Management Of Preterm Labor Research Articles

A 26-Year-Old Pregnant Woman With Ventricular Tachycardia and Shock

(N Engl J Med. 2021;384:272–282) A 26-year-old patient, pregnant with monochorionic, diamniotic twins at 32 weeks gestation, was transferred to the hospital following cardiac arrest caused by ventricular tachycardia. This was the patient’s third pregnancy and the previous 2 were uncomplicated. One week before presenting to the hospital, the patient had a cough, sore throat and ear pain, and new edema in her legs. She was prompted to seek care at an emergency department when pain in her right leg progressed. While in the emergency department, painful contractions began, the cervix was 2 cm dilated, and preterm labor management began. There was no further cervical dilation after 24 hours but the patient remained hospitalized. After 5 days the edema had worsened, and an occlusive thrombus was found in the left peroneal vein. Intravenous heparin was administered. The next day, the patient experienced chest pain before becoming unresponsive. Monomorphic ventricular tachycardia was detected. Spontaneous circulation resumed after epinephrine and cardioversion were administered. The patient underwent tracheal intubation and then emergency cesarean section, which resulted in 2 health male infants and an intraoperative blood loss of 1600 mL.

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

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 37weeks, obstetric outcomes, maternal compliance with medication use, and side effects. A randomized controlled, unblinded trial was performed. Ninety women with preterm labor occurring at 24 to 34weeks were either randomized to a vaginal progesterone group (44 women) receiving tocolytic and antenatal corticosteroids treatment combined with vaginal micronized progesterone (400mg everyday) or to the no-progesterone group (46 women) receiving tocolytic and antenatal corticosteroids treatment only. Latency periods were more prolonged in the vaginal progesterone group than in the no-progesterone group (32.8 ± 18.7 vs. 25.8 ± 22.7days, p = 0.045). Gestational age at delivery in the vaginal progesterone group was also higher than in the no-progesterone group (37 vs. 35weeks, p = 0.027). There were significant reduction rates of preterm birth less than 34weeks (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). Combined treatment with vaginal progesterone 400mg could prolong the latency period in preterm labor when compared with no progesterone.

Uterocervical Angle and Cervical Length as a Tool to Predict Preterm Birth in Threatened Preterm Labor.

ObjectiveTo evaluate the diagnostic performance of uterocervical angle (UCA) and UCA with cervical length (CL) in predicting preterm delivery in threatened preterm labor.MethodsA multicenter prospective observational cohort study was conducted in 160 pregnant women having threatened preterm labor at Srinagarind and Udonthani Hospitals in Thailand between March 2019 and June 2020. Researchers measured UCA and CL by transvaginal ultrasonography. Medical records were reviewed for patient characteristics, and patients were followed up until the date of delivery to assess for the outcome of preterm birth. The cut-off point of UCA was determined from receiver operating characteristic curve analysis. The sensitivity, specificity, likelihood ratio, positive and negative predictive values (PPV and NPV) of UCA and of UCA with CL for predicting preterm birth were determined.ResultsThe incidence of preterm birth in women having threatened preterm labor was 27%. The sensitivity, specificity, PPV and NPV of UCA ≥110.97 degrees for predicting preterm birth were 65.1%, 43.6%, 29.8% and 77.3%, respectively. The sensitivity, specificity, PPV and NPV of UCA ≥110.97 degrees with CL <3.4 centimeters for predicting preterm birth were 48.8%, 68.4%, 36.2% and 78.4%. The specificity and NPV of UCA with CL were higher than for UCA alone.ConclusionWith adequate sensitivity and high NPV, UCA by TVS can be supplemented with CL measurement in threatened preterm labor management to increase the diagnostic performance for predicting preterm birth.

Oral dydrogesterone as an adjunctive therapy in the management of preterm labor: a randomized, double blinded, placebo\u2010controlled trial

