Volume 10, Issue 2 (4-2024)
Journal of Research in Applied and Basic Medical Sciences 2024, 10(2): 130-145 |
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Heshmatnia F, Jafari M, Karimi M, Azizi M, Sayadi M, Yadollahi P. Efficacy of hyoscine butylbromide and promethazine on the labor's active phase duration: a systematic review and meta-analysis of randomized controlled trials. Journal of Research in Applied and Basic Medical Sciences 2024; 10 (2) :130-145
URL: http://ijrabms.umsu.ac.ir/article-1-310-en.html
URL: http://ijrabms.umsu.ac.ir/article-1-310-en.html
Fatemeh Heshmatnia 
, Maryam Jafari , Mahdiyeh Karimi , Marzieh Azizi , Mehrab Sayadi , Parvin Yadollahi *
, Maryam Jafari , Mahdiyeh Karimi , Marzieh Azizi , Mehrab Sayadi , Parvin Yadollahi *
Department of Midwifery, Maternal-fetal medicine Research Center, School of Nursing and Midwifery, Shiraz University of Medical Sciences, Shiraz, Iran (Corresponding Author) , yadollahi_556@yahoo.com
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Fig. 1. PRISMA flow diagram
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Fig. 2. Forest plot showing the observed outcomes and the estimate of the random-effects model for the duration of the first stage of labor in 10, 20, and 40 mg HBB RCTs
To explore potential sources of heterogeneity, a sensitivity analysis was conducted by removing studies. By eliminating 20 studies(16, 20, 35-37, 39, 40, 42, 43, 45, 47-49, 52, 54, 55, 58-60, 68) (including the entire 10 mg subgroup), A significant statistical difference was still found regarding the effect of HBB on the first stage of labor despite a reduction in heterogeneity to 42%
(p = 0.02) (Z=15.78, p = 0.001). We couldn't find any common feature between the eliminated studies. A funnel plot of the estimated Study's bias is shown in Figure 3.
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Fig. 3. Forest plot showing the observed outcomes and the estimate of the random-effects model for the duration of the second stage of labor in HBB RCTs
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Fig. 4. Forest plot showing the observed outcomes and the estimate of the random effects model for the duration of the third stage of labor in HBB RCTs
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Fig. 5. Forest plot showing the observed outcomes and the estimate of the random-effects model for the duration of the first stage of labor in Primipara, Multiparous, and Primipara and Multiparous women
Gravidity of Participants:
We investigate the effects of previous pregnancy on HBB efficacy in reducing labor duration. A total of 24 studies report data for primipara women and six studies for multiparous women. Studies that didn't specify participants' status were excluded.
Primipara Women:
In 24 studies (3, 16, 19, 32, 35, 38-40, 44, 45, 48, 50-52, 55, 57-60, 64, 66, 69), data for primipara women were reported separately; these studies were included in the analysis. The observed MD of included studies ranged from -146.00 min to 54.49 min, with most estimates being negative (96%). According to the Cochran’s Q test. A hetroginty was appeared in studies (Chi² = 254.35, (p < 0.00001); I² = 92%). The estimated combined MD based on this model was -66.04 min (95% CI: -79.36 to -52.73) and (Z = 9.72, p < 0.001.) According to the results were summarized in Figure 5, HBB decreased the first stage of labor duration by 66.04 min in primipara women.
Multiparous Women:
A total of 6 studies (35, 40, 44, 55, 61, 65) that reported data for multiparous women were included in the analysis. The observed MD ranged from -153.96 min to -32.40 min, with most estimates being negative (100%). The true outcomes appear to be heterogeneous (Tau² = 1372.18; Chi² = 77.41, df = 5 (p < 0.00001); I² = 94%). Based on the random-effects model, the estimated combined MD was -100.61 min (95% CI: -133.04 to -68.18 and p<0.001). So, HBB decreased the first stage of labor duration by 100.61 min in multiparous women (Figure 5).
Promethazine
Promethazine in the First Stage:
A total of 5 RCT studies that use Promethazine to reduce labor duration and met criteria were included in the analysis (3, 26, 67-69). These studies report the first stage duration as the primary outcome. The observed mean differences for these studies ranged from -81.42 min to 65.97 min, with most estimates being negative (60%). The true outcomes appear to be heterogeneous (Tau² = 3974.01; Chi² = 62.01, df = 4 ( p < 0.00001); I² = 94%). The estimated combined