The effect of intravenous hyoscine butylbromide on slow progress in labor (BUSCLAB): A double-blind randomized placebo-controlled trial

Lise Christine Gaudernack; Angeline Elisabeth Styve Einarsen; Ingvil Krarup Sørbye; Mirjam Lukasse; Nina Gunnes; Trond Melbye Michelsen

doi:10.1371/journal.pmed.1004352

. 2024 Mar 28;21(3):e1004352. doi: 10.1371/journal.pmed.1004352

The effect of intravenous hyoscine butylbromide on slow progress in labor (BUSCLAB): A double-blind randomized placebo-controlled trial

Lise Christine Gaudernack ^1,^2,^‡,^*, Angeline Elisabeth Styve Einarsen ^1,^3,^‡, Ingvil Krarup Sørbye ^1,³, Mirjam Lukasse ^2,⁴, Nina Gunnes ⁵, Trond Melbye Michelsen ^1,^3,^*

Editor: Gordon C Smith⁶

PMCID: PMC11008832 PMID: 38547322

Abstract

Background

Prolonged labor is a common condition associated with maternal and perinatal complications. The standard treatment with oxytocin for augmentation of labor increases the risk of adverse outcomes. Hyoscine butylbromide is a spasmolytic drug with few side effects shown to shorten labor when used in a general population of laboring women. However, research on its effect on preventing prolonged labor is lacking. We aimed to assess the effect of hyoscine butylbromide on the duration of labor in nulliparous women showing early signs of slow labor.

Methods and findings

In this double-blind randomized placebo-controlled trial, we included 249 nulliparous women at term with 1 fetus in cephalic presentation and spontaneous start of labor, showing early signs of prolonged labor by crossing the alert line of the World Health Organization (WHO) partograph. The trial was conducted at Oslo University Hospital in Norway from May 2019 to December 2021. One hundred and twenty-five participants were randomized to receive 1 ml hyoscine butylbromide (Buscopan) (20 mg/ml), while 124 received 1 ml sodium chloride intravenously. Randomization was computer-generated, with allocation concealment by opaque sequentially numbered sealed envelopes. The primary outcome was duration of labor from administration of the investigational medicinal product (IMP) to vaginal delivery, which was analyzed by Weibull regression to estimate the cause-specific hazard ratio (HR) of vaginal delivery between the 2 treatment groups, with associated 95% confidence interval (CI). A wide range of secondary maternal and perinatal outcomes were also evaluated. Time-to-event outcomes were analyzed by Weibull regression, whereas continuous and dichotomous outcomes were analyzed by median regression and logistic regression, respectively. All main analyses were based on the modified intention-to-treat (ITT) set of eligible women with signed informed consent receiving either of the 2 treatments. The follow-up period lasted during the postpartum hospital stay. All personnel, participants, and researchers were blinded to the treatment allocation. Median (mean) labor duration from IMP administration to vaginal delivery was 401 (440.8) min in the hyoscine butylbromide group versus 432.5 (453.6) min in the placebo group. We found no statistically significant association between IMP and duration of labor from IMP administration to vaginal delivery: cause-specific HR of 1.00 (95% CI [0.77, 1.29]; p = 0.993). Among 255 randomized women having received 1 dose of IMP, 169 women (66.3%) reported a mild adverse event: 75.2% in the hyoscine butylbromide group and 57.1% in the placebo group (Pearson’s chi-square test: p = 0.002).

More than half of eligible women were not included in the study because they did not wish to participate or were not included upon admission. The participants might have represented a selected group of women reducing the external validity of the study.

Conclusions

One intravenous dose of 20 mg hyoscine butylbromide was not found to be superior to placebo in preventing slow labor progress in a population of first-time mothers at risk of prolonged labor. Further research is warranted to answer whether increased and/or repeated doses of hyoscine butylbromide might have an effect on duration of labor.

Trial registration

ClinicalTrials.gov (NCT03961165) EudraCT (2018-002338-19)

Lise Christine Gaudernack and team assess the effect of hyoscine butylbromide on the duration of labor in nulliparous women showing early signs of slow labor.

Author summary

Why was this study done?

➢ Approximately 10% of first-time mothers experience prolonged labor, which is associated with increased risk of operative delivery, postpartum hemorrhage, perineal tears, infections, and transfer to the neonatal intensive care unit (NICU).
➢ Intravenous synthetic oxytocin is widely used to treat slow labor progress, but the treatment is potentially harmful. Augmentation of contractions may lead to uterine hyperstimulation, which is associated with fetal distress and operative delivery. Hence, assessment of other treatments is needed.
➢ Previous research demonstrates that spasmolytics may shorten duration of labor, but studies of the effect of this treatment on preventing prolonged labor are lacking.

What did the researchers do and find?

➢ We performed a double-blind randomized placebo-controlled study including 249 nulliparous women showing first signs of slow labor progress.
➢ The participants were randomized to receive either a single intravenous dose of the spasmolytic drug hyoscine butylbromide (Buscopan) (20 mg) or a single intravenous dose of saline solution (placebo).
➢ We found no statistically significant difference in labor duration between the 2 treatment groups. There was a decrease in postpartum hemorrhage and a slight increase in maternal heart rate in the hyoscine butylbromide group.
➢ No maternal serious adverse events were observed nor did we observe any neonatal adverse events.

What do these findings mean?

➢ Hyoscine butylbromide was not found to impact duration of labor from treatment administration to delivery for first-time mothers with long labors.
➢ Hyoscine butylbromide can safely be used during labor.
➢ The effect of hyoscine butylbromide is short-lasting; a single intravenous dose of 20 mg might not have been sufficient to shorten labor in this selected group of nulliparous women.
➢ Randomized controlled trials (RCTs) assessing the effect of higher or repeated doses of hyoscine butylbromide for women experiencing long labors are needed.

Introduction

Slow progress in labor is a common challenge in obstetric care, especially among first-time mothers (nulliparous women). Slow labor might lead to prolonged labor, most commonly defined as by the World Health Organization (WHO): an active labor lasting >12 h [1]. Prolonged labor causes as many as 2 out of 3 unplanned cesarean sections [2,3]. In addition to increased risk of operative delivery, prolonged labor is associated with chorioamnionitis [4], a negative birth experience [5,6], shoulder dystocia [7], low Apgar scores [7], and admission to the neonatal intensive care unit (NICU) [4,7]. There are also increased risks of severe postpartum hemorrhage [8], anal incontinence [9], urinary retention [10], hematomas [10], and ruptured sutures [10]. Hence, prolonged labor is a major clinical problem in obstetrics that needs to be identified and treated.

When progress in labor is too slow, augmentation with synthetic oxytocin is commonly used to increase contractions [11]. However, oxytocin has an unpredictable therapeutic index and has been described as the drug most commonly related to preventable adverse events during labor [11,12]. Treatment with oxytocin might be associated with increased risks of fetal asphyxia [13–15], operative delivery [15–17], a negative birth experience [15,16,18], anal sphincter injuries [19], postpartum urinary retention [20], postpartum hemorrhage [21], and delayed initiation of breastfeeding [16,22–24]. Given the uncertainty regarding efficacy of oxytocin and the considerable side effects, there is a need to evaluate alternative adjuvant treatments to prevent prolonged labor.

Antispasmodics are drugs that relieve spasms of smooth muscle tissue, breaking the connection between the parasympathetic nerves and the smooth muscle by acting as antagonists of acetylcholine at muscarinic receptors and thereby inhibiting muscle spasms [25]. In general medicine, the drug is used for reducing spasms in the intestines and urinary tract, abdominal pain of unclear cause, irritable bowel disease, advanced cancer, colonoscopy, radiological examinations, and spasmodic conditions in the female genitalia [26]. The cervix is composed of connective tissue and smooth muscle which constitutes about 50% to 60% of the internal cervix and innervated by parasympathetic nerve fibers [27]. Musculotropic antispasmodics like hyoscine butylbromide (equivalent to butylscopolamine bromide, Buscopan) directly relax smooth muscles [27]. Antispasmodics are most commonly used during labor in low- and middle-income countries [25]. Hyoscine butylbromide is an antispasmodic drug with a rapid onset (<20 min) [28]. A Cochrane review including 17 randomized controlled trials (RCTs) on the use of spasmolytics and duration of labor found a statistically significant reduction in the mean duration of the first stage of labor (i.e., the dilation phase) of 74 min [25]. A systematic review including 20 RCTs and a meta-analysis including 9 RCTs found a reduction in the mean duration of labor of 58 min and 55 min, respectively, when nulliparous women were treated with hyoscine butylbromide [29,30]. To our knowledge, except from 1 study from Saudi Arabia [31], there are no studies from high-income countries exploring the effect of hyoscine butylbromide on labor duration. Previous studies have been conducted in India, Pakistan, Iran, Iraq, Turkey, Nigeria, Mexico, Egypt, and Jamaica [29,30,32]. We have only found 1 Egyptian study on the effect of hyoscine butylbromide on slow labor [33].

In contrast to previous research on the effect of hyoscine butylbromide on labor duration in general, the double-blind randomized placebo-controlled trial BUSCLAB (BUSCopan in LABor) aimed to assess the effect of hyoscine butylbromide on the duration of the active phase of labor in nulliparous women showing early signs of slow labor.

Methods

This study is reported as per the Consolidated Standards of Reporting Trials (CONSORT) guidelines (S1 CONSORT Checklist).

Study design

We conducted a double-blind randomized placebo-controlled trial in a tertiary hospital in Norway with around 2,500 births annually. Further detailed information on the design may be found in the published protocol article [34]. The study protocol, including the sample size calculations, is provided in S1 Text.

The study was approved by the Regional Committee for Medical and Health Research Ethics South East Norway (2018/2380) and the Norwegian Medicines Agency (18/09179-14) and was registered in ClinicalTrials.gov (NCT03961165) and EudraCT (2018-002338-19) prior to inclusion of the first participant. The study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guideline.

Participants

In the period from May 2019 to July 2021, all nulliparous women scheduled to give birth at Oslo University Hospital Rikshospitalet were sent an information-and-invitation letter to participate in the study approximately 6 weeks prior to their due date. A total of 1,900 women were invited.

Inclusion criteria

Women aged 18 years or older with a singleton fetus in a cephalic presentation at term were potentially eligible for participation in the study. The participants had to be in active labor, i.e., having regular contractions and a cervical dilation of at least 3 cm. Start of labor had to be spontaneous, and progress of labor had to be slower than 1 cm per hour, as indicated by the WHO partograph (Fig 1).

Fig 1 — Reprinted with permission from Professor Tina Lavender. WHO, World Health Organization.

The WHO partograph is a chart widely used for measuring labor progress and contains 2 diagonal lines: an alert line and an action line [35]. The alert line corresponds to an average dilation rate of 1 cm per hour. If the labor curve crosses to the right of this alert line, it means that the dilation is less than 1 cm per hour and may indicate early signs of slow labor progress. The action line starts 4 h to the right of the alert line. If the labor curve crosses the action line, intravenous infusion of oxytocin should be started to augment labor. In case of intact membranes, amniotomy should be performed and infusion of oxytocin started after 1 h if slow progress of labor persists [11].

We aimed to include all eligible women who crossed the alert line of the WHO partograph to assess whether a single intravenous dose of 1 ml hyoscine butylbromide (20 mg/ml) could reduce duration of labor in a group of women showing first signs of prolonged labor. All participating women provided written informed consent, signed by both the woman and the midwife in charge of her. As the participants were informed about the study in a letter sent to them during pregnancy, some women had signed the consent form before admission to hospital, confirming that they would participate provided labor would be slow and the inclusion criteria for participation were fulfilled. Other participants signed after admission to labor and delivery. All midwives in the labor ward were trained in the study procedures and could provide oral information when needed.