BackgroundPreterm birth is a major challenge in obstetric and perinatal care. It is the leading cause of neonatal death. The primary aim of this study was to evaluate the efficacy of oral dydrogesterone on latency period in managing preterm labor. The secondary aims were to evaluate the gestational age at delivery, percentage of preterm delivery before 34 weeks and 37 weeks, time to recurrent uterine contraction, pregnancy outcomes, neonatal outcomes, compliance and side effects.MethodsThis was a randomized, double blinded, placebo-controlled trial. Forty-eight pregnant women with preterm labor, singleton pregnancy, and gestational age of 24–34 weeks were enrolled into the study. The study group received 10 mg of oral dydrogesterone three times per day and the control group received placebo. All pregnant women received standard treatment with tocolytic and antenatal corticosteroids.ResultsThe median latency periods were not significantly different between the dydrogesterone group (27.5 days) and placebo group (34 days, p = 0.45). Additionally, there were no differences in the gestational age at delivery, percentage of preterm delivery before 34 weeks and 37 weeks, pregnancy outcomes, neonatal outcomes, compliance and side effects. However, the time to the recurrence of uterine contractions in participants that had recurrent preterm labor was longer in the dydrogesterone group than in the placebo group (30.6 ± 12.3 vs 13.7 ± 5.0 days, p = 0.01).ConclusionsAdjunctive treatment with 30 mg of oral dydrogesterone could not prolong latency period in preterm labor when compared to placebo.Trial registrationClinicalTrials.gov (Clinical trials registration: NCT 03935152, registered on May 2,2019).

Diagnosis and Management of Preterm Labour

Diagnosis and Management of Preterm Labour

Non-Invasive Ring Electrode With a Wireless Electrical Recording and Stimulating System for Monitoring Preterm Labor.

Preterm labor and birth are the primary causes of neonatal morbidities and mortalities. The early detection and treatment of preterm uterine muscular contraction are crucial for the management of preterm labor. In this work, a ring electrode with a wireless electrical recording and stimulating (RE-WERS) system was designed, fabricated, and investigated for the non-invasive monitoring of uterine contraction/relaxation as a diagnostic and therapeutic tool for preterm labor. By using an organ bath system, we confirmed that the uterine contraction force in mice can be decreased by the application of electrical stimulation. Then, the RE-WERS system was inserted non-invasively through the vagina to the cervix of a pregnant minipig, and it successfully recorded the uterine contraction and reflect signals when various electrical stimulating conditions were applied. The difference in the uterine signals before and after the injection of a labor induction drug, such as oxytocin and prostaglandin [Formula: see text], was recorded, and the difference was remarkable. In addition, the uterine signal that was recorded was well matched with the signal of the electromyography (EMG) kit during open abdominal surgery. It seemed that the continuous and various electrical stimulations affected the delay or inhibition of childbirth in the pregnant minipig.

Midwifery continuity of care versus standard maternity care for women at increased risk of preterm birth: A hybrid implementation-effectiveness, randomised controlled pilot trial in the UK.

BackgroundMidwifery continuity of care is the only health system intervention shown to reduce preterm birth (PTB) and improve perinatal survival, but no trial evidence exists for women with identified risk factors for PTB. We aimed to assess feasibility, fidelity, and clinical outcomes of a model of midwifery continuity of care linked with a specialist obstetric clinic for women considered at increased risk for PTB.Methods and findingsWe conducted a hybrid implementation–effectiveness, randomised, controlled, unblinded, parallel-group pilot trial at an inner-city maternity service in London (UK), in which pregnant women identified at increased risk of PTB were randomly assigned (1:1) to either midwifery continuity of antenatal, intrapartum, and postnatal care (Pilot study Of midwifery Practice in Preterm birth Including women’s Experiences [POPPIE] group) or standard care group (maternity care by different midwives working in designated clinical areas). Pregnant women attending for antenatal care at less than 24 weeks' gestation were eligible if they fulfilled one or more of the following criteria: previous cervical surgery, cerclage, premature rupture of membranes, PTB, or late miscarriage; previous short cervix or short cervix this pregnancy; or uterine abnormality and/or current smoker of tobacco. Feasibility outcomes included eligibility, recruitment and attrition rates, and fidelity of the model. The primary outcome was a composite of appropriate and timely interventions for the prevention and/or management of preterm labour and birth. We analysed by intention to treat. Between 9 May 2017 and 30 September 2018, 334 women were recruited; 169 women were allocated to the POPPIE group and 165 to the standard group. Mean maternal age was 31 years; 32% of the women were from Black, Asian, and ethnic minority groups; 70% were in employment; and 46% had a university degree. Nearly 70% of women lived in areas of social deprivation. More than a quarter of women had at least one pre-existing medical condition and multiple risk factors for PTB. More than 75% of antenatal and postnatal visits were provided by a named/partner midwife, and a midwife from the POPPIE team was present at 80% of births. The incidence of the primary composite outcome showed no statistically significant difference between groups (POPPIE group 83.3% versus standard group 84.7%; risk ratio 0.98 [95% confidence interval (CI) 0.90 to 1.08]; p = 0.742). Infants in the POPPIE group were significantly more likely to have skin-to-skin contact after birth, to have it for a longer time, and to breastfeed immediately after birth and at hospital discharge. There were no differences in other secondary outcomes. The number of serious adverse events was similar in both groups and unrelated to the intervention (POPPIE group 6 versus standard group 5). Limitations of this study included the limited power and the nonmasking of group allocation; however, study assignment was masked to the statistician and researchers who analysed the data.ConclusionsIn this study, we found that it is feasible to set up and achieve fidelity of a model of midwifery continuity of care linked with specialist obstetric care for women at increased risk of PTB in an inner-city maternity service in London (UK), but there is no impact on most outcomes for this population group. Larger appropriately powered trials are needed, including in other settings, to evaluate the impact of relational continuity and hypothesised mechanisms of effect based on increased trust and engagement, improved care coordination, and earlier referral on disadvantaged communities, including women with complex social factors and social vulnerability.Trial registrationWe prospectively registered the pilot trial on the UK Clinical Research Network Portfolio Database (ID number: 31951, 24 April 2017). We registered the trial on the International Standard Randomised Controlled Trial Number (ISRCTN) (Number: 37733900, 21 August 2017) and before trial recruitment was completed (30 September 2018) when informed that prospective registration for a pilot trial was also required in a primary clinical trial registry recognised by WHO and the International Committee of Medical Journal Editors (ICMJE). The protocol as registered and published has remained unchanged, and the analysis conforms to the original plan.

