaying delivery, and prolongation of the duration of pregnancy.

Cumulative Risk of the Oxytocin Receptor Gene Interacts with Prenatal Exposure to Oxytocin Receptor Antagonist to Predict Children's Social Communication Development.

Compelling evidence for the far-reaching role of oxytocin (OT) in social cognition and affiliative behaviors set the basis for examining the association between genetic variation in the OT receptor (OXTR) gene and risk for autism spectrum disorder (ASD). In the current study, gene-environment interaction between OXTR and prenatal exposure to either OT or OXTR antagonist (OXTRA) in predicting early social communication development was examined. One hundred and fifty-three children (age: M = 4.32, SD = 1.07) were assigned to four groups based on prenatal history: children whose mothers prenatally received OXTRA and Nifedipine to delay preterm labor (n = 27); children whose mothers received Nifedipine only to delay preterm labor (n = 35); children whose mothers received OT for labor augmentation (n = 56), and a no intervention group (n = 35). Participants completed a developmental assessment of intelligence quotient (IQ), adaptive behavior, and social communication abilities. DNA was extracted via buccal swab. A genetic risk score was calculated based on four OXTR single nucleotide polymorphisms (rs53576, rs237887, rs1042778, and rs2254298) previously reported to be associated with ASD symptomatology. OXTRrisk-allele dosage was associated with more severe autism diagnostics observation schedule (ADOS) scores only in the OXTRA group. In contrast, in the Nifedipine, OT, and no intervention groups, OXTRrisk-allele dosage was not associated with children's ADOS scores. These findings highlight the importance of both genetic and environmental pathways of OT in signaling early social development and raise the need for further research in this field. Autism Res 2019, 12: 1087-1100. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In the current study, we examined if the association between prenatal exposure to an oxytocin receptor antagonist (OXTRA) and autism spectrum disorder (ASD) related impairments are dependent on an individual's genetic background for the oxytocin receptor gene (OXTR). Children who carried a greater number of risk alleles for the OXTR gene and whose mothers received OXTRA to delay preterm labor showed more ASD-related impairments. The results highlight the importance of both genetic and environmental pathways of oxytocin in shaping early social development.

Is Nifedipine as a Tocolytic Effective in Facilitating In Utero Transfer?

OBJECTIVE: Previous studies have reported that air medical transfer of women in preterm labor can be safely accomplished, without preterm birth occurring; in fact, many women were later discharged without preterm birth occurring. The purpose of this study was to determine if nifedipine, when used as a tocolytic, is effective at facilitating in utero transfer of women in preterm labor in the Top End of the Northern Territory of Australia. METHODS: This was a retrospective descriptive study over a 3-year period of all women transported in preterm labor between 23 + 6 to 36 + 6 weeks' gestation of pregnancy (N = 325). RESULTS: The average gestation period was 32 + 2 weeks. The mean retrieval time was 6 hours. The mean time of birth from referral was 33 hours. A number of women gave birth to a preterm newborn in a remote health center (17%). There were 3 in-flight preterm births, and 49% of women were discharged without a preterm birth occurring. All women transported by air medical retrieval were admitted to the tertiary hospital for at least 24 hours. CONCLUSION: In this study, nifedipine was used successfully to facilitate in utero transfer in many cases. Nearly half of the women referred were discharged without preterm birth occurring. Findings compare favorably with other published studies.

Preterm Labor: Prevention and Management.

In the United States, preterm delivery is the leading cause of neonatal morbidity and is the most common reason for hospitalization during pregnancy. The rate of preterm delivery (before 37 weeks' gestation) has been declining since 2007. Clinical diagnosis of preterm labor is made if there are regular contractions and concomitant cervical change. Less than 10% of women with a clinical diagnosis of preterm labor will deliver within seven days of initial presentation. Women with a history of spontaneous preterm delivery are 1.5 to two times more likely to have a subsequent preterm delivery. Antenatal progesterone is associated with a significant decrease in subsequent preterm delivery in certain pregnant women. Current recommendations are to prescribe vaginal progesterone in women with a shortened cervix and no history of preterm delivery, and to use progesterone supplementation regardless of cervical length in women with a history of spontaneous preterm delivery. Cervical cerclage has been used to help correct structural defects or cervical weakening in high-risk women with a shortened cervix. A course of corticosteroids is the only antenatal intervention that has been shown to improve postdelivery neonatal outcomes, including a reduction in neonatal mortality, intracranial hemorrhage, necrotizing enterocolitis, and neonatal infection. Tocolytics, especially prostaglandin inhibitors and calcium channel blockers, may allow time for the administration of antenatal corticosteroids and transfer to a tertiary care facility if necessary. When used in specific at-risk populations, magnesium sulfate provides neuroprotection and decreases the incidence of cerebral palsy in preterm infants.