Exclusion criteria

Women were excluded from participation in the study if they met any of the following exclusion criteria: treatment with synthetic oxytocin before start of active labor, preeclampsia, previous major uterine surgery, intestinal stenosis, ileus or megacolon, persisting maternal tachycardia (heart rate >130 beats/min), myasthenia gravis, untreated glaucoma, hypersensitivity to hyoscine butylbromide, maternal heart disease in need of telemetry surveillance during labor, persisting fetal tachycardia (fetal baseline heart rate >170 beats/min), or known fetal heart disease. Antihistamines, tricyclic and tetracyclic antidepressants, antipsychotic drugs, tiotropium, ipratropium, atropine, metoclopramide, and beta-adrenergic medications should not be administered with hyoscine butylbromide, and administration of any of these medications was regarded as an exclusion criterion.

Randomization and blinding

The allocation sequence based on computer-generated random numbers was generated by an independent statistician who was not part of the trial and did not take part in the statistical analyses. Participants were assigned to either the study drug or placebo by block randomization with mixed block sizes of 2, 4, and 6. The treatment was concealed in sealed opaque envelopes with consecutive numbers.

Midwives at the labor and delivery ward enrolled eligible participants by the abovementioned inclusion and exclusion criteria. The participants were assigned to treatment based on the prespecified allocation written in the envelopes. The envelopes were kept in a locked room at the postnatal ward, situated on a different floor from the labor and delivery ward.

An authorized midwife at the postnatal ward opened the envelope and revealed the allocated treatment. This midwife had no other involvement in the study and was the only person unblinded to which treatment the participant received. The envelope was labeled with the participant’s name and date of birth and resealed with a special blue tape that would leave colored traces if reopening had been attempted. After opening the envelope, the midwife prepared a syringe with either 1 ml hyoscine butylbromide (20 mg/ml) or 1 ml sodium chloride (9 mg/ml, 0.9%). In case of a serious adverse event, unblinding was done by opening the woman’s envelope. All packaging identifying the allocated treatment was discarded. The 2 treatments had identical appearance. The midwife gave the syringe to a third person, blinded to its content. This third person brought the syringe to the midwife in charge of the study participant at the labor and delivery ward.

The investigational medicinal product (IMP), either hyoscine butylbromide or sodium chloride (placebo), was administered to the woman by authorized site personnel only. Authorization was given by the principal investigator (PI) after oral and written information and individual training in the study procedures. The IMP had to be given within 45 min after the vaginal examination showing that the woman was eligible (i.e., had crossed the alert line of the WHO partograph). Fetal cardiotocography (CTG) lasting at least 10 min was performed before IMP was given and 30 min post administration. Furthermore, maternal heart rate was measured before and 30 min after IMP administration. All participants were given standard care as per ward procedure.

Procedures following treatment administration

Occurrence, degree, and duration of adverse effects were registered 30 min after the IMP was given and daily at the postnatal ward, see S1 Fig and the protocol article for this study [34]. Measurements of the pH levels of arterial and venous umbilical cord blood were obtained immediately after delivery. The Apgar score of the newborn was also assessed 5 and 10 min after birth.

Infant pulse oximetry with O₂ saturation was performed routinely when the neonate was approximately 4 h old. Physical examination was performed on the first or second day postpartum by an experienced pediatrician. All infants were observed as per ward procedure by trained personnel at the postnatal ward throughout their stay. Physical examination of the mother included measurements of the heart rate and blood pressure at least twice a day during the hospital stay.

All women and infants were followed for adverse events from randomization to discharge from the hospital up to 3 days after delivery, in accordance with clinical practice.

Baseline characteristics

Baseline characteristics included maternal age (in years), height (in cm), weight (in kg), body mass index (BMI) (in kg/m²), marital status (married, cohabiting, single, or unknown), higher education (yes or no), chronic diseases (yes or no), and use of medication during pregnancy (yes or no) in addition to maternal and fetal heart rates at baseline (in beats/min) and cervical dilation at baseline (in cm). Maternal age was categorized as <25 years, 25 to 29 years, 30 to 34 years, and ≥35 years, and maternal BMI was categorized according to the WHO’s definitions of underweight (BMI: <18.5 kg/m²), normal weight (BMI: 18.5 to 24.9 kg/m²), overweight (BMI: 25.0 to 29.9 kg/m²), and obesity (BMI: ≥30.0 kg/m²).

Outcomes

We evaluated a total of 23 outcomes in the present study: 3 time-to-event outcomes, 9 continuous outcomes, and 11 dichotomous outcomes.

The primary outcome of the study was duration of labor from IMP administration to vaginal delivery (in minutes), which is a time-to-event variable, with vaginal delivery as the event of interest and emergency cesarean section as a competing event.

Secondary time-to-event outcomes included duration of labor from onset of active labor to vaginal delivery (in minutes), with emergency cesarean section as a competing event, and duration of labor from IMP administration to a fully dilated cervix of 10 cm, with emergency cesarean section prior to a cervical dilation of 10 cm as a competing event.

Secondary continuous outcomes included cervical dilation rates (in cm per hour) from IMP administration to a fully dilated cervix and from IMP administration to the next vaginal examination, changes in maternal and fetal heart rates 30 min after IMP administration (in beats/min), duration of oxytocin infusion (in minutes), amount of infused oxytocin (in international units [IU]), estimated blood loss (in ml), and pH levels of the umbilical artery and vein.

Secondary dichotomous outcomes included operative vaginal delivery, emergency cesarean section, postpartum hemorrhage ≥500 ml, ≥1,000 ml, and ≥1,500 ml, respectively, pH level of the umbilical artery <7.0, pH level of the umbilical vein <7.1, 5- and 10-min Apgar scores <7, and admission of the newborn to the NICU within the first couple of hours after birth.

Sample size calculations

The sample size calculations were based on an RCT by Dencker and colleagues from 2009, which found that among first-time mothers with spontaneous start of labor, the mean duration of labor from randomization to delivery was 5.2 h, with a standard deviation (SD) of 2.8 h [36]. A difference in means of 60 min in labor duration was considered clinically relevant, as all the other studies on spasmolytics found a difference of more than 55 min. With a statistical power of 80% and an SD of 2.8 as given in Dencker and colleagues, our sample size calculations showed that we would require 246 women in total to discover a difference in duration of labor of 60 min between the 2 treatment groups. More details on the sample size calculations may be found in the study protocol (S1 Text) and the statistical analysis plan (S2 Text, Section 2.3).

Analysis sets

We considered 4 different analysis sets. The restricted intention-to-treat (ITT) set comprised all eligible, randomized trial participants with a signed informed consent, regardless of protocol adherence. The full-analysis (FA) set comprised all trial participants in the restricted ITT set who received the IMP, thereby excluding trial participants not given the IMP due to reasons unrelated to the allocated treatment. The FA set was thus regarded as a modified ITT set for which the ITT principle was still preserved. The per-protocol (PP) set comprised all trial participants in the FA set with no major protocol deviations (S2 Text, Section 3.2.2). Finally, the safety set comprised all randomized trial participants who ever received the IMP, irrespective of eligibility.

From May 2019 to December 2021, 1,900 women were assessed for eligibility. A total of 261 women were initially randomized to treatment. Ten of the randomized women were subsequently excluded due to fullfilling one of the exclusion criteria, and 1 randomized woman later withdrew her consent, leaving 250 women in the restricted ITT set (126 in the hyoscine butylbromide group and 124 in the placebo group). Furthermore, 1 woman in the hyoscine butylbromide group did not receive the IMP, and the FA set therefore comprised 249 women (125 in the hyoscine butylbromide group and 124 in the placebo group). The PP set included 248 women (124 in the hyoscine butylbromide group and 124 in the placebo group), excluding 1 woman in the hyoscine butylbromide group whose midwife was unblinded to the IMP administered. The safety set included 255 women: the 249 women in the FA set in addition to 6 non-eligible, erronously randomized women who received 1 dose of the IMP. The CONSORT flow diagram of the enrollment of trial participants is shown in Fig 2.

Descriptive statistics of baseline characteristics of the women in the FA set, overall and by treatment group, are given in Table 1. There were no signs of imbalance between the 2 treatment groups with respect to any of the baseline characteristics other than slight differences in the continuous variables for maternal weight (Mann–Whitney U test: p = 0.028) and BMI (Mann–Whitney U test: p = 0.009). Still, we found no statistically significant association between categorical maternal BMI and treatment group.

Table 1. Descriptive statistics of baseline characteristics, by treatment group, based on the FA set.

Continuous variables are given by mean (SD) (normal data) or median (IQR) (non-normal data). Categorical variables are given by numbers (percentages).

Baseline characteristic	Total (n = 249)		Hyoscine butylbromide (n = 125)		Placebo (n = 124)
Maternal age (in years)
Mean (SD)	32.0	(4.0)	31.7	(4.4)	32.3	(3.6)
Maternal age (in years)
<25	8	(3.2%)	6	(4.8%)	2	(1.6%)
25–29	55	(22.1%)	31	(24.8%)	24	(19.4%)
30–34	124	(49.8%)	59	(47.2%)	65	(52.4%)
≥35	62	(24.9%)	29	(23.2%)	33	(26.6%)
Maternal height (in cm)
Mean (SD)	167.1	(6.7)	167.0	(6.6)	167.2	(6.8)
Maternal weight (in kg)
Median (IQR)	62.0	(12.0)	61.0	(11.0)	63.0	(14.0)
Maternal BMI (in kg/m ² )
<18.5	9	(3.6%)	7	(5.6%)	2	(1.6%)
18.5–24.9	188	(75.5%)	97	(77.6%)	91	(73.4%)
25.0–29.9	39	(15.7%)	16	(12.8%)	23	(18.5%)
≥30.0	13	(5.2%)	5	(4.0%)	8	(6.5%)
Maternal marital status
Married	87	(34.9%)	47	(37.6%)	40	(32.3%)
Cohabiting	150	(60.2%)	70	(56.0%)	80	(64.5%)
Single	10	(4.0%)	7	(5.6%)	3	(2.4%)
Unknown	2	(0.8%)	1	(0.8%)	1	(0.8%)
Maternal higher education
No	13	(5.2%)	4	(3.2%)	9	(7.3%)
Yes	234	(94.0%)	119	(95.2%)	115	(92.7%)
Missing	2	(0.8%)	2	(1.6%)	0	(0.0%)
Maternal chronic diseases
No	157	(63.1%)	82	(65.6%)	75	(60.5%)
Yes	91	(36.5%)	43	(34.4%)	48	(38.7%)
Missing	1	(0.4%)	0	(0.0%)	1	(0.8%)
Maternal medication during pregnancy
No	150	(60.2%)	82	(65.6%)	68	(54.8%)
Yes	99	(39.8%)	43	(34.4%)	56	(45.2%)
Maternal pain score at baseline
Median (IQR)	3.0	(5.0)	3.0	(5.0)	3.0	(5.0)
Missing	1	(0.4%)	0	(0.0%)	1	(0.8%)
Maternal heart rate at baseline (in beats/min)
Mean (SD)	86.5	(14.9)	87.5	(15.7)	85.4	(13.9)
Fetal heart rate at baseline (in beats/min)
Mean (SD)	139.8	(10.5)	139.6	(10.2)	139.9	(10.9)
Cervical dilation at baseline (in cm)
Median (IQR)	5.0	(2.0)	5.0	(2.0)	5.0	(2.0)

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BMI, body mass index; FA, full analysis; IQR, interquartile range; SD, standard deviation.