The All Babies Count Initiative: Impact of a Health System Improvement Approach on Neonatal Care and Outcomes in Rwanda.

Poor-quality care contributes to a significant portion of neonatal deaths globally. The All Babies Count (ABC) initiative was an 18-month district-wide approach designed to improve clinical and system performance across 2 rural Rwandan districts. This pre-post intervention study measured change in maternal and newborn health (MNH) quality of care and neonatal mortality. Data from the facility and community health management information system and newly introduced indicators were extracted from facility registers. Medians and interquartile ranges were calculated for the health facility to assess changes over time, and a mixed-effects logistic regression model was created for neonatal mortality. A difference-in-differences analysis was conducted to compare the change in district neonatal mortality with the rest of rural Rwanda. Improvements were seen in multiple measures of facility readiness and MNH quality of care, including antenatal care coverage, preterm labor management, and postnatal care quality. District hospital case fatality decreased, with a statistically significant reduction in district neonatal mortality (odds ratio [OR]=0.54; 95% confidence interval [CI]=0.36, 0.83) and among preterm/low birth weight neonates (OR=0.47; 95% CI=0.25, 0.90). Neonatal mortality was reduced from 30.1 to 19.6 deaths/1,000 live births in the intervention districts and remained relatively stable in the rest of rural Rwanda (difference in differences -12.9). The ABC initiative contributed to improved MNH quality of care and outcomes in rural Rwanda. A combined clinical and health system improvement approach could be an effective strategy to improve quality and reduce neonatal mortality.

Factors associated with stillbirth in selected countries of South Asia: A systematic review of observational studies.

BackgroundDespite having the high rate of stillbirth in most of the countries of South Asia, there is a lack of synthesized evidence based on factors associated with stillbirth. This study systematically synthesizes the evidence on factors associated with stillbirth in the four selected countries of South Asia.MethodsThis review was conducted using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Studies that examined factors associated with stillbirth in South Asia were searched using five major electronic search databases including MEDLINE, CINAHL, Embase, PsycINFO, and Scopus, published between January 2000 and December 2019. In the meta-analysis, significant heterogeneity was detected among studies (I2 >50%), and hence a random effect model was used.ResultsA total of 20 studies met the inclusion criteria. The pooled rate of stillbirth from the studies in Bangladesh, India, Nepal, and Pakistan was 25.15 per 1000 births. Pregnancy complications, maternal health conditions, fetal complications, lack of antenatal care, and lower Socio Economic Status (SES) were the most common factors associated with stillbirth in countries of South Asia.ConclusionThis study confirmed that stillbirth in selected countries of South Asia remains high. To reduce stillbirth, a greater focus needs to be on timely management of preterm labor, maternal hypertension, and provision of financial support for quality antenatal and delivery care. The interventions should be targeted for women living in remote areas, who are less educated and those with low SES.

