A randomized controlled trial of propranolol in nulliparous patients with prolonged labor.

In this trial, individuals with prolonged latent labor who received a dose of IV propranolol did not deliver more rapidly compared to standard management. There were no differences in cesarean section rate or other adverse safety events. Among those who deliver vaginally, propranolol does appear to help labor progress faster. Our findings differ from the existing literature, as we did not observe a difference in overall time to delivery between groups. A meta-analysis of nine trials involving 1,182 patients found that propranolol administration during labor induction shortened time to delivery by 91 minutes [ 20 ]. While we did find a reduction in time to delivery among those who had vaginal births, the clinical significance of this finding remains uncertain as it is not possible to predict which patients will ultimately have a successful vaginal delivery at the start of an induction. Furthermore, there is significant heterogeneity in populations studied in the included trials. Our study specifically examines patients with prolonged latent labor and does not show benefit in this population. It is possible that propranolol is useful in other populations. Similarly, while data exists suggesting that propranolol administration reduces cesarean delivery rate by half in patients with labor arrest [ 8 ], our study was unable to reproduce these results. This is consistent with various other trials that have shown no difference in cesarean delivery rate with propranolol administration [ 10 , 12 – 13 ] across various populations including multiparous individuals and active stage arrest. Trials have varied in the oxytocin protocols as well as the timing and number of propranolol administration. While some studies have included patients in multiparous patients and active phase arrest, [ 10 , 12 ] the present study only included nulliparous patients with prolonged latent labor. Importantly, in our trial, all patients met criteria for prolonged latent labor despite interventions including amniotomy and oxytocin titration. The high rates of cesarean delivery (greater than 50%) among patients in our trial reflect the abnormal labor curves of the individuals included in the study, consistent with prior data showing that prolonged latent labor is associated with nearly double the cesarean risk, particularly among those who do not reach active labor [ 21 ].We did find a difference in the cesarean indication among the two groups. 43% of patients in the propranolol group had a cesarean induction of failed induction compared to 9% of patients in the expected management group. In contrast, 45% of patients managed expectantly underwent cesarean for non-reassuring fetal heart tracing indication compared to 13% in the propranolol group. We acknowledge that our study was not powered to assess differences in cesarean indications, and we cannot determine whether propranolol directly influenced these outcomes. However, it is possible that propranolol’s effect on improving uterine contractility contributed to more coordinated contractions, potentially reducing fetal stress and lowering the rate of cesareans for non-reassuring fetal heart tracings. At the same time, when labor arrest persisted despite enhanced contractility, cesareans were more likely classified as failed inductions. This observation warrants further investigation in future studies. Our findings demonstrate a clear lack of benefit for propranolol in achieving a faster time to delivery among patients with prolonged labor who have already received standard labor interventions. While we observed a shorter time to active labor in the propranolol group, the study was not powered to detect statistical differences in this secondary outcome, and its clinical significance is uncertain without a corresponding reduction in time to delivery. There is a signal of efficacy among those who delivered vaginally, so future studies are needed to identify which subset of patients may benefit from propranolol during induction of labor. Those studies should also consider the observed two-fold higher absolute rate of postpartum hemorrhage in the propranolol group, even though this difference was not statistically significant. While propranolol is generally thought to enhance uterine contractility, this finding raises an important exploratory question about potential PPH risk that warrants further investigation. One strength of this study is the randomization of patients with prolonged latent labor. Furthermore, unlike prior reports, our study focused solely on nulliparous patients in the latent phase of labor; this homogenous population allowed us to better understand the role of propranolol in this particular group without confounders. This trial is also pragmatic in that we allowed providers to maintain regular labor practices. A weakness of our study is that neither the patients nor the providers were blinded to the allocation group. However, the primary outcome, time to delivery, is an objective measure unlikely to be influenced by treatment awareness. Therefore, the investigators determined that producing placebos would have significantly increased costs without adding meaningful benefit. This was also a single center study, and the results may not be generalizable to other centers with different labor management practices and/or labor outcomes. Labor management practices vary both institutionally and geographically, and it is possible that different labor-management practices may influence the efficacy of this intervention. Lastly, our study is likely underpowered to detect the difference in the primary outcome as we considered a 4-hour difference to be clinically significant. We found no evidence of benefit in the addition of propranolol for the management of prolonged latent labor in nulliparous patients. The administration of propranolol did not achieve a shorter time to delivery with no difference in the cesarean rates, maternal or neonatal morbidity compared to usual care. Larger studies are needed to better characterize the ideal population for propranolol use during induction of labor.