Statistical analysis

All statistical analyses were prespecified in the statistical analysis plan (S2 Text), which was dated and signed by the PI and the trial statistician prior to the final database lock and unblinding of the treatment allocation of all trial participants.

The analyses of the outcomes were primarily based on the FA set. Sensitivity analyses similar to the main analyses based on the PP set were conducted for comparison purposes. Furthermore, analyses of the cervical dilation rate from IMP administration to a fully dilated cervix of 10 cm were restricted to trial participants with a cervical dilation of 10 cm prior to delivery, and analyses of operative vaginal delivery were restricted to trial participants with vaginal delivery. Since we observed no imbalance in relevant baseline characteristics between the 2 treatment groups in the FA set (Table 1), all analyses were crude except for the analyses of the changes in maternal and fetal heart rates 30 min after IMP administration, which were adjusted for maternal and fetal heart rates at baseline, respectively (S2 Text, Section 5.2). Furthermore, we did not correct for multiple testing in any of the analyses, as there was only a single primary outcome in the present study. All efficacy analyses of the secondary outcomes were therefore regarded as supportive.

We used Weibull regression to analyze duration of labor from IMP administration to vaginal delivery (primary outcome). The choice of such a parametric survival model would potentially increase the statistical power of detecting a real difference between the treatment groups, given that the event times follow a Weibull distribution. We estimated the cause-specific hazard ratio (HR) of vaginal delivery between the hyoscine butylbromide group and the placebo group, with associated 95% confidence interval (CI), treating emergency cesarean section as a censoring event. Correspondingly, we estimated the cause-specific HR of emergency cesarean section, treating vaginal delivery as a censoring event. We also calculated the respective cumulative incidences of vaginal delivery and emergency cesarean section by treatment group. Cox regression was applied in a sensitivity analysis to check the robustness of the results of the main analysis. To explore a potential treatment effect modification by labor progression before IMP administration, we conducted subgroup analyses similar to the main analysis by considering the interaction between IMP and cervical dilation before IMP administration (<5 cm or ≥5 cm).

Secondary time-to-event outcomes were analyzed in the same way as the primary outcome.

We analyzed the secondary continuous outcomes by using median regression to estimate the difference in medians between the 2 treatment groups, as the conditions for linear regression were not met.

Secondary dichotomous outcomes were analyzed by using binary logistic regression, estimating odds ratios (ORs) between the 2 treatment groups. Pearson’s chi-square test or Fisher’s exact test, as appropriate, was also performed in a sensitivity analysis of each outcome.

There were no missing data on any of the outcomes except for changes in maternal and fetal heart rates due to missing values of the heart rates 30 min after IMP administration (both 0.4%), pH level of the umbilical artery (32.9%), pH level of the umbilical vein (13.3%), and 10-min Apgar score (2.4%).

We used mean (single) imputation, performed separately within each treatment group, to handle missing data on the maternal and fetal heart rates 30 min after IMP administration before the respective changes were calculated. Missing data on the pH levels of the umbilical artery and vein were handled by using multiple imputation, including allocated treatment, categorical maternal age, and categorical maternal BMI in the imputation model. The multiple imputation was performed separately for the 2 pH levels in the main analyses, whereas a mutual imputation process for both pH levels was used in sensitivity analyses. To handle missing data on the 10-min Apgar score, we used best-case (single) imputation, with 10-min Apgar score ≥7 defined as the best-case scenario. Worst-case (single) imputation of this outcome was used in a sensitivity analysis. For all outcomes with missing values, complete-case analyses were also conducted as sensitivity analyses.

Further details regarding the statistical analysis are provided in S2 Text.

Monitors

The study was supervised by an external clinical study monitor from the Clinical Trials Unit at Oslo University Hospital. The monitor performed reviews every 6 months throughout the study period. The clinical data managers and the study monitor remotely and proactively monitored the electronic case report forms (eCRFs) to improve the data quality.

Results

Out of 1,900 first-time mothers invited during pregnancy, 1,121 did not meet the inclusion criteria, 138 delivered at another hospital, and 45 did not participate for reasons unknown. Of the 596 eligible women, 100 did not wish to be included and 235 were not included upon admission. The remaining 261 were included in the study, 11 of whom were later excluded because they did not fulfill the inclusion criteria (Fig 2).

Numbers and percentages of women giving birth within 2, 4, 6, 8, 10, and 12 h after IMP administration, by treatment group and mode of delivery (vaginal delivery or emergency cesarean section), are displayed in Fig 3. The proportion of women giving birth within 6 h after IMP administration was higher in the hyoscine butylbromide group compared to the placebo group (42.1% versus 30.7%).

Fig 3 — Emergency cesarean section was defined as cesarean section of which an indication developed during labor. IMP, investigational medicinal product.

Descriptive statistics and results of the main analyses of the outcomes under study are presented in Table 2. Results of all analyses prespecified in the statistical analysis plan, including sensitivity analyses and subgroup analyses, may be found in S1 Table. Furthermore, S2 Table presents the results of post hoc adjusted sensitivity analyses where the main analyses were adjusted for categorical maternal age at baseline (all outcomes), categorical maternal BMI at baseline (all outcomes), and cervical dilation at baseline (3 outcomes related to duration of labor and 2 outcomes related to cervical dilation rate only).

Table 2. Descriptive statistics of outcomes, by treatment group, and results of the main statistical analyses, based on the FA set.

Outcome	Total (n = 249)		Hyoscine butylbromide (n = 125)		Placebo (n = 124)		Effect measure	Point estimate	95% CI	p value
Duration of labor from IMP administration to vaginal delivery (in min)							HR⁵	1.00	[0.77, 1.29]	0.993
Median (IQR)	429.0	(279.5)	401.0	(304.0)	432.5	(262.0)
Censoring¹	21	(8.4%)	11	(8.8%)	10	(8.1%)
Duration of labor from onset of active labor to vaginal delivery (in min)							HR⁵	1.02	[0.79, 1.32]	0.893
Median (IQR)	720.5	(293.5)	727.0	(318.0)	712.5	(268.0)
Censoring¹	21	(8.4%)	11	(8.8%)	10	(8.1%)
Duration of labor from IMP administration to cervical dilation of 10 cm (in min)							HR⁶	0.93	[0.72, 1.20]	0.555
Median (IQR)	308.0	(255.0)	291.0	(258.0)	314.0	(264.0)
Censoring²	15	(6.0%)	10	(8.0%)	5	(4.0%)
Cervical dilation rate from IMP administration to cervical dilation of 10 cm (in cm/hour) ³							DM	0.04	[−0.16, 0.25]	0.683
Median (IQR)	0.9	(0.9)	0.9	(0.9)	0.9	(0.9)
Cervical dilation rate from IMP administration to first vaginal examination after IMP administration (in cm/hour)							DM	0.10	[−0.31, 0.51]	0.626
Median (IQR)	0.7	(1.3)	0.7	(1.4)	0.6	(1.3)
Change in maternal heart rate (in beats/min)							DM⁷	3.03	[0.35, 5.71]	0.027
Median (IQR)	4.0	(14.5)	5.0	(17.0)	2.0	(12.0)
Missing	1	(0.4%)	0	(0.0%)	1	(0.8%)
Change in fetal heart rate (in beats/min)							DM⁸	0.00	[−1.52, 1.52]	1.000
Median (IQR)	0.0	(9.5)	0.0	(10.0)	0.0	(8.0)
Missing	1	(0.4%)	0	(0.0%)	1	(0.8%)
Duration of oxytocin infusion (in min)							DM	49.00	[−50.74, 148.74]	0.334
Median (IQR)	217.0	(361.0)	247.0	(324.0)	196.0	(400.5)
Amount of infused oxytocin (in IU)							DM	0.24	[−0.52, 1.00]	0.537
Median (IQR)	1.4	(3.4)	1.6	(2.7)	1.3	(3.9)
Operative delivery							OR	0.89	[0.54, 1.48]	0.661
No	142	(57.0%)	73	(58.4%)	69	(55.6%)
Yes	107	(43.0%)	52	(41.6%)	55	(44.4%)
Operative vaginal delivery ⁴							OR	0.86	[0.50, 1.47]	0.585
No	142	(62.3%)	73	(64.0%)	69	(60.5%)
Yes	86	(37.7%)	41	(36.0%)	45	(39.5%)
Emergency cesarean section							OR	1.10	[0.45, 2.69]	0.835
No	228	(91.6%)	114	(91.2%)	114	(91.9%)
Yes	21	(8.4%)	11	(8.8%)	10	(8.1%)
estimated blood loss (in ml)							DM	−50.00	[−96.45, −3.55]	0.035
Median (IQR)	400.0	(200.0)	400.0	(200.0)	435.0	(325.0)
Postpartum hemorrhage ≥500 ml							OR	0.66	[0.39, 1.12]	0.126
No	168	(67.5%)	90	(72.0%)	78	(62.9%)
Yes	81	(32.5%)	35	(28.0%)	46	(37.1%)
Postpartum hemorrhage ≥1,000 ml							OR	0.63	[0.27, 1.47]	0.285
No	224	(90.0%)	115	(92.0%)	109	(87.9%)
Yes	25	(10.0%)	10	(8.0%)	15	(12.1%)
Postpartum hemorrhage ≥1,500 ml							OR	0.13	[0.02, 1.11]	0.063
No	241	(96.8%)	124	(99.2%)	117	(94.4%)
Yes	8	(3.2%)	1	(0.8%)	7	(5.6%)
pH level of the umbilical artery							DM	0.01	[−0.02, 0.04]	0.514
Median (IQR)	7.2	(0.1)	7.2	(0.1)	7.2	(0.1)
Missing	82	(32.9%)	39	(31.2%)	43	(34.7%)
pH level of the umbilical artery <7.00							OR	NA	NA	NA
No	166	(66.7%)	86	(68.8%)	80	(64.5%)
Yes	1	(0.4%)	0	(0.0%)	1	(0.8%)
Missing	82	(32.9%)	39	(31.2%)	43	(34.7%)
pH level of the umbilical vein							DM	−0.00	[−0.02, 0.02]	0.851
Median (IQR)	7.3	(0.1)	7.3	(0.1)	7.3	(0.1)
Missing	33	(13.3%)	12	(9.6%)	21	(16.9%)
pH level of the umbilical vein <7.10							OR	NA	NA	NA
No	216	(86.7%)	113	(90.4%)	103	(83.1%)
Missing	33	(13.3%)	12	(9.6%)	21	(16.9%)
5-min Apgar score <7							OR	NA	NA	NA
No	248	(99.6%)	124	(99.2%)	124	(100.0%)
Yes	1	(0.4%)	1	(0.8%)	0	(0.0%)
10-min Apgar score <7							OR	NA	NA	NA
No	243	(97.6%)	123	(98.4%)	120	(96.8%)
Missing	6	(2.4%)	2	(1.6%)	4	(3.2%)
Admission to the NICU							OR	1.33	[0.29, 6.08]	0.710
No	242	(97.2%)	121	(96.8%)	121	(97.6%)
Yes	7	(2.8%)	4	(3.2%)	3	(2.4%)

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¹Due to emergency cesarean section.

²Due to emergency cesarean section prior to cervical dilation of 10 cm.

³Restricted to 234 trial participants with cervical dilation of 10 cm prior to delivery.

⁴Restricted to 228 trial participants with vaginal delivery.

⁵Based on Weibull regression, with emergency cesarean section treated as a censoring event.

⁶Based on Weibull regression, with emergency cesarean section prior to cervical dilation of 10 cm treated as a censoring event.

⁷Adjusted for maternal heart rate at baseline.

⁸Adjusted for fetal heart rate at baseline.