Effectiveness and safety of atosiban versus conventional treatment in the management of preterm labor

ObjectiveTo compare the efficacy of atosiban with conventional treatment of the threatened preterm labor. Materials and methodsAll the data of pregnant women with threatened preterm labor from January 1 to December 31, 2017, who received atosiban were collected. Pregnant women with conventional treatment (including β-agonists, indomethacin, magnesium sulphate and calcium channel blockers, alone or in combination) were used as control. ResultsThe proportion of women not requiring an alternative tocolytic treatment within 48 h and remaining undelivered was significantly higher in atosiban treatment group (89.3%; n = 25/28) compared with conventional treatment (24.2%; n = 8/33) (P < 0.0001). For therapy efficacy, there was also no significant difference between atosiban groups and conventional treatment groups in the low gestational ages. However, for the high gestational ages, atosiban treatment group showed higher efficacy (84%; n = 21/25 vs. 37.5%; n = 3/8) (P < 0.05). Moreover, a significantly higher proportion of women in the atosiban treated group (89.3%; n = 25/28) was observed compared with the conventional treatment groups (51.5%; n = 17/33) who did not receive an alternative tocolytic within 48 h (P < 0.01). Maternal and fetal safety was significantly superior with atosiban treatment. ConclusionsOur results support that atosiban would represent an advance over current tocolytic therapy especially for the high gestational ages.

Clinical practice guidelines on diabetes mellitus and pregnancy: ΙI. Gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is the most common metabolic disease of pregnancy and is associated with several perinatal complications. GDM is defined as diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation. In Europe, in 2016, the prevalence of GDM was estimated to be 5.4% (3.8-7.8). It varied depending on maternal age, year of data collection, country, area of Europe, week of gestation at testing, and diagnostic criteria. The Hellenic Endocrine Society and the Hellenic Society of Maternal-Fetal Medicine commissioned an expert group to construct national guidelines on "Diabetes mellitus and pregnancy: Gestational diabetes mellitus." Following a search for the best available evidence and critical appraisal of the results, the writing group generated a series of consensus recommendations regarding screening tests for the general population, monitoring and management, fetal monitoring, management of preterm labor, planning of labor and delivery, puerperium and breastfeeding, and long-term follow-up of GDM.

Maternal azithromycin therapy for Ureaplasma parvum intraamniotic infection improves fetal hemodynamics in a nonhuman primate model

Ureaplasma parvum infection is a prevalent cause of intrauterine infection associated with preterm birth, preterm premature rupture of membranes, fetal inflammatory response syndrome, and adverse postnatal sequelae. Elucidation of diagnostic and treatment strategies for infection-associated preterm labor may improve perinatal and long-term outcomes for these cases. This study assessed the effect of intraamniotic Ureaplasma infection on fetal hemodynamic and cardiac function and the effect of maternal antibiotic treatment on these outcomes. Chronically catheterized pregnant rhesus monkeys were assigned to control (n=6), intraamniotic inoculation with Ureaplasma parvum (107 colony-forming units/mL, n=15), and intraamniotic infection plus azithromycin treatment (12.5 mg/kg twice a day intravenously, n=8) groups. At approximately 135 days' gestation (term=165 days), pulsed and color Doppler ultrasonography was used to obtain measurements of fetal hemodynamics (pulsatility index of umbilical artery, ductus venosus, descending aorta, ductus arteriosus, aortic isthmus, right pulmonary artery, middle cerebral artery and cerebroplacental ratio, and left and right ventricular cardiac outputs) and cardiac function (ratio of peak early vs late transmitral flow velocity [marker of ventricular function], Tei index [myocardial performance index]). These indices were stratified by amniotic fluid proinflammatory mediator levels and cardiac histology. Umbilical and fetal pulmonary artery vascular impedances were significantly increased in animals from the intraamniotic inoculation with Ureaplasma parvum group (P<.05). Azithromycin treatment restored values to control levels. Amniotic fluid prostaglandin F2 alpha levels were significantly higher in animals with abnormal umbilical artery pulsatility index (>1.1) than in those with normal blood flow (P<.05; Spearman ρ=0.6, P<.05). In the intraamniotic inoculation with Ureaplasma parvum group, left ventricular cardiac output was significantly decreased (P<.001), and more animals had abnormal right-to-left ventricular cardiac output ratios (defined as >1.6, P<.05). Amniotic fluid interleukin-6 concentrations were elevated in cases of abnormal right-to-left ventricular cardiac output ratios compared with those in normal cases (P<.05). Fetal hemodynamic alterations were associated with intraamniotic Ureaplasma infection and ameliorated after maternal antibiotic treatment. Doppler ultrasonographic measurements merit continuing investigation as a diagnostic method to identify fetal cardiovascular and hemodynamic compromise associated with intrauterine infection or inflammation and in the evaluation of therapeutic interventions or clinical management of preterm labor.