Nifedipine versus placebo in the treatment of preterm prelabor rupture of membranes: a randomized controlled trial: Assessment of perinatal outcome by use of tocolysis in early labor-APOSTEL IV trial.

OBJECTIVE: Preterm birth is the most common cause of neonatal morbidity and mortality. Around one third of preterm deliveries starts with preterm prelabor rupture of membranes (PPROM). The aim of this trial was to study the effect of prolonged tocolysis with nifedipine versus placebo in women with PPROM on perinatal outcome and prolongation of pregnancy. STUDY DESIGN: The Apostel IV was a nationwide multicenter randomized placebo controlled trial. We included women with PPROM without contractions between 24(+0) and 33(+6) weeks of gestation. Participants were randomly allocated to daily 80mg nifedipine or placebo, until the start of labor, with a maximum of 18 days. The primary outcome measure was a composite of poor neonatal outcome, including perinatal death, bronchopulmonary dysplasia, periventricular leukomalacia>grade 1, intraventricular hemorrhage>grade 2, necrotizing enterocolitis>stage 1 and culture proven sepsis. Secondary outcomes were gestational age at delivery and prolongation of pregnancy. Analysis was by intention to treat. To detect a reduction of poor neonatal outcome from 30% to 10%, 120 women needed to be randomized. TRIAL REGISTRY: NTR 3363. RESULTS: Between October 2012 and December 2014 we randomized 25 women to nifedipine and 25 women to placebo. Due to slow recruitment the study was stopped prematurely. The median gestational age at randomization was 29.9 weeks (IQR 27.7-31.3) in the nifedipine group and 27.0 weeks (IQR 24.7-29.9) in the placebo group. Other baseline characteristics were comparable. The adverse perinatal outcome occurred in 9 neonates (33.3%) in the nifedipine group and 9 neonates (32.1%) in the placebo group (RR 1.04, 95% CI 0.49-2.2). Two perinatal deaths occurred, both in the nifedipine group. Bronchopulmonary dysplasia was seen less frequently in the nifedipine group (0% versus 17.9%; p=0.03). Prolongation of pregnancy did not differ between the nifedipine and placebo group (median 11 versus 8 days, HR 1.02; 95% CI 0.58-1.79). CONCLUSION: This randomized trial did not show a beneficial effect of prolonged tocolysis on neonatal outcomes or prolongation of pregnancy in women with PPROM without contractions. However, since results are based on a small sample size, a difference in effectiveness cannot be excluded.

Elección de un tocolítico: revisión de las evidencias clínicas / Tocolitic Agent election: a review according to clinic evidences

Existen diversas opciones farmacológicas para prevenir el trabajo de parto prematuro: beta agonistas, sulfato de magnesio, inhibidores de la ciclooxigenasa (COX), calcioantagonistas, antagonistas de los receptores de la oxitocina (atosiban) y donantes de óxido nítrico. Los beta agonistas son eficaces para retrasar el parto en el trabajo de parto prematuro, pero no está claramente demostrado que este beneficio se traduzca en una mejoría de los resultados neonatales; además, son los tocolíticos que producen más efectos secundarios en la madre. El sulfato de magnesio no ha demostrado ser un buen tocolítico, pero utilizado de forma preventiva posee un efecto neuroprotector sobre el feto. Según los resultados de un metanálisis reciente, los inhibidores de la COX y los calcioantagonistas, como el nifedipino, son los tocolíticos más efectivos para retrasar el parto. El nifedipino presenta además un mejor perfil de tolerabilidad fetal y neonatal que el atosiban y los beta agonistas. En cambio, persisten las dudas sobre la tolerabilidad fetal y neonatal de los inhibidores de la COX. Con respecto al atosiban, a pesar de su elevado coste no parece que aporte ventajas frente a otros tocolíticos en la prolongación del embarazo y mejoría de los resultados neonatales. Las evidencias disponibles no apoyan el uso de los donantes de óxido nítrico en la tocólisis (AU)

No disponible

Progesterone and nifedipine for maintenance tocolysis after arrested preterm labor: A systematic review and meta-analysis of randomized controlled trial.