CI, confidence interval; DM, difference in medians; FA, full analysis; HR, hazard ratio; IMP, investigational medicinal product; IQR, interquartile range; IU, international units; NA, not applicable; NICU, neonatal intensive care unit; OR, odds ratio; SD, standard deviation.

Overall, the observed median (mean) duration of labor from IMP administration to delivery, irrespective of mode of delivery, was 412.0 (459.7) min in the hyoscine butylbromide group and 436.0 (464.3) min in the placebo group. The corresponding numbers restricted to vaginal deliveries were 401.0 (440.8) min and 432.5 (453.6) min, respectively (Table 2). We found no evidence of an effect of hyoscine butylbromide on duration of labor from IMP administration to vaginal delivery, with a cause-specific HR of vaginal delivery of 1.00 (95% CI [0.77, 1.29]; p = 0.993) (Table 2). Correspondingly, the cause-specific HR of emergency cesarean section was 1.11 (95% CI [0.47, 2.62; p = 0.811) (S1 Table). The assumptions of proportional hazards and Weibull-distributed baseline hazard rate were evaluated and found valid. Results of the sensitivity analysis in which Cox regression was applied were similar to those of the main analysis (S1 Table). Curves of the respective cause-specific hazard rates of vaginal delivery and emergency cesarean section as functions of time since IMP administration are displayed in Fig 4. Fig 5 displays curves of the respective cumulative incidences of vaginal delivery and emergency cesarean section as functions of time since IMP administration.

Fig 4 — Emergency cesarean section was defined as cesarean section of which an indication developed during labor. The curves of the case-specific hazard rates of vaginal delivery of hyoscine butylbromide and placebo are completely overlapping. IMP, investigational medicinal product.

Fig 5 — Emergency cesarean section was defined as cesarean section of which an indication developed during labor. IMP, investigational medicinal product.

Results of a post hoc competing-risks regression analysis of time from IMP administration to vaginal delivery were similar to the results of the main analysis, with a sub-hazard ratio (SHR) of 1.00 (95% CI [0.77, 1.30]; p = 0.990).

Similar to the analysis of the primary outcome, we did not find any statistically significant associations between treatment group and duration of labor from onset of active labor to vaginal delivery and duration of labor from IMP administration to a fully dilated cervix of 10 cm, respectively (Table 2 and S1 Table). The respective cumulative incidences of vaginal delivery and emergency cesarean section are plotted against time since onset of active labor in Fig 6. Fig 7 displays curves of the respective cumulative incidences of cervical dilation of 10 cm and emergency cesarean section prior to cervical dilation of 10 cm as functions of time since IMP administration.

Fig 6 — Emergency cesarean section was defined as cesarean section of which an indication developed during labor.

Fig 7 — Emergency cesarean section was defined as cesarean section of which an indication developed during labor. IMP, investigational medicinal product.

SHRs obtained from post hoc competing-risks regression analyses of the secondary time-to-event outcomes were similar to the cause-specific HRs from the main analyses.

Change in maternal heart rate from IMP administration to 30 min after IMP administration was higher in the hyoscine butylbromide group than in the placebo group, with a difference in medians of 3.03 beats/min (95% CI [0.35, 5.71] beats/min; p = 0.027) (Table 2). Furthermore, estimated blood loss was slightly lower in the hyoscine butylbromide group compared to the placebo group: difference in medians of −50.00 ml (95% CI [−96.45, −3.55] ml; p = 0.035) (Table 2). However, this association was no longer statistically significant in the post hoc adjusted sensitivity analysis including adjustment for categorical maternal age and categorical maternal BMI at baseline (S2 Table). We found no statistically significant associations between treatment group and any of the remaining secondary continuous outcomes (Table 2).

None of the secondary dichotomous outcomes were significantly associated with treatment group except for postpartum hemorrhage ≥1,500 ml (1 case in the hyoscine butylbromide group and 7 cases in the placebo group) in one of the sensitivity analyses (Fisher’s exact test: p = 0.036 [S1 Table]). However, we observed no statistically significant association in the main analysis of this outcome, with an OR of 0.13 (95% CI [0.02, 1.11]; p = 0.063). Four of the outcomes (pH level of the umbilical artery <7.0, pH level of the umbilical vein <7.1, and 5- and 10-min Apgar scores <7) were not analyzed due to small numbers, i.e., cells with few or no observations (Table 2).

We observed 169 women (66.3%) in the safety set with any adverse event across all system organ classes (234 adverse events in total): 97 women (75.2%) in the hyoscine butylbromide group (146 adverse events in total) and 72 women (57.1%) in the placebo group (88 adverse events in total) (Pearson’s chi-square test: p = 0.002). The numbers and percentages of women with adverse events are presented for both treatment groups by system organ class in Table 3. In the hyoscine butylbromide group, there was a higher number of reported tachycardia cases compared to the placebo group: 51 women (39.5%) versus 3 women (2.4%) (Pearson’s chi-square test: p < 0.001). Similarly, a significant difference was observed in the occurrence of visual disturbances, with 8 women (6.2%) in the hyoscine butylbromide group and 1 woman (0.8%) in the placebo group (Fisher’s exact test: p = 0.036). No fetal adverse events occurred during the trial nor were any maternal serious adverse events observed.

Table 3. Numbers and percentages of women with adverse events within each system organ class, overall and by treatment group.

System organ class	Total (n = 255)	Hyoscine butylbromide (n = 129)	Placebo (n = 126)	p
*Immune system disorders*	3 (1.2%)	2 (1.6%)	1 (0.8%)	1.000²
Dyspnoea	1	1	0
Pruritus	1	0	1
Chest discomfort	1	1	0
Cough	1	0	1
*Neurological disorders*	11 (4.3%)	5 (3.9%)	6 (4.8%)	0.728¹
Malaise	2	1	1
Lightheadedness	2	1	1
Headache	3	2	1
Giddiness	3	1	2
Trembling	1	0	1
*Eye disorders*	9 (3.5%)	8 (6.2%)	1 (0.8%)	0.036²
Visual disturbance	9	8	1
*Cardiac disorders*	54 (21.2%)	51 (39.5%)	3 (2.4%)	<0.001¹
Maternal tachycardia	54	51	3
*Vascular disorders*	6 (2.4%)	2 (1.6%)	4 (3.2%)	0.443²
Hypotension	2	0	2
Hypertension	1	1	0
Dizziness	2	1	1
Flushing	1	0	1
*Gastrointestinal disorders*	13 (5.1%)	8 (6.2%)	5 (4.0%)	0.418¹
Nausea	5	2	3
Vomiting	3	2	1
Dry mouth	6	5	1
*Renal and urinary disorders*	139 (54.5%)	71 (55.0%)	68 (54.0%)	0.864¹
Urinary retention	139	71	68
*Other disorders*	2 (0.8%)	1 (0.8%)	1 (0.8%)	1.000²
Increased labor pain	1	0	1
Uterine tachysystole	1	1	0

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¹Pearson’s chi-square test.

²Fisher’s exact test.

A more thorough analysis of the CTG as well as an evaluation of the birth experience will be provided in future publications.

Discussion

By contrast with previous reports, we show no effect of hyoscine butylbromide on duration of labor from IMP administration to vaginal delivery. Furthermore, we found no associations between treatment group and duration of labor from IMP administration to a fully dilated cervix of 10 cm or from onset of active labor to vaginal delivery, nor did we find any differences between the treatment groups regarding cervical dilation rate. Administration of hyoscine butylbromide was associated with increased maternal heart rate 30 min after IMP administration and decreased postpartum hemorrhage; although, the differences between the 2 treatment groups were small and probably not clinically significant.

BUSCLAB strongly suggests that the efficacy of 20 mg hyoscine butylbromide in shortening labor in nulliparous women with signs of prolonged labor is either nonexistent or weak. To our knowledge, BUSCLAB is the first RCT to assess the effect of hyoscine butylbromide on prevention of slow progress in labor as defined by the WHO partograph. Two meta-analyses of RCTs reported a statistically significant decrease in the duration of labor of almost 1 h for nulliparous women receiving hyoscine butylbromide compared to placebo [29,30]. However, slow labor progress was not an inclusion criterion in these studies. The majority of the included RCTs used hyoscine butylbromide as part of active management of labor, a procedure including artificial rupture of membranes at onset of active labor and augmentation with synthetic oxytocin if progress of labor is slower than 1 cm per hour [37]. This procedure contrasts with the procedure at the study hospital, which follows the WHO recommendations of starting oxytocin infusion if 4 h have passed without progress. Three of the RCTs included in the meta-analysis found no statistically significant effect of hyoscine butylbromide on the duration of labor [38–40]. In the current study, the observed difference in mean duration of labor from IMP administration to any mode of delivery (including emergency cesarean section) between the hyoscine butylbromide group and the placebo group was −5 min. The corresponding result restricted to women with vaginal delivery was −13 min. However, this does not incorporate the inherent incomplete nature of the data when considering duration of labor from IMP administration to vaginal delivery, as the time is not fully observed for women with emergency cesarean section.

In our study, we aimed to include women at risk of prolonged labor by crossing the alert line of the WHO partograph, as these women are have higher occurence of operative delivery and prolonged labor. Research by the WHO found that 19.2% of nulliparous women crossed the alert line and 11.7% crossed the action line [41]. Among the women crossing the alert line only, the rate of cesarean section was 5% and 20% had an operative vaginal delivery. Among the women also crossing the action line, the cesarean section rate was 26%, and the vaginal operative rate was 25%. In comparison, for the women not crossing any of the 2 lines, the cesarean section rate was 0.7% and the operative vaginal delivery rate was 11% [41].

Maged and colleagues studied the effect of hyoscine butylbromide on Egyptian women with slow labor [33]. The study found a statistically significant reduction in the mean duration of labor from IMP administration to a fully dilated cervix of 10 cm associated with hyoscine butylbromide when compared to placebo: 322 min versus 451 min [33]. The authors described a stepwise inclusion, where slow labor was defined as a cervical dilation rate of less than 1.2 cm per hour. A group of 187 out of 1,168 women fulfilled this criterion, 56 of whom were delivered by cesarean section. Thereafter, 31 women responded to hydration and oxytocin, leaving 100 women to be included in the study. In our study, there was only a single inclusion criterion regarding slow labor: a cervical dilation rate lower than 1 cm per hour in the active phase of labor. Hence, the study sample in the study by Maged and colleagues may differ from that of our study. In the former study, a single intravenous dose of 40 mg hyoscine butylbromide was used, which is twice as high as in the present study.

The prespecified dose of 20 mg hyoscine butylbromide may have been too low to affect the duration of labor in our sample of first-time mothers already showing signs of slow labor. In the systematic review by Mohaghegh and colleagues including 3,108 participants [29], the authors performed a sub-analysis comparing hyoscine butylbromide doses of 40 mg and 20 mg with respect to duration of labor. Both doses were shown to shorten the mean duration of the first stage of labor: difference of 69 min with a dose of 40 mg compared to placebo versus 61 min with a dose of 20 mg compared to placebo.

The percentages of women giving birth 2, 4, 6, 8, 10, and 12 h after IMP administration in our study were quite similar in the 2 treatment groups but with a marked difference at 6 h in favor of the hyoscine butylbromide group. This may suggest that hyoscine butylbromide might affect the cervical dilation rate but that the effect is temporary. The half-life of the drug is short (29 min) [42], so increased and/or repeated doses might be necessary to achieve the desired effect on duration of labor.