Pharmacology for Preterm Labor.

Preterm birth occurs with 10% of deliveries and yet accounts for more than 85% of perinatal morbidity and mortality. Management of preterm labor prior to delivery includes a multipronged pharmacologic approach targeting utilization of reproductive hormones for continuation of pregnancy, advancement of fetal lung maturity, and the decrease of uterine contractility (tocolysis). This article will review and compare guidelines on pharmacologic management of preterm labor as recommended by the American College of Obstetricians and Gynecologists and the European Association of Perinatal Medicine. The classifications of drugs discussed include exogenous progesterone, corticosteroids, and tocolytics (β-adrenergic agonists, magnesium sulfate, calcium channel blockers, prostaglandin inhibitors, nitrates, and oxytocin receptor blockers). For each of these drug classes, the following information will be presented: mechanism of action, maternal/fetal side effects, and nursing implications.

Identification of the uterine‐relaxant effect of mundulone as a natural‐product for therapeutic control of preterm labor

IntroductionPreterm birth rate continues to rise with over 15 million cases/year and remains the greatest contributor to neonatal morbidities and mortalities. Currently, there are no FDA‐approved tocolytics for the management of preterm labor due to the off‐target side effects and short duration of benefit of current off‐label therapeutics. High‐throughput screening of oxytocin‐induced Ca2+‐mobilization in uterine myometrial cells identified mundulone and mundulone acetate (MA) as hit‐antagonists. The aim of this work was to:1) examine the uterine‐selectivity of mundulone and MA by counterscreening vascular smooth muscle cells (VSMCs)—the major off‐target limiting the use of current tocolytics, 2) determine cytotoxic effects, 3) identify synergistic combinations of mundulone (and MA) with current tocolytics to increase efficacy and/or potency to decrease off‐target side effects and 4) determine the ex vivo tocolytic efficacy and potency on human myometrial tissue and confirm uterine selectivity at the tissue level by evaluating their effect on constriction of fetal ductus arteriosus (DA), a major off target of known tocolytics.MethodsPrimary human myometrial cells were isolated from tissue collected at the time of cesarean delivery from women at term (≥39 weeks) pregnancy. A phenotypic high‐throughput Ca2+‐ mobilization assay was performed to compare concentration‐response (10‐ point, 3‐fold dilutions) between myometrial and aorta VSMCs (Emax and IC50). The high‐throughput Ca2+‐mobilization assay was adapted for combination screening in 8×8 concentration‐response matrix format. Current tocolytics used for combination included: atosiban, indomethacin and nifedipine. Three models (Bliss independence, HSA and Loewe additivity) were used to determine synergy using Combenefit software. Cytotoxicity of mundulone and MA were determined using WST‐1 cell viability assay using myometrial, hepatic and renal cells. Ex vivo organ bath studies using myometrial tissue and isolated term fetal DA vessels were performed to examine concentration‐response on contractility and vessel diameter, respectively.ResultsMA was found to display a greater selectivity towards myometrial cells when counter screened against aorta VSMCs. Fold change (FC) in efficacy (Emax) was 13.5 and FC in potency was &gt;4.5 for MA while fold change in potency for mundulone was only &gt;2.3. We found that mundulone displayed synergism with two current tocolytics (atosiban and nifedipine), while MA displayed synergistic efficacy with nifedipine. Mundulone was found to affect the viability of myometrial cells while MA demonstrated a selectivity index of &gt;10 (Ratio of IC50 in cell viability assay to IC50 in Ca2+‐mobilization assay). Both mundulone and MA showed concentration dependent inhibition of uterine contractions, without affecting fetal DA vasoreactivity at the tissue level.ConclusionBased on differences in uterine‐selectivity and tocolytic efficacy between mundulone and MA, this natural product could benefit from medicinal chemistry efforts to study structural activity relationship.Support or Funding InformationNICHD grant HD088830 and Turner Hazinski research award.

Comparative study of oral Nifedipine tablet and transdermal Nitroglycerin patch in preterm labour

Preterm labour (PTL) is defined as the onset of labour in pregnancy from 28 weeks to 36weeks and 6 days. One of the most challenging problem of obstetrician in the era of modern obstetrics is the management of preterm labour and preterm births (PTB); Being the most common cause of perinatal morbidity and mortality PTB accounts for 70-80% of perinatal deaths. More than a million preterm infants die per year, worldwide. Aim: To Compare the Tocolytic effect of Oral Nifedipine tablet and Transdermal Nitroglycerin (TDN) patch in preterm labour and its effect on maternal and fetal outcome. Materials and Methods: It was a Double Blinded placebo controlled study conducted at Dr. D. Y. Patil Medical College, Hospital & Research Center, Pimpri, from November 2018 to April 2019. The study population comprised of patients who attended the casualty and outpatient department. Eighty-eight women with singleton pregnancy from 28weeks to 36weeks 6 days in preterm labour with intact membranes and cervical dilatation from 1 up to 3 cm; without contraindication for tocolysis were enrolled in the study. After taking the informed consent, subjects were randomised into two groups; 46 subjects in group A received oral Nifedipine tablet, out of which 4 left the study and 46 in group B received TDN patch. The variables analysed were, delay in delivery for 48 hours, 7 days or more than 7 days, period of gestation at delivery, effect on maternal and fetal outcome and side-effect profile of drugs. Result: The percentage of women delivering after 48 hours of administration of oral Nifedipine were 66.67% and TDN patch were 76%. Failure of tocolysis, defined as delivery within 48 hours, was significantly more with Nifedipine group (8/42-19.05%) as compared to TDN patch group (3/46-6.5%). Headache was significantly higher in group B as compared to group A (p< 0.001). Maternal tachycardia was more common in group A compared to group B (p< 0.001). Conclusion: Transdermal Nitroglycerin (TDN) patch is more effective than oral tablet Nifedipine in suppression of preterm labour and prolonging pregnancy. Although the rate of side effects were more with Nitroglycerin, most common was headache which can be controlled with analgesics. Cardiovascular side effect were nil compared with Nifedipine. Nitroglycerin is well tolerated and safe for the mother and fetus.

POPPIE: protocol for a randomised controlled pilot trial of continuity of midwifery care for women at increased risk of preterm birth

BackgroundHigh rates of preterm births remain a UK public health concern. Preterm birth is a major determinant of adverse infant and longer-term outcomes, including survival, quality of life, psychosocial effects on the family and health care costs. We aim to test whether a model of care combining continuity of midwife care with rapid referral to a specialist obstetric clinic throughout pregnancy, intrapartum and the postpartum period is feasible and improves experience and outcomes for women at increased risk of preterm birth.MethodsThis pilot, hybrid, type 2 randomised controlled implementation trial will recruit 350 pregnant women at increased risk of preterm birth to a midwifery continuity of care intervention or standard care. The intervention will be provided from recruitment (antenatal), labour, birth and the postnatal period, in hospital and community settings and in collaboration with specialist obstetric clinic care, when required. Standard care will be the current maternity care provision by NHS midwives and obstetricians at the study site. Participants will be followed up until 6–8 weeks postpartum. The composite primary outcome is the appropriate initiation of any specified interventions related to the prevention and/or management of preterm labour and birth. Secondary outcomes are related to: recruitment and attrition rates; implementation; acceptability to women, health care professionals and stakeholders; health in pregnancy and other complications; intrapartum outcomes; maternal and neonatal postnatal outcomes; psycho-social health; quality of care; women’s experiences and health economic analysis. The trial has 80% power to detect a 15% increase in the rate of appropriate interventions (40 to 55%). The analysis will be by ‘intention to treat’ analysis.DiscussionLittle is known about the underlying reasons why and how models of midwifery continuity of care are associated with fewer preterm births, better maternal and infant outcomes and more positive experiences; nor how these models of care can be implemented successfully in the health services. This will be the first study to provide direct evidence regarding the effectiveness, implementation and evaluation of a midwifery continuity of care model and rapid access to specialist obstetric services for women at increased risk of preterm birth.Trial registrationISRCTN37733900. Retrospectively registered on 21 August 2017.