There were 867 inductions of labor during the study period of July 2021 to June 2022, 622 of which were not eligible for recruitment. Of the 245 meeting initial inclusion criteria, 31 declined enrollment, 67 developed severe preeclampsia, 39 had clinically-significant asthma, 17 received insulin and 11 received beta blockage agents. 80 nulliparous participants were randomized into the two treatment groups ( figure 1 ). Maternal demographic characteristics by treatment group are provided in table 1 . The groups did not differ in their demographic and obstetrical outcomes at randomization. There were no demographic differences between the groups. Individuals who self-identify as Black comprised 46% of the cohort. Sixty-five percent of participants had public insurance. The median gestational age of both groups was just over 39 weeks gestation. The most common indications for induction were elective 39-week inductions (39%) and late-term (31%) [ 19 ]. Dilation at randomization were similar between the two groups. A total of 35 individuals (44%) had a successful induction and delivered vaginally ( table 2 ). The primary outcome of time to delivery by any mode from the start of induction was not different between the two groups. Propranolol administration did not achieve a faster median time to delivery compared to usual care, (propranolol: 27.7 hrs vs. usual care: 30.4 hrs, p=0.76 unadj, 0.35 adj) ( table 2 ). There was evidence of reduction in time to vaginal delivery after adjusting for age and BMI (propranolol: 22.8 hrs vs. usual care: 29.5 hrs, p=0.15 unadj, p=0.03 adj). Equal proportions of individuals delivered within 24hrs (propranolol: 27.5% vs. usual care: 27.5%, p= 1.0). There was no difference in the cesarean delivery rate between the two groups (57.5% versus 55.0%, p=1.0) and no difference in time to active labor (propranolol: 19.5 hrs vs. usual care: 26.0 hrs, p= 0.21). There were no significant differences in rates of terbutaline use, placement of intrauterine pressure catheter, amnioinfusion, or epidural use ( table 3 ). There were no cases of endometriosis, 3 rd /4 th degree laceration, or venous thrombosis. More patients receiving propranolol underwent a cesarean delivery for failed induction indication (43.5% versus 9.09%, p=0.008). Patients receiving propranolol were less likely to undergo a cesarean delivery for a non-reassuring fetal heart rate indication (13.0% versus 45.5% p=0.008). ( Table 3 ) There were no differences in neonatal outcomes including severe respiratory distress syndrome, Apgar scores, hypoxic ischemic encephalopathy, or NICU admission ( table 3 ). There were no cases of neonatal hypoglycemia, blood transfusion, hypoxic ischemic encephalopathy, intraventricular hemorrhage grade 3 or 4, necrotizing enterocolitis, or head cooling in either group.