OBJECTIVE: No treatment is recommended for routine maintenance tocolysis after an arrested preterm birth. Our present study aimed to evaluate the effect of progesterone and nifedipine as maintenance tocolysis therapy after an arrested preterm birth. MATERIALS AND METHODS: For relevant studies, we systematically searched the literature in databases of PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library. Only randomized controlled trials were included. RESULTS: Nine trials were included in our review. Nifedipine and progesterone were used for maintenance tocolysis. Compared to placebo treatment or no treatment, maintenance tocolysis with progesterone could significantly prolong the delivery gestational weeks [standard mean difference (SMD) 1.64; 95% confidence interval (CI), 1.21, 2.07; p < 0.00001], reduce the proportion of patients with delivery before 37 weeks (risk ratio 0.63; 95% CI, 0.47, 0.83; p = 0.001), and increase the birth weight (SMD 317.71; 95% CI, 174.89, 460.53; p < 0.0001). However, no such benefits were observed after maintenance tocolysis with nifedipine. Both nifedipine and progesterone had no significant influences on the following outcomes: neonatal intensive care unit stay, proportion of neonatal intensive care unit admission, neonatal mortality, and incidence of respiratory distress syndrome. CONCLUSION: Our results with maintenance tocolysis with progesterone may be useful for patients who had an episode of threatened preterm labor successfully treated with acute tocolytic therapy.

Alternativas terapéuticas para la tocólisis en el manejo de la amenaza de parto pretérmino / Therapeutic alternatives for the tocolysis in the management of the threatened preterm labour

La amenaza de parto pretérmino (APP) es una urgencia obstétrica que, en ausencia de intervención, desemboca en un parto prematuro. Detener la APP y prolongar la gestación todo lo posible permite trasladar a la gestante a un centro apropiado, administrar los cuidados necesarios y conceder un mayor periodo de maduración al feto, esencial para reducir la morbimortalidad asociada al parto prematuro. El empleo de tocolíticos al inicio de este proceso es esencial. En este artículo se revisa el escenario clínico y la información sobre los tocolíticos actualmente autorizados en España, dos de ellos por vía intravenosa (ritodrina y atosibán) y otro por vía oral (nifedipino solución oral) (AU)

Threatened preterm labour is an urgent obstetric condition leading to a preterm birth in the absence of medical intervention. Intervention must focus on stopping birth progression in order for the patient and the fetus be administered an adequate medical care, providing a temporal window for fetus´ maturation. This medical management is aimed to reduce the morbimortality associated to preterm birth. This manuscript consists of a review of the toclytics of more extended use in our context. Currently, three drugs are authorised as tocolytics in Spain: ritodrine and atosiban (intravenous) and nifedipine (oral solution) (AU)

Preterm uterine contractions ultimately delivered at term: safe but not out of danger.

OBJECTIVES: Patients with pregnancies complicated with premature uterine contractions (PMC), but delivered at term are considered as false preterm labor (PTL), and represent a common obstetric complication. We aimed to assess obstetric and neonatal outcomes of pregnancies complicated with PMC, but delivered at term, as compared to term normal pregnancies. STUDY DESIGN: Obstetric, maternal and neonatal outcomes of singleton pregnancies complicated with PMC between 24-33(6)/7 weeks (PMC group), necessitating hospitalization and treatment with tocolytics and/or steroids, during 2009-2014, were reviewed. The study group included only cases who eventually delivered ≥37 weeks, which were compared to a control group of subsequent term singleton deliveries who had not experienced PMC during pregnancy. Neonatal adverse composite outcome included: phototherapy, RDS, sepsis, blood transfusion, cerebral injury, NICU admission. RESULTS: The PMC group (n=497) was characterized by higher rates of nulliparity (p=0.002), infertility treatments (p=0.02), and polyhydramnios (p<0.001), as compared to controls (n=497). Labor was characterized by higher rates of instrumental deliveries (p=0.03), non-reassuring fetal heart rate tracings (p<0.001) prolonged third stage of labor (p=0.04), and increased rate of post-partum maternal anemia (Hb<8g/dL) p=0.004, in the PMC group as compared to controls. Neonates in the PMC groups had lower birth weights compared to controls, 3149g±429 vs. 3318g±1.1, p<0.001, respectively. By logistic regression analysis, PMC during pregnancy was independently associated with neonatal birth-weight <3rd percentile (adjusted OR 4.6, 95% CI 1.5-13.7). CONCLUSIONS: Pregnancies complicated with PMC, even-though delivered at term, entail adverse obstetric and neonatal outcomes, and may warrant continued high risk follow up.

Different treatment regimens of magnesium sulphate for tocolysis in women in preterm labour.