Oral Dydrogesterone in the Management of Preterm Labor

Oral Dydrogesterone in the Management of Preterm Labor

OR08-6 RGS2 Expression Attenuates Contractile Signaling in Myometrial Smooth Muscle In Vitro

Labour activation is regulated by a shift in the balance of pro-quiescent mechanisms that maintain pregnancy, and inflammatory and endocrine signals that stimulate uterine contractility. The prostaglandins (PG) and oxytocin act at Gq protein coupled receptors thought to drive labour contractions. However, emerging evidence suggests a twofold effect of PGE2 on the pregnant uterus, driving pro-labour or pro-quiescent signaling depending on the receptor subtype activated. It is possible that PGE2, abundant within the pregnant uterus, mediates pro-quiescent effects by activating Gs coupled receptors to upregulate regulator of G-protein signaling 2 (RGS2), a GTPase activating protein that can dampen smooth muscle contractility by turning off Gq signals. Approaching labour, inflammatory signals may downregulate RGS2 expression to derepress contractility. Understanding the regulatory role of RGS2 on uterine contractility may provide insights for improved clinical management of spontaneous preterm labour, to prevent premature birth. We hypothesise that RGS2, regulated by mediators that control quiescence and labour, reduces contractile functions of Gq coupled signals in the pregnant uterus. To test this hypothesis, we used primary myometrial smooth muscle (MSM) cells isolated from uterine biopsies collected at term (>37 weeks) non-labour caesarean deliveries. Treatment with 1μM PGE2 increased RGS2 mRNA and protein expression, peaking at 1 and 2 hours respectively. Pretreatment with 1ng/ml IL-1β or TNFα partially repressed the PGE2 effect, suggesting RGS2 may be downregulated in the inflammatory milieu that accompanies labour. To study the effect of RGS2 on MSM function, cells were loaded with Fluo-4 NW to detect intracellular calcium changes as a measure of contractility following challenge with 100nM oxytocin. Enhanced RGS2 expression, following PGE2 treatment or adenoviral overexpression, reduced oxytocin-mediated calcium flux, suggesting RGS2 attenuates this contractile signal. In addition to oxytocin, labour contractions likely integrate activation of many other GPCRs, signaling of which may also be regulated by RGS2. A PCR-based array analysis revealed expression of >300 GPCRs in MSM cells and tissue. The highly expressed histamine receptor 1 was targeted to begin exploring additional signals attenuated by RGS2 in MSM. Histamine (1μM) challenged cells generated a calcium response that was attenuated by PGE2-induced RGS2, and RGS2 adenoviral overexpression. Together our results show RGS2 is upregulated by pro-quiescent signals abundant in pregnancy, and downregulated by inflammatory mediators implicated in labour. Enhanced RGS2 expression reduces contractile responses to oxytocin and histamine, which we propose is consistent with a pro-quiescent role in pregnancy. Funding: CIHR, NSERC Project Grants; AIHS MD-PhD Studentship.

Insights from outside BJOG

Insights from outside BJOG

Oxytocin Receptor Antagonists, Atosiban and Nolasiban, Inhibit Prostaglandin F2\u03b1-induced Contractions and Inflammatory Responses in Human Myometrium

Oxytocin receptor antagonists (OTR-A) have been developed as tocolytics for the management of preterm labour due to the significant role of oxytocin (OT) in the onset of both term and preterm labour. Similar to OT, prostaglandins (PGs) play key roles in myometrial contractility and cervical ripening. Inhibition of PG synthesis/activity is used to delay preterm birth. Thus, targeting the PG pathway in combination with an OTR-A may be an effective strategy for delaying preterm delivery. In this study, we examined the effects of atosiban and nolasiban on PGF2α-induced contractions and pro-inflammatory responses in human pregnant myometrium. Both OTR-As, atosiban and nolasiban, inhibited PGF2α-induced contractions in a dose-dependent manner (p < 0.001 and p < 0.01, respectively). These inhibitory effects involved the suppression of PGF2α-mediated increase in intracellular calcium levels. In addition, the OTR-As significantly suppressed PGF2α-induced activation of pro-inflammatory pathways such as NF-κB and mitogen activated protein kinases (MAPKs), and the subsequent expression of contraction-associated-protein, COX-2. We have demonstrated that atosiban and nolasiban not only inhibit contractions elicited by OT, but also inhibit contractions and inflammation induced by PGF2α. This suggests a possible crosstalk between OTR and PG receptor signalling and highlights the importance of understanding G protein-coupled receptor interactions/crosstalk in the development of future tocolytics.