This was a randomized study conducted from July 2021 through June 2022 at a single tertiary care hospital in Newark, Delaware. Prior to initiation of the study, approval was obtained from a convened Institutional Review Board (CC#40172) at our institution on 12/21/2020 and registered with ClinicalTrials.gov ( NCT04741698 ) on 2/5/2021 ( https://clinicaltrials.gov/ct2/show/NCT04741698 ). This study was a randomized controlled trial for inpatient individuals on labor and delivery undergoing cervical ripening with misoprostol in combination with foley catheter at term diagnosed with protracted latent labor. The first patient was randomized on 7/27/2021. CONSORT (Consolidated Standards of Reporting Trials) guidelines were followed during the design, conduct, and reporting of this trial. A data safety monitoring board (DSMB) was established to independently evaluate the safety of the study. An interim safety assessment was performed for pre-defined adverse outcomes with recommendations to continue the study without changes. Nulliparous individuals who presented to labor and delivery and required cervical ripening were eligible for the trial. Individuals ≥ 18 years of age undergoing term induction of labor at ≥ 37 0/7 weeks gestation with a cephalic, singleton pregnancy and bishop score of ≤6 or cervical dilation ≤2cm and intact membranes were eligible. Individuals who had a prolonged latent phase of labor were approached for recruitment. For the purposes of this study, we defined prolonged latent phase of labor as cervical dilation less than 6 cm and unchanged after 8 hours or more of ruptured membranes (spontaneous or artificial) and oxytocin infusion. These definitions of prolonged labor have previously been used [ 13 ] to determine efficacy of interventions before cesarean delivery in patient’s whose labor courses are not progressing normally, but do not yet meet American College of Obstetricians and Gynecologists’ criteria for failed induction or labor arrest. Individuals were excluded if they had a known prior uterine scar, fetal demise, known major fetal congenital anomaly, HIV infection, or Hepatitis C infection before the start of labor induction. Additional exclusion criteria are as follows: severe preeclampsia or a patient who was receiving a beta blocker for any other indication, maternal heart rate less than 70 beats per minute, maternal blood pressure less than 90 mm Hg systolic or less than 50 mm Hg diastolic, asthma, diabetes requiring insulin treatment during labor (given the concern regarding postnatal hypoglycemia with beta blocker use), and cardiac contraindication to beta blockade. Gestational age was determined using routine obstetrical guidance[ 14 ]. All individuals provided individual written informed consent. All individuals in this trial underwent combination Foley catheter and misoprostol induction of labor. A Foley catheter was placed above the level of the internal os and inflated with 30cc of sterile water[ 15 ]. Catheters were taped to the inner thigh with gentle traction and deflated and removed after 12 hours if still in place. Additionally, one 25-mcg-misoprostol tablet was placed high into the posterior vaginal fornix at the time of foley catheter placement. Subsequent doses, if utilized, were repeated every three hours up to five additional doses or a maximum of 24 hours [ 16 ]. Oxytocin was initiated if there was a contraindication to another misoprostol dose or following foley catheter expulsion. Our hospital protocol begins with 2 milliunits per minute of oxytocin increasing by 1 to 2 milliunits every 30 minutes until regular uterine contractions occur. Thirty milliunits of oxytocin is considered the maximum dose with no limit on the length of time a participant can remain at 30 milliunits[ 17 ]. Patients meeting criteria for prolonged latent phase of labor were approached for participation. All individuals provided written informed consent. Amniotomy was performed at the discretion of the obstetrical providers. If the patient had not yet had membranes ruptured and cervix was ≥4 cm dilated, it was recommended that an amniotomy be performed at time of randomization if clinically feasible[ 18 ]. Labor interventions including amnioinfusion, fetal scalp electrode, tocolysis, and management of the second stage (including operative delivery) were at the discretion of the managing providers. All patients had continuous fetal monitoring throughout their labor. Cervical examinations were performed approximately every 4 hours in latent labor and every 2 hours in active labor. Cesarean delivery was at the discretion of the provider. Participants meeting study criteria were randomized to either 2mg propranolol or usual care management. The 2 mg IV dose was selected based on protocol used in prior studies evaluating propranolol in labor [ 6 – 13 ], although we acknowledge that the optimal dosing