BACKGROUND: Magnesium sulphate has been used to inhibit preterm labour to prevent preterm birth. There is no consensus as to the safety profile of different treatment regimens with respect to dose, duration, route and timing of administration. OBJECTIVES: To assess the efficacy and safety of alternative magnesium sulphate regimens when used as single agent tocolytic therapy during pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials comparing different magnesium sulphate treatment regimens when used as single agent tocolytic therapy during pregnancy in women in preterm labour. Quasi-randomised trials were eligible for inclusion but none were identified. Cross-over and cluster trials were not eligible for inclusion. Health outcomes were considered at the level of the mother, the infant/child and the health service. INTERVENTION: intravenous or oral magnesium sulphate given alone for tocolysis.Comparison: alternative dosing regimens of magnesium sulphate given alone for tocolysis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and quality and extracted data. MAIN RESULTS: Three trials including 360 women and their infants were identified as eligible for inclusion in this review. Two trials were rated as low risk of bias for random sequence generation and concealment of allocation. A third trial was assessed as unclear risk of bias for these domains but did not report data for any of the outcomes examined in this review. No trials were rated to be of high quality overall.Intravenous magnesium sulphate was administered according to low-dose regimens (4 g loading dose followed by 2 g/hour continuous infusion and/or increased by 1 g/hour hourly until successful tocolysis or failure of treatment), or high-dose regimens (4 g loading dose followed by 5 g/hour continuous infusion and increased by 1 g/hour hourly until successful tocolysis or failure of treatment, or 6 g loading dose followed by 2 g/hour continuous infusion and increased by 1 g/hour hourly until successful tocolysis or failure of treatment).There were no differences seen between high-dose magnesium sulphate regimens compared with low-dose magnesium sulphate regimens for the primary outcome of fetal, neonatal and infant death (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.12 to 1.56; one trial, 100 infants). Using the GRADE approach, the evidence for fetal, neonatal and infant death was considered to be VERY LOW quality. No data were reported for any of the other primary maternal and infant health outcomes (birth less than 48 hours after trial entry; composite serious infant outcome; composite serious maternal outcome).There were no clear differences seen between high-dose magnesium sulphate regimens compared with low-dose magnesium sulphate regimens for the secondary infant health outcomes of fetal death; neonatal death; and rate of hypocalcaemia, osteopenia or fracture; and secondary maternal health outcomes of rate of caesarean birth; pulmonary oedema; and maternal self-reported adverse effects. Pulmonary oedema was reported in two women given high-dose magnesium sulphate, but not in any of the women given low-dose magnesium sulphate.In a single trial of high and low doses of magnesium sulphate for tocolysis including 100 infants, the risk of respiratory distress syndrome was lower with use of a high-dose regimen compared with a low-dose regimen (RR 0.31, 95% CI 0.11 to 0.88; one trial, 100 infants). Using the GRADE approach, the evidence for respiratory distress syndrome was judged to be LOW quality. No difference was seen in the rate of admission to the neonatal intensive care unit. However, for those babies admitted, a high-dose regimen was associated with a reduction in the length of stay in the neonatal intensive care unit compared with a low-dose regimen (mean difference -3.10 days, 95% confidence interval -5.48 to -0.72).We found no data for the majority of our secondary outcomes. AUTHORS' CONCLUSIONS: There are limited data available (three studies, with data from only two studies) comparing different dosing regimens of magnesium sulphate given as single agent tocolytic therapy for the prevention of preterm birth. There is no evidence examining duration of therapy, timing of therapy and the role for repeat dosing.Downgrading decisions for our primary outcome of fetal, neonatal and infant death were based on wide confidence intervals (crossing the line of no effect), lack of blinding and a limited number of studies. No data were available for any of our other important outcomes: birth less than 48 hours after trial entry; composite serious infant outcome; composite serious maternal outcome. The data are limited by volume and the outcomes reported. Only eight of our 45 pre-specified primary and secondary maternal and infant health outcomes were reported on in the included studies. No long-term outcomes were reported. Downgrading decisions for the evidence on the risk of respiratory distress were based on wide confidence intervals (crossing the line of no effect) and lack of blinding.There is some evidence from a single study suggesting a reduction in the length of stay in the neonatal intensive care unit and a reduced risk of respiratory distress syndrome where a high-dose regimen of magnesium sulphate has been used compared with a low-dose regimen. However, given that evidence has been drawn from a single study (with a small sample size), these data should be interpreted with caution.Magnesium sulphate has been shown to be of benefit in a wide range of obstetric settings, although it has not been recommended for tocolysis. In clinical settings where health benefits are established, further trials are needed to address the lack of evidence regarding the optimal dose (loading dose and maintenance dose), duration of therapy, timing of therapy and role for repeat dosing in terms of efficacy and safety for mothers and their children. Ongoing examination of different regimens with respect to important health outcomes is required.

RETRACTED: Nicorandil vs nifedipine for the treatment of preterm labour: a randomized clinical trial.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. The editors were alerted to the following concerning features of this trial: The submission date is impossible. Patients were recruited at 24 to 34 weeks (mean 31 w). 18% of participants delivered after 37 weeks. Average recruitment 26 per month. Recruitment ended September 2014 but the paper was received by journal on 23 October 2014. The second author, Sayyed T, is co-author of related retracted papers in BJOG. In view of these concerns we wrote to Dr Rezk who had no satisfactory explanation and declined to share the data. We have therefore decided to retract.