Our study participants had a mean duration of active labor of 744 min, exceeding the WHO’s 12-h definition of prolonged active phase of labor [1]. By comparison, the mean duration of active labor in the general population of first-time mothers in our hospital was 385 min in 2014 [17]. It is possible that women with prolonged labor as in the present study would have benefited from repeated doses of hyoscine butylbromide. According to the summary of product characteristics, hyoscine butylbromide can be administered in doses of 20 mg and repeated after 30 min with a maximum daily dose of 100 mg [43]. The medication also has a short-lasting effect [42]. Thus, the effect could have been improved if hyoscine butylbromide had been administered repeatedly, and later studies should consider a procedure with repeated doses.

The mean age of the trial participants in our study was higher than in the studies by Mohaghegh and colleagues, Riemma and colleagues, and Maged and colleagues: 32 years versus 26, 25.5, and 24 years, respectively [29,30,33]. These 3 studies included both nulliparous and multiparous women, implying that the mean age of nulliparous women alone must have been even lower. Advanced maternal age of first-time mothers is a well-known risk factor for prolonged labor [44]. Thus, the trial participants in the present study were more prone to prolonged labor than participants in the previous studies. Still, if hyoscine butylbromide had the hypothesized effect, one might anticipate that the effect would be even more pronounced in our study sample of women at higher risk of prolonged labor. On the other hand, it is possible that such a treatment is not appropriate or sufficient for these women, and there might be other reasons for slow progress of labor in this population.

In all of the studies included in the meta-analysis by Riemma and colleagues [30] and the systematic review by Mohaghegh and colleagues [29], IMP was given at onset of active labor (cervical dilation of 3 to 5 cm). This is in contrast to our study, where hyoscine butylbromide was given whenever slow progress of labor was identified and at a cervical dilation of 3 to 9 cm.

Our finding of decreased maternal blood loss in the hyoscine butylbromide group is in accordance with previous research by Imaralu and colleagues, who also found a statistically significant reduction in postpartum hemorrhage associated with hyoscine butylbromide [45]. However, the observed association might be spurious given that postpartum hemorrhage was a secondary outcome in the present study, and the association was also no longer statistically significant in the post hoc adjusted sensitivity analysis. Theoretically, the antispasmodic effect of hyoscine butylbromide may be associated with relaxation of smooth muscle, uterine atony, and postpartum hemorrhage. A short-lasting increase in maternal pulse is one of few side effects of hyoscine butylbromide [43]. A paper on side effects of hyoscine butylbromide based on the BUSCLAB study will be published later.

Our study provides novel information on oxytocin by measuring the exact dose that was given for labor augmentation; 88.0% (110/125) in the hyoscine butylbromide group and 84.7% (105/124) in the placebo group received oxytocin during labor. We also recorded the total time of oxytocin augmentation (in minutes) for each study participant, excluding time periods corresponding to a temporary cessation of augmentation with oxytocin. Our hypothesis was that the hyoscine butylbromide group would require lower doses of oxytocin due to more efficient contractions and a shorter duration of the first stage of labor. However, we found no statistically significant association between treatment group and amount of infused oxytocin, which is in line with our observation that hyoscine butylbromide did not seem to shorten the duration of labor.

An advantage of our study compared to Maged and colleagues is that we used survival analysis (Weibull regression and Cox regression) for all time-to-event outcomes of duration of labor, thereby taking into account the incomplete observation of labors ending with emergency cesarean section. In the presence of such data, this analytical approach is preferable to, e.g., the two-sample t test and the Mann–Whitney U test, as used by Maged and colleagues [33]. The present study also has some limitations. One potential weakness was the selection of trial participants. More than half of eligible women were not included; 100 did not wish to participate in the study, and 235 were not included upon admission (Fig 2). The FA set excluded a total of 11 women from the initial ITT set of all randomized women (including both eligible and non-eligible women): 10 non-eligible women erroneously randomized to treatment, 1 eligible woman who later withdrew her signed informed consent, and 1 eligible woman who did not receive the IMP due to reasons unrelated to the allocated treatment. Thus, the FA set was regarded as a modified ITT set. In addition, women giving birth at the study hospital were older than nulliparous women in general. Hence, the study participants may have represented a selected group of women with reduced external validity of the study as a result.

Furthermore, this study was not powered to assess the association between treatment group and mode of delivery. This is a clinically important outcome that needs to be investigated in larger studies. Since we designed the present study, the guidelines for labor progress have changed. In the current guidelines from the WHO, active labor is defined as regular contractions and cervical dilation of 5 cm or more [46]. The use of this definition would have led to shorter duration of labor and shorter time from IMP administration to delivery than reported in the present study. Hence, the effect of hyoscine butylbromide might have been more pronounced, and we may have underestimated the effect of hyoscine butylbromide. Larger and/or repeated doses of the study medication might reduce duration of labor when labor is at risk of being prolonged, a hypothesis well suited for further research.

A substantial number of self-reported and observed mild adverse events were noticed, with a higher occurrence of maternal tachycardia (grouped as cardiac disorders) and visual disturbance (grouped as eye disorders) in the hyoscine butylbromide group. These adverse events align with well-established common side effects of hyoscine butylbromide. However, it is of interest that the most common adverse event was urinary retention, a frequently observed condition following prolonged labor involving high frequency of epidural anesthesia and operative vaginal delivery. However, there was no difference in the proportion of urinary retention between the hyoscine butylbromide group and the placebo group, and such events cannot necessarily be directly attributed to the administration of hyoscine butylbromide.

In this double-blind randomized placebo-controlled trial, we found no evidence of shorter duration of labor associated with a single intravenous dose of 20 mg hyoscine butylbromide when compared to placebo in a sample of first-time mothers at risk of prolonged labor. Reassuringly, our study suggests that hyoscine butylbromide can be administered during labor without adverse effects for the offspring and only mild adverse effects for the mother.

Supporting information

S1 CONSORT Checklist. Consolidated Standards of Reporting Trials (CONSORT) Checklist.

(PDF)

pmed.1004352.s001.pdf^{(235.1KB, pdf)}

S1 Text. Study protocol BUSCLAB 001, Version No 14, May 26, 2021.

(PDF)

pmed.1004352.s002.pdf^{(2.4MB, pdf)}

S2 Text. Statistical Analysis Plan, Version 1.0, May 19, 2022.

(PDF)

pmed.1004352.s003.pdf^{(757.3KB, pdf)}

S1 Fig. Trial flow diagram.

(a) Investigational medicinal product (IMP). (b) Physical examination fetus included cardiotocography (CTG) with continuous fetal heart rate tracing. (c) Vital signs mother included blood pressure and pulse. Maternal height and body weight was obtained from the pregnancy chart. (d) Pain measurement using visual analogue score. (e) Physical examination newborn included an examination of general appearance.

(PDF)

pmed.1004352.s004.pdf^{(110.9KB, pdf)}

S1 Table. Results of all main analyses, sensitivity analyses, and subgroup analyses.

(XLSX)

pmed.1004352.s005.xlsx^{(27.2KB, xlsx)}

S2 Table. Results of post hoc adjusted sensitivity analyses.

(XLSX)

pmed.1004352.s006.xlsx^{(21.9KB, xlsx)}

Acknowledgments

We would like to thank all the women that participated in the study and all the midwives that contributed. We are also grateful to Oslo Metropolitan University for financial support.

Abbreviations

BMI: body mass index
CI: confidence interval
CTG: cardiotocography
eCRF: electronic case report form
FA: full analysis
HR: hazard ratio
IMP: investigational medicinal product
ITT: intention-to-treat
IU: international unit
NICU: neonatal intensive care unit
OR: odds ratio
PI: principal investigator
PP: per-protocol
RCT: randomized controlled trial
SD: standard deviation
SHR: sub-hazard ratio
WHO: World Health Organization

Data Availability

There are ethical and legal restrictions on sharing these clinical data. The primary outcome was time from administration of the Investigational Medicinal Product to delivery. The data underlying this outcome contains date and time of birth and cannot be shared. Moreover, combinations of the variables collected could possibly identify participants and thereby compromise participant privacy. In addition, the participants have not consented to sharing of collected data with international researchers according to GDPR recommendations. Contact email to the study sponsor: mirnyb@ous-hf.no.

Funding Statement

Foundation Dam/ The Norwegian Women’s Public Health Association has funded the PhD project and paid salary for AESE, MD. Grant number (2020/FO283405). Oslo University Hospital has founded the PhD project and paid salary for LCG, RM, MPH, PhD No Grant number available. The funding sources did not participate in the study's design, manuscript preparation, analysis and approval, or the decision to submit the manuscript for publication.

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PLoS Med. doi: 10.1371/journal.pmed.1004352.r001

Decision Letter 0

Richard Turner

25 May 2023

Dear Dr Gaudernack,

Thank you for submitting your manuscript entitled "The Effect of Intravenous Butylscopolamine Bromide on Slow Progress in Labor (BUSCLAB): A Double-Blind Randomized Placebo-Controlled Trial" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external assessment.

However, we first need you to complete your submission by providing the metadata that are required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by May 29 2023 11:59PM.

Once your full submission is complete, your paper will undergo a series of checks in preparation for full assessment

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Richard Turner PhD

Consulting Editor, PLOS Medicine

plosmedicine@plos.org

PLoS Med. doi: 10.1371/journal.pmed.1004352.r002

Decision Letter 1

Alexandra Schaefer

5 Jul 2023

Dear Dr. Gaudernack,

Thank you very much for submitting your manuscript "The Effect of Intravenous Butylscopolamine Bromide on Slow Progress in Labor (BUSCLAB): A Double-Blind Randomized Placebo-Controlled Trial" (PMEDICINE-D-23-01299R1) for consideration at PLOS Medicine.

Your paper was evaluated by an asscociate editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Jul 21 2023 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Alexandra Schaefer, PhD

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

GENERAL COMMENTS

Please respond to all editor and reviewer comments.

Please cite the reference numbers in square brackets (e.g., “We used the techniques developed by our colleagues [19] to analyze the data”). Citations should be preceding punctuation.

Please cite your Supporting Information as outlined here: https://journals.plos.org/plosmedicine/s/supporting-information

We suggest referring to Buscopan® (Buscopan) as butylscopolamine bromide throughout your manuscript. In general, we recommend using the international nonproprietary name (rINN), which in your case would seem to be hyoscine butylbromide.

Please remove the statements following the Acknowledgments from the main text. The data should only be included in the corresponding section in the online submission form.

ACADEMIC EDITOR COMMENTS

Like one of the reviewers, I have never heard of anyone using this treatment so some more information on its use would be helpful.

I also think that it would be useful to present the mean and 95% CI of the difference in labour duration between intervention and control (apologies if they did this and I missed it). They give the hazard ratio. However, the meta-analysis expresses the effect in terms of mean difference. It would help in comparing their results with the meta-analysis to have the mean and 95% CI of their difference. If, for example, the 95% CI of the mean difference in the current study included the point estimate of the mean difference from the meta-analysis, you might conclude that the trial doesn't tell you very much.

EDITOR-IN-CHIEF COMMENTS

For the main text, please present the data from the intention-to-treat (ITT) analysis and explain how you accounted for missing follow-up in your analysis. In accordance with the statistical reviewer's comments, please justify the use of Weibull regression (versus Cox proportional analysis) for your survival analysis and demonstrate that Weibull regression is a valid choice for your study. In addition, please provide more details on the clinical background of butylscopolamine bromide in labor (e.g., is it commonly used in labor? Which countries commonly use it?).

COMPETING INTEREST STATEMENT

All authors must declare their relevant competing interests per the PLOS policy, which can be seen here: https://journals.plos.org/plosmedicine/s/competing-interests

For authors with ties to industry, please indicate whether any of the interests has a financial stake in the results of the current study.

DATA AVAILABILITY STATEMENT

PLOS Medicine requires that the de-identified data underlying the specific results in a published article be made available, without restrictions on access, in a public repository or as Supporting Information at the time of article publication, provided it is legal and ethical to do so. Please see the policy at http://journals.plos.org/plosmedicine/s/data-availability and FAQs at http://journals.plos.org/plosmedicine/s/data-availability#loc-faqs-for-data-policy

The Data Availability Statement (DAS) requires revision. For each data source used in your study:

a) If the data are freely or publicly available, note this and state the location of the data: within the paper, in Supporting Information files, or in a public repository (include the DOI or accession number).

b) If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.

c) If the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries (again, this cannot be a study author).

ABSTRACT

Please report your abstract according to CONSORT for abstracts, following the PLOS Medicine abstract structure (Background, Methods and Findings, Conclusions); https://www.equator-network.org/reporting-guidelines/consort-abstracts/

Please ensure that all numbers presented in the abstract are present and identical to numbers presented in the main manuscript text.

PLOS Medicine requests that main results are quantified with 95% CIs as well as p values. Please include. When reporting p values please report as p<0.001 and where higher as the exact p value p=0.002, for example. For the purposes of transparent data reporting, if not including the aforementioned please clearly state the reasons why not.

Please include any important dependent variables that are adjusted for in the analyses.

Throughout, suggest reporting statistical information as follows to improve clarity for the reader “22% (95% CI [13%,28%]; p</=)”. Please amend throughout the abstract and main manuscript.

Please note the use of commas to separate upper and lower bounds, as opposed to hyphens as these can be confused with reporting of negative values.

When a p value is given, please specify the statistical test used to determine it. Please report p values as p<0.001 and where higher as 'p=0.002'

Abstract Background:

*Provide the context of why the study is important. The final sentence should clearly state the study question.

Abstract Methods and Findings:

* Please ensure that all numbers presented in the abstract are present and identical to numbers presented in the main manuscript text.

* Please include the study design, population and setting, number of participants, years during which the study took place, length of follow up, and main outcome measures.

* Please include the actual amounts and/or absolute risk(s) of relevant outcomes (including NNT or NNH where appropriate), not just relative risks or correlation coefficients. (example for absolute risks: PMID: 28399126).

* Please include a summary of adverse events if these were assessed in the study.

* In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

Please specify who was blinded to the intervention and control.

Please define the intervention and control states.

Please provide the number in each group.

Please state that analysis was intention to treat.

Please provide the number of participants lost to follow up in each group.

AUTHOR SUMMARY

At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary.

The summary should include 2-3 single sentence, individual bullet points under each of the questions.

It may be helpful to review currently published articles for examples which can be found on our website here https://journals.plos.org/plosmedicine/

INTRODUCTION

ll.84-85: Please reference the studies referred to in the statement.

ll.84-86: Please revise the two sentences to emphasize the aspect of your study investigating the effect of butylscopolamine bromide on slow labor and not labor in general.

Please address past research and explain the need for and potential importance of your study (e.g., more details on the implications of prolonged labor, past research on butylscopolamine bromide in labor). Indicate whether your study is novel and how you determined that. If there has been a systematic review of the evidence related to your study (or you have conducted one), please refer to and reference that review and indicate whether it supports the need for your study.

METHODS AND RESULTS

Please complete the CONSORT checklist and ensure that all components of CONSORT are present in the manuscript, including [how randomization was performed, allocation concealment, blinding of intervention, definition of lost to follow-up, power statement]. Please include the completed CONSORT checklist as Supporting Information.

When completing the checklist, please use section and paragraph numbers, rather than page numbers.

In accordance with ICMJE requirements, PLOS Medicine requires prospective, public registration of a data sharing plan (as part of mandatory clinical trials registration) for all clinical trials that began enrollment on or after January 1, 2019.

The main analysis should be intention to treat (ie, all individuals randomized are included in the analysis in the groups to which they were originally assigned. If the study included dropouts, specify whether their data are imputed and if so using what method. Please refer to as modified ITT).

Please include any important dependent variables that are adjusted for in the analyses.

Suggest reporting statistical information as detailed above – see under ABSTRACT

Please present numerators and denominators for percentages, at least in the Tables [not necessarily each time they're mentioned].

Please report the number of patients, and account for all methods used in your study.

Please define the length of follow up (eg, in mean, SD, and range).

Please provide the actual numbers of events for the outcomes, not just summary statistics or ORs.

In the trial registry, the secondary outcomes measure ‘changes in maternal and fetal heart rates 30 minutes after IMP administration (in beats/min)” and the secondary dichotomous outcomes are not listed and appear to differ from the primary and secondary outcome measures in the submitted manuscript. Please clarify and explain the discrepancy. If the outcomes were not prespecified in the protocol, please indicate that they were post hoc and explain why they were added. Post hoc comparisons should be presented as hypothesis generating rather than conclusive.

In addition, the trial registration/protocol lists the outcomes of ‘Pain scores using a Visual Analogue Scale at baseline and 30 minutes after administration of IMP’, ‘Urinary retention, defined as need for urinary catheter before the participants leave the delivery ward’, ‘Anal sphincter injury’, ‘Birth experience measured by the validated questionnaire Child Birth Experience Questionnaire’. (a) Can you please present those results as part of this manuscript, or indicate why that is not possible? (b) Can you please indicate when you plan to publish those results?

Please present the safety data for the study including numbers of specific events and whether or not adverse events are thought to be related to treatment.

Please include the study protocol document and analysis plan, with any amendments, as Supporting Information to be published with the manuscript if accepted.

l.211: “[…] admission of the newborn to the NICU within the first hours after birth.” – In the trial registry, this outcome measure is defined as ‘Within 2 hours after birth’, please revise.

ll.332-334: We suggest adding details about the treatment group in which an association for postpartum hemorrhage ≥ 1500 mL in one of the sensitivity analyses was seen.

DISCUSSION

Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion. Please remove any subheadings.

l.414: Please add a period at the end of the sentence.

FIGURES

For all Figures, please ensure that you have complied with our figures requirements http://journals.plos.org/plosmedicine/s/figures.

Please provide titles and legends for all figures (including those in Supporting Information files).

Please consider avoiding the use of red and green in order to make your figure more accessible to those with colour blindness

In the flow diagram, please indicate the number of individuals in each group analyzed in the ITT analysis. In addition, please change the abbreviation for ‘months’ from ‘mo’ to ‘mos’.

Please in the figure legend/description, define abbreviations used in each figure (including those in Supporting Information files).

Figure 1: The quality of Figure 1 is low.

Figure 2: Please define ‘NaCl’.

Figure 3: Please add a unit for percentage.

Figure S5: Figure S5 (Supplementary Material S5) appears not be cited in the main text of your manuscript. Please revise.

Figure S5: Please define ‘NaCl’. Please change ‘45 unkonown’ to 45 unknown’, ‘1 missing signed consentform’ to 1’ missing signed consent form’, ‘1 not given IMP due to maternal illness not mentioned in exclution criteria’ to ‘‘1 not given IMP due to maternal illness not mentioned in exclusion criteria’,

TABLES

Please note the use of commas to separate upper and lower bounds, as opposed to hyphens as these can be confused with reporting of negative values. Suggest reporting statistical information as detailed above – see under ABSTRACT

Please provide titles and legends for all tables (including those in Supporting Information files).

Please define all abbreviations used in the table below each table (including those in Supporting Information files).

Table 1: Please remove the p-values presented in Table 1 and the according footnotes.

Table S4: Please define ‘CTG’, ‘IMP, ‘VAS’

REFERENCES

PLOS uses the numbered citation (citation-sequence) method and first six authors, et al.

Please ensure that journal name abbreviations match those found in the National Center for Biotechnology Information (NCBI) databases (http://www.ncbi.nlm.nih.gov/nlmcatalog/journals), and are appropriately formatted and capitalised.

Please also see https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references for further details on reference formatting.

Where website addresses are cited, please specify the date of access.

Comments from the reviewers:

Reviewer #1: This study assess the effect of butylscopolamine bromide on the duration of the active phase of labor in primiparous women showing early signs of slow labor.

Table 1 - Report either mean or median depending on whether you have a gaussian or non-gaussian distribution. This accounts fopr several of your variables.

Table 2 - report either mean or median depending on whether you have a gaussian or non-gaussian distribution.

Table 2 - Why do you report OR and not RR, when reporting results from an RCT?

Table 2 - suggest information on missing values moved to a footnote below the table, to improve readability.

Table 2 - instead of reporting PPH > 1000 ml yes n (%) or no n(%), simply just report n(%) for the women with pph >1000 ml. This goes for all outcomes. Report the positive findings, so instead of Apgar <7 at 5 minutes - no, please report the actual number and percentage who has a low apgar.

I am not sure why you should adjust for maternal heart rate prior to intervention. Your randomization should have equally distributed your participants into two groups. When looking at your table 1, you have no reason to believe otherwise.

Figure (no number) and figure 2 should be merged into one diagram. In my point of view no need for two almost identical diagrams.

Abstract-Introduction

Suggest leaving out some of the comments on oxytocin and focus on the possible effect of buscopan

Abstract - result

Only report either mean (SD) or median (IQR) - not both. Why do you report HZ and not RR?

Methods

I might have missed it, but I could locate any detailed information on recruitment, information of eligible (oral?), when signing the informed consent. I have checked the published protocol as well. However, it seems, you only describe a written information 6 weeks prior to due date. When do they sign the informed consent? Are there any delay between randomization and intervention? Do you have any post randomization dropouts due to a possible delay?

Results

There is no need to include information both the text and, in the consort, flow diagram on recruitment. Suggest that you leave the detailed description to the consort flowchart and shorten the initial text of your result section.

Please consider moving the result on the primary outcome further up in the result section. You write 1.5 page before you report your primary finding.

CEQ - I cannot find any information on the result of the CEQ. And is the CEQ translated and validated in a Norwegian setting? In the protocol you refer to the original Swedish questionnaire.

Reviewer #2: Thank you for the opportunity to read and comment on the paper "The Effect of Intravenous Butylscopolamine Bromide on Slow Progress in Labor (BUSCLAB): A Double-Blind Randomized Placebo-Controlled Trial" by Gaudernack et al.

The trial aim to compare iv administration of a spasmolytic drug (Butylscopolamine Bromide) with placebo (saline) in nulliparous women with early signs of prolonged labour on the duration on labor from trial medication to delivery.

I congratulate the authors on this trial; it was well-planned and timely registered, and the paper is overall well written. The rationale to perform a trial in a developed counrty seems good.

First of all, are spasmolytics really commonly administered drugs during labor (L 76-77)? Could the authors give other references than ref. 22 to support this statement, since I am not sure that this is the case in developed countries (it is certainly not used in the UK or in Denmark).

A very important point in comparing this trial to other trials would be the study population. I am uncertain if this trial actually aims to prevent or treat prolonged labor as the participants are described to "show early signs" of prolonged labor. Does this population differ considerably from that of the previous studies, as the active labor phase was defined from 3 cm cervical dilation, and the mean cervical dilation at inclusion was 5 cm? Deviating from the alert line at 3 or 4 cm is likely to be a common (?) situation in nullips. Could the authors comment on this aspect and refer to studies using the WHO partograph.

Please also comment on the use of oxytocin, which was approximately four hours' duration in each group. Do the authors have information about the cervical dilation at time of oxytocin administration? Please state the number of women who had oxytocin in each group as these women are likely to be "true" prolonged labor parturients.

I can tell from the protocol that the primary outcome was the mean duration from IMP to delivery, bus this is not very clear from this manuscript. Please add "mean" to the primary outcome.

The nomenclature primiparous can certainly be used to describe women carrying their first child/during their first labor; however, using this term might be confusing, as it is also used to describe women with one previous labor. I suggest to use the word nulliparous to describe the women in this trial so that there is no doubt to the reader.

Introduction; I suggest to markedly reduce the information on possible oxytocin disadvantages as it takes up too much space and is not the focus of this study.

Discussion; This paragraph could overall be much better structured into summary, interpretation of the results (including more general discussion of why this trial is negative as compared to previous trials with significant effect of BB rather than discussing one demographic or outcome at a time), weaknesses (i.e. possible bias in the randomization process with envelopes and using an unblinded person to prepare the medication, precision in including the targeted population including concurrent use of oxytocin) and strengths, generalizability, future research (including moving the discussion about to this place in the discussion as studying multiple administrations is a hypothesis from the trial), and conclusion.

Minor points

The line "However, the effect of 40 mg vs 20 mg was not compared in the meta-analysis" is unclear as it is stated in the previous lines that the meta-analysis did compare these two doses (L 385). Please revise.

L 388 I suggest to replace "the same" with "our" hospital.

L 407-409 The authors should consider if the rationale is the other way around; in a population with a higher risk of prolonged labor (i.e. in this case higher maternal in this study) it could be more difficult to show an effect of the intervention.

Conclusion: The statement "Larger and/or repeated doses of the medication might reduce duration of labor when labor is prolonged, a hypothesis well suited for further research" (L 450-452) is not a conclusion to be drawn from this data and should be deleted or moved.

Reviewer #3: This is an interesting RCT on the Effect of Intravenous Butylscopolamine Bromide on Slow Progress in Labor. However, there are a few major issues needing attention.

1. The main analysis (called 'FA') is basically complete case analysis. There is no intention to treat analysis at all in the paper. 'Intention to treat' means 'once randomised always analysed', therefore means analysis of 261 randomised participants which was not possible and not done. The excluded 12 participants may introduce bias to the results as randomisation was disrupted, which is a limitation of the study.

2. Statistical analysis:

a) Firstly, why using Weibull regression for time to event analysis instead of Cox model? Weibull model requires strong assumption that the change in hazard rate is linear. However we didn't see this anywhere, then why Weibull model?

b) Competing risk analysis. As the emergency cesarean section is a competing risk event, it's not adequate just to censor it. This competing risk issue can be addressed in the competing risk framework using, for example, Fine-Gray model.

c) The primary analysis needs to be adjusted for important/key baseline variables which seems not done in the paper.

3. Sample size calculation. A short paragraph on sample size with important details is needed in the main paper, rather than just refer to the protocol.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2024 Mar 28;21(3):e1004352. doi: 10.1371/journal.pmed.1004352.r003

Author response to Decision Letter 1

9 Sep 2023

Attachment

Submitted filename: Response to reviewers 080923 (1).docx

pmed.1004352.s007.docx^{(110.3KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1004352.r004

Decision Letter 2

Alexandra Schaefer

20 Oct 2023

Dear Dr. Gaudernack,

Many thanks for your considered and detailed responses to the editors' and reviewers' comments. I have discussed the paper at length with my colleagues and the academic editor, and it has also been seen again by two of the original reviewers. We appreciate your detailed explanation regarding the intention to treat analysis; however, both reviewers still have some concerns that need to be addressed (including on this point). In addition, the editors require that you add the safety data (ie, adverse events) to this manuscript (per CONSORT).

Based on the reviewers’ and editors’ comments, I invite you to submit another revision of the paper that addresses these comments. Please be sure to address all of the general editorial comments at the end of this letter.

When submitting your revised paper, please once again include a detailed point-by-point response to the editorial comments. As before, please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript. ***Please note when preparing your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask that you submit this second revision by November 10th. If this date is not feasible, or you have any questions, please email me directly (aschaefer@plos.org). However, please note that I will be on holiday from October 20 through November 3rd; if you need to contact me during that time, please reach out to our Executive Editor, Heather Van Epps (hvanepps@plos.org).

Sincerely,

Alexandra

Alexandra Schaefer, PhD

PLOS Medicine

aschaefer@plos.org

--------------------------------------------

Major editorial points:

1. Per CONSORT, it is essential that you report the safety data for the trial, including the number of specific events and whether the adverse events are considered to be related to treatment (along with details about how the AEs were recorded in the Methods section). The adverse events should be presented in a table unless they are very brief, in which case it is sufficient to include them as a paragraph in the main text (with appropriate statistics).

2. Regarding the statisticians point about ITT, we suggest that you consider using ‘modified ITT’ to ensure full transparency regarding the participants who were included in the analysis.

--------------------------------------------

Academic editor comments:

You have calculated the mean and 95% CI of the difference in the duration of labor, but you do not include it because of the effect of not observing the full duration of labor in women who had an intrapartum cesarean section. While the explanation is appreciated, if you feel that this measure is not interpretable, it may be best to remove the reference to the meta-analysis results where this is the outcome. It would be good to calculate the difference in exactly the same way as was done in the trials that made up the meta-analysis, compare your results with the meta-analysis, and then discuss the limitations of this as an outcome. If you prefer not to present your own results with this measure, it remains rather questionable whether it makes sense to discuss the same measure from previous studies.

--------------------------------------------

Reviewer comments:

Reviewer 1:

Thank you for the opportunity to review the revised document. The paper has without doubt improved since last revision. However, I still suggest further improvement prior to submission. These are however minor.

1. Abstract: The abstract should be further condensed to improve the readability. A suggestion could be to follow the CONSORT guidance for abstracts: Hopewell S, Clarke M, Moher D, Wager E, Middleton P, Altman DG, Schulz KF; CONSORT Group. CONSORT for reporting randomised trials in journal and conference abstracts. Lancet. 2008 Jan 26;371(9609):281-3. doi: 10.1016/S0140-6736(07)61835-2. PMID: 18221781.

2. Methods: Trial design: line 144 -145 suggest delete - or move: initiate the whole section by stating: further detailed information on the design can be found in the published protocol (ref).

3. Result section: You have now deleted all information regarding the participant flow for this section, this is not according to the CONSORT guidance.

4. You need to briefly include information on recruitment, randomization and who received intervention and differences/no differences in baseline characteristics.

5. Line 371 You report both median and mean. You should only report one, depending on Gaussian or non-gaussian distribution.

6. Discussion: PPH difference of 50 ml, and maternal heartrate difference of 3 beat/min, are those differences of clinical relevance?

7. Table 1: For your dichotomous outcome - consider only to report one in the table (not both Yes and No) and the number of missing when relevant. I prefer you report "Yes"

8. Table 2: Since you have reported n in the first row for each column, I suggest that you leave out "number of events" in the first three rows. It improves the readability and I prefer not to use "events" about the included women.

9. For your dichotomous outcome - consider only to report one in the table and the number of missing when relevant.

Reviewer 3 (statistics):

Thanks authors for their great effort to improve the manuscript. The authors have addressed some of my concerns well however there are still a few remaining issues needing to be addressed.

1) Re intention to treat (ITT), I appreciate authors have argued with great effort and respect, however I am still not convinced. I would like to insist that the analysis is simply not an ITT analysis. Therefore, can't use the name of ITT and also need to discuss this in the limitation.

2) Re Weibull regression, although it's fine to use once the assumptions are met, still needs to add one or two sentences to explain why Weibull was chosen over Cox in the main paper as it was not the straightforward first choice in the situation.

3) Re 'The primary analysis needs to be adjusted for important/key baseline variables', it is the best practice these days to do the adjustment even if the variables are perfectly balanced as research shows by this way it will narrow down the 95% CI of the estimates (more precise), therefore the adjustment for main analyses is still recommended.

--------------------------------------------

General editorial points:

1. TITLE: We suggest changing the title to “Evaluation of Intravenous Hyoscine Butylbromide for Slow Progress in Labor (BUSCLAB): A Double-Blind Randomized Placebo-Controlled Trial”

2. ABSTRACT:

a. Please revise your abstract once more be sure to carefully follow the CONSORT Abstract checklist.

b. Please only report the primary outcomes of the trial in your abstract. We are in the process of overhauling our workflows and policies (with a new Executive Editor), and we now require that trial abstracts only report secondary outcomes if all secondary outcomes of the trial are included. This is to ensure transparent and unbiased reporting and to avoid placing undue emphasis on specific secondary outcomes. For trials that have many secondary outcomes, such as yours, the abstract should be limited to reporting the primary outcome.

c. Please include a brief summary of the adverse events assessed in the study.

d. In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

3. METHODS AND RESULTS:

a. ll.287-303: This information should be reported in the Results section of the manuscript, rather than the Methods section.

4. AUTHOR SUMMARY: In the final bullet point of ‘What Do These Findings Mean?’, please describe the main limitations of the study in non-technical language.

5. DISCUSSION:

a. ll. 471-472: For a better understanding, please make it clear that 69 min and 61 min refers to the difference in the first stage of labor compared with placebo (eg, reduced by 69 min…)

b. Causal language - In trials, there is usually a distinction in the language in terms of causal vs associational for primary and secondary trial outcomes, respectively. It would be preferable to use associational language in the discussion( and other sections) when referring to secondary outcomes (e.g., l.520).

c. Please remove the ‘Conclusion’ subheading from the discussion, as the one-paragraph conclusion should be part of the discussion section.

6. Figure 4: Are the lines for the hazard rates (vaginal delivery) of hyoscine butylbromide and placebo congruent (only one line is visible)?

7. Table 1: In the second row (Maternal age (in years)), please either include the unit in parentheses (“years”) and then remove "years" from each age group in the list below; OR remove the unit from the heading and keep "years" as the unit with each age group.

8. Table 1: Please note that the footnote ‘6’ is not formatted as superscript.

9. SUPPLEMENT, S2 Trial Flow Diagram: I cannot locate footnote ‘e’ in the figure description?

10. REFERENCES: Where website addresses are cited, when specifying the date of access please replace the word ‘cited’ with ‘accessed’.

11. Please add the following statement, or similar, to the Methods: "This study is reported as per the Consolidated Standards of Reporting Trial (CONSORT) guideline (S1 Checklist)."

12. Please remove the statements following the Acknowledgments from the main text (Declaration of interest, Role of the funding source, Data sharing). The data should only be included in the corresponding section in the online submission form.

13. Please include this information “Contact email to the study sponsor: mirnyb@ous-hf.no” in the Data availability statement in the manuscript submission form.

14. If you have not already done so, please upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

15. We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

16. To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

17. Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

--------------------------------------------

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

PLoS Med. 2024 Mar 28;21(3):e1004352. doi: 10.1371/journal.pmed.1004352.r005

Author response to Decision Letter 2

20 Nov 2023

Attachment

Submitted filename: Respons to reviewers.docx 10.11.23 (1).docx

pmed.1004352.s008.docx^{(33.7KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1004352.r006

Decision Letter 3

Alexandra Schaefer

22 Dec 2023

Dear Dr. Gaudernack,

Thank you very much for re-submitting your manuscript "The Effect of Intravenous Hyoscine Butylbromide on Slow Progress in Labor (BUSCLAB): A Double-Blind Randomized Placebo-Controlled Trial" (PMEDICINE-D-23-01299R3) for review by PLOS Medicine.

Thank you for your detailed response to the editors' and reviewers' comments. I have discussed the paper with my colleagues and the academic editor, and it has also been seen again by the statistical reviewer. The changes made to the paper were satisfactory to the reviewer. As such, we intend to accept the paper for publication, pending your attention to the editorial comments below in a further revision. When submitting your revised paper, please once again include a detailed point-by-point response to the editorial comments.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Due to the upcoming holiday season, we are happy to provide additional time to complete the revision. Please email me (aschaefer@plos.org) or the journal staff on plosmedicine@plos.org if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Dec 29 2023 11:59PM.

Sincerely,

Alexandra Schaefer, PhD

Associate Editor

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

EDITORIAL POINTS

As discussed, please report the full safety data for the trial, including the number of specific events and whether the adverse events are considered to be related to treatment (along with details about how the AEs were recorded in the Methods section). The adverse events should be presented in a table unless they are very brief, in which case it is sufficient to include them as a paragraph in the main text (with appropriate statistics).

DATA AVAILABILITY

Thank you for providing the Data Availability Statement (DAS) statement. In line with PLOS’ policy on data availability, we kindly ask you to share a “minimal data set”. PLOS defines the “minimal data set” to consist of the data set used to reach the conclusions drawn in the manuscript with related metadata and methods, and any additional data required to replicate the reported study findings in their entirety. Authors do not need to submit their entire data set, or the raw data collected during an investigation. If possible, please submit the following data:

The values behind the means, standard deviations and other measures reported;

The values used to build graphs.

ABSTRACT

1) ll.55-56 “Women giving birth at the study hospital were older and had higher educational level than nulliparous women in general.” – This detail may be more appropriate for inclusion in the Results/Discussion section rather than the Abstract. If stated in the Results/Discussion section, pleas provide reference.

2) l. 57 "...in the study of various reasons." - Please specify "various reasons". Also, according to the flow chart, more than 80% of eligible women were excluded. Editorial suggestion: "More than 80% of eligible women were excluded from the study because they did not meet the inclusion criteria." Please make it clear that this is the main limitation(s) of the study's methodology; the phrase "The main limitation of the study..." may be useful.

AUTHOR SUMMARY

1) Under ‘What Did the Researchers Do and Find?’, please split the two bullet points into four to make the details provided more accessible. Editorial suggestion:

What Did the Researchers Do and Find?

• We performed a double-blind randomized placebo-controlled study, including 249 nulliparous women showing first signs of slow labor progress.

• The participants were randomized to receive either a single intravenous dose of the spasmolytic drug hyoscine butylbromide (Buscopan®) (20 mg) or a single intravenous dose of saline solution (placebo).

• We found no statistically significant difference in labor duration between the two treatment groups. There was a decrease in postpartum hemorrhage and a slight increase in maternal heart rate in the hyoscine butylbromide group.

• No maternal serious adverse events were observed, nor did we observe any neonatal adverse events.

2) Under ‘What Do These Findings Mean?’, the first bullet point seems to repeat an observation rather than being an interpretation of the finding. Editorial suggestion: Hyoscine butylbromide was not found to impact duration of labor from treatment administration to delivery for first-time mothers with long labors.

3) The last bullet under ‘What Do These Findings Mean?’ point should only describe the main limitation of the study's methodology. The sentence starting “Randomized controlled trials assessing the effect of higher or…” may be added as a separate bullet point prior to the limitation.

METHODS AND RESULTS

1) At the beginning of the Results section, please include a few sentences about the study population, i.e., the number screened for eligibility, the number deemed eligible, the number not enrolled, etc. (according to the flowchart).

2) ll. 375-377 “…was markedly higher..”: Did you test for significance? If not, please temper language.

3) l.408: Please use causal language for the description of primary outcomes. In trials, there is usually a distinction in the language in terms of causal vs associational for primary and secondary trial outcomes. It would be beneficial to use associational language in the discussion and other sections for secondary outcomes.

DISCUSSION

1) ll.446-449: Please use causal language for the description of primary outcomes.

2) ll.474-481: Please provide reference for the first and last sentence of the paragraph if referring to the same reference.

3) l.558: Please specify ‘various reasons’.

4) l.564: “In addition, women giving birth at the study hospital were older and had higher educational level than nulliparous women in general.” - Please provide reference.

REFERENCES

Please thoroughly revise all references and ensure that journal name abbreviations match those found in the National Center for Biotechnology Information (NCBI) databases (http://www.ncbi.nlm.nih.gov/nlmcatalog/journals), and are appropriately formatted and capitalised (e.g., for reference [17] BMC Pregnancy and Childbirth should be BMC Pregnancy Childbirth)

FIGURES

1) Figure 2: Please remove any CONSORT labeling. The top of the flowchart should show the enrollment/assessment of eligibility box.

2) Figure 3: Please remove the headings ‘Absolute frequency’ and ‘Relative frequency’.

3) Figure 4: Please ensure to present 95% confidence intervals in the figure.

4) Figure 4: Please note that the lower graph of Figure 4 is titled ‘emergency cesarean section delivery’ while in other figures you use the title ‘emergency cesarean section’. Please revise.

5) Figure 3-7: Please in the figure description, add details about the dose of hyoscine butylbromide, the definition of placebo as well as the definition of ‘emergency cesarean section’.

SOCIAL MEDIA

To help us extend the reach of your research, please provide any X (formerly known as Twitter) handle(s) that would be appropriate to tag, including your own, your coauthors’, your institution, funder, or lab. Please respond to this email with any handles you wish to be included when we tweet this paper.

Comments from Reviewers:

Reviewer #3: Thanks authors for their great effort to improve the manuscript. I am satisfied with the response and revision. No further issues needing attention.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2024 Mar 28;21(3):e1004352. doi: 10.1371/journal.pmed.1004352.r007

Author response to Decision Letter 3

22 Jan 2024

Attachment

Submitted filename: Answer to reviewers 190124.docx

pmed.1004352.s009.docx^{(23.1KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1004352.r008

Decision Letter 4

Alexandra Schaefer

25 Jan 2024

Dear Dr Gaudernack,

On behalf of my colleagues and the Academic Editor, Gordon C Smith, I am pleased to inform you that we have agreed to publish your manuscript "The Effect of Intravenous Hyoscine Butylbromide on Slow Progress in Labor (BUSCLAB): A Double-Blind Randomized Placebo-Controlled Trial" (PMEDICINE-D-23-01299R4) in PLOS Medicine.

I appreciate your thorough responses to the reviewers' and editors' comments throughout the editorial process. We look forward to publishing your manuscript, and editorially there are only a few remaining stylistic/presentation points that should be addressed prior to publication. We will carefully check whether the changes have been made. If you have any questions or concerns regarding these final requests, please feel free to contact me at aschaefer@plos.org.

Please see below the minor points that we request you respond to:

1) ll.452-459: Thank you for providing the full safety data. In the main text, we ask you to include one or two sentences detailing the most common adverse events (e.g., those affecting >10% of the study population).

2) Table 3: We feel that the adverse events should be presented in a more conventional manner. Please state the specific disorders/conditions/AEs included in each of the organ-specific categories. You do not need to include a "No" category. For guidance, we recommend Table 2 of the paper by Bruinsma A et al. (2022; doi: 10.1016/j.eurox.2022.100165).

2) Figure 2: Please change "1 mL 20 mg hyoscine butylbromide" to "1 mL (20 mg/mL) hyoscine butylbromide" and "1 mL sodium chloride" to "1 mL (9 mg/mL) sodium chloride".

3) Figure 4: In the figure description, we suggest adding a note that the lines for vaginal delivery and emergency cesarean section are congruent.

4) The supplementary files "S2 Experimental Flow Diagram" and "S5 Results" were not submitted. Please be sure to submit all files.

5) Please be sure to update the Data Availability and Competing Interest fields in the online submission form according to the files you provided as supporting information.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Alexandra Schaefer, PhD

Associate Editor

PLOS Medicine

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 CONSORT Checklist. Consolidated Standards of Reporting Trials (CONSORT) Checklist.

(PDF)

pmed.1004352.s001.pdf^{(235.1KB, pdf)}

S1 Text. Study protocol BUSCLAB 001, Version No 14, May 26, 2021.

(PDF)

pmed.1004352.s002.pdf^{(2.4MB, pdf)}

S2 Text. Statistical Analysis Plan, Version 1.0, May 19, 2022.

(PDF)

pmed.1004352.s003.pdf^{(757.3KB, pdf)}

S1 Fig. Trial flow diagram.

(PDF)

pmed.1004352.s004.pdf^{(110.9KB, pdf)}

S1 Table. Results of all main analyses, sensitivity analyses, and subgroup analyses.

(XLSX)

pmed.1004352.s005.xlsx^{(27.2KB, xlsx)}

S2 Table. Results of post hoc adjusted sensitivity analyses.

(XLSX)

pmed.1004352.s006.xlsx^{(21.9KB, xlsx)}

Attachment

Submitted filename: Response to reviewers 080923 (1).docx

pmed.1004352.s007.docx^{(110.3KB, docx)}

Attachment

Submitted filename: Respons to reviewers.docx 10.11.23 (1).docx

pmed.1004352.s008.docx^{(33.7KB, docx)}

Attachment

Submitted filename: Answer to reviewers 190124.docx

pmed.1004352.s009.docx^{(23.1KB, docx)}

Data Availability Statement

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PERMALINK

The effect of intravenous hyoscine butylbromide on slow progress in labor (BUSCLAB): A double-blind randomized placebo-controlled trial

Lise Christine Gaudernack

Angeline Elisabeth Styve Einarsen

Ingvil Krarup Sørbye

Mirjam Lukasse

Nina Gunnes

Trond Melbye Michelsen

Roles

Abstract

Background

Methods and findings

Conclusions

Trial registration

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Introduction

Methods

Study design

Participants

Inclusion criteria

Fig 1. WHO partograph in management of labor (26).

Exclusion criteria

Randomization and blinding

Procedures following treatment administration

Baseline characteristics

Outcomes

Sample size calculations

Analysis sets

Fig 2. CONSORT flow diagram of the BUSCLAB (BUSCopan in LABor) study.

Table 1. Descriptive statistics of baseline characteristics, by treatment group, based on the FA set.

Statistical analysis

Monitors

Results

Fig 3. Absolute and relative frequencies of deliveries as functions of time since administration of the IMP for 1 ml (20 mg) hyoscine butylbromide and 1 ml (9 mg) sodium chloride, respectively.

Table 2. Descriptive statistics of outcomes, by treatment group, and results of the main statistical analyses, based on the FA set.

Fig 4. Cause-specific hazard rates of vaginal delivery and emergency cesarean section as functions of time since administration of the IMP for 1 ml (20 mg) hyoscine butylbromide and 1 ml (9 mg) sodium chloride (placebo), respectively.

Fig 5. Cumulative incidences of vaginal delivery and emergency cesarean section as functions of time since administration of the IMP for 1 ml (20 mg) hyoscine butylbromide and 1 ml (9 mg) sodium chloride, respectively.

Fig 6. Cumulative incidences of vaginal delivery and emergency cesarean section as functions of time since onset of active labor for 1 ml (20 mg) hyoscine butylbromide and 1 ml (9 mg) sodium chloride, respectively.

Fig 7. Cumulative incidences of cervical dilation of 10 cm and emergency cesarean section prior to cervical dilation of 10 cm as functions of time since administration of the IMP for 1 ml (20 mg) hyoscine butylbromide and 1 ml (9 mg) sodium chloride, respectively.

Table 3. Numbers and percentages of women with adverse events within each system organ class, overall and by treatment group.

Discussion

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Richard Turner

Roles

Decision Letter 1

Alexandra Schaefer

Roles

Author response to Decision Letter 1

Decision Letter 2

Alexandra Schaefer

Roles

Author response to Decision Letter 2

Decision Letter 3

Alexandra Schaefer

Roles

Author response to Decision Letter 3

Decision Letter 4

Alexandra Schaefer

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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