for this indication has not yet been fully established. Computer-generated randomization with blocks of size 6 was used with 1:1 assignment to treatment group [ 19 ]. Neither the patients nor the providers were blinded to the assigned treatment group. The primary outcome measure was time to delivery (hours) defined as time from initiation of induction method to delivery time, regardless of mode of delivery. Secondary outcome measures included: cesarean delivery rate, time to vaginal delivery (hours), time to active labor (defined as dilatation ≥6cm), delivery within 12 and 24 hours, maternal length of stay (defined as length of time from admission for induction to discharge postpartum in days) and indication for cesarean delivery. Maternal secondary outcomes analyzed included 3rd/4th degree perineal laceration, blood transfusion, endometritis, wound separation–infection (defined by the need for additional wound closure or the need for antibiotics), venous thromboembolism, or hysterectomy. Labor secondary outcomes analyzed were intra-amniotic infection (defined by the presence of maternal fever ≥100·4°F in the presence of maternal or fetal tachycardia or fundal tenderness), use of terbutaline, placement of intrauterine pressure catheter, amnioinfusion, or epidural use. Neonatal morbidity outcomes included hypoglycemia, severe respiratory distress syndrome (defined as intubation and mechanical ventilation for a minimum of 12 hours), culture proven–presumed neonatal sepsis, neonatal blood transfusion, hypoxic ischemic encephalopathy, intraventricular hemorrhage grade 3 or 4, necrotizing enterocolitis, or receipt of head cooling. Other neonatal outcomes analyzed were neonatal intensive care unit (NICU) admission, NICU admission >48 hours, and neonatal length of stay (days). Trained research staff, uninvolved with the clinical care, collected all induction, labor and delivery information, maternal demographics, and maternal and neonatal outcomes. A 4-hour reduction in time to delivery was considered clinically meaningful. The mean time to delivery for patients undergoing combination pharmacologic and mechanical induction of labor is 11 hours ±6.5 [ 18 ]. Assuming 80% power, equal group sizes, and a two-sided p-value, a crossover–dropout rate of 10%, we assumed a total sample size of 80 (40 per arm). Descriptive statistics are reported by randomization group. Statistical analyses were performed using an intention-to-treat principle. Univariate analyses compared groups’ secondary outcomes using Wilcoxon rank sum for continuous variables and Pearson chisquared or Fisher’s exact test for categorical variables, as appropriate. Delivery outcomes for groups were compared using Cox regression for time variables and logistic regression for binary variables. Results are presented both unadjusted and adjusted for maternal age, BMI and model of delivery (when the outcome was not cesarean delivery). Statistical significance for the primary outcome was set at p<0.05 without adjustment for multiple comparisons. All analyses were based on assigned group and completed with R statistical software (version 4.02, R Foundation for Statistical Computing, Vienna, Austria). The datasets generated and analyzed during this study are available upon request.

Over thirty percent of pregnant individuals undergo cesarean delivery in the United States and rates continue to grow [ 1 ]. Prolonged labor remains a common cause of cesarean delivery, accounting for 34 percent of all cesarean deliveries performed in the United States [ 2 ]. Moreover, prolonged labor has been associated with obstetrical morbidity with increased risk of chorioamnionitis [ 3 , 4 ], endometritis and postpartum hemorrhage (PPH). Contraction strength and frequency are modifiable causes of protracted latent labor, with important clinical implications. Separate from oxytocin receptors, alpha- and beta-adrenergic receptors in the myometrium have been shown to affect contractility with alpha-adrenergic receptors stimulation promoting uterine contraction and beta-adrenergic receptor activity causing relaxation [ 5 ]. Propranolol-hydrochloride, is a nonselective β-adrenergic receptor blocker that blocks β2 adrenergic receptors expressed on the uterine myometrium, suggesting it may inhibit relaxation of the uterus [ 5 ], but data surrounding the obstetrical use of propranolol for prolonged labor is mixed . While some reports have shown therapeutic effect and lower cesarean delivery rates with the administration of propranolol [ 6 – 8 ], others have not shown such results [ 9 – 13 ]. Additional investigation is warranted to better understand the utility of propranolol with prolonged labor. The objective of this study was to determine if administration of propranolol reduces the duration of labor among nulliparous individuals with prolonged latent labor following induction (IOL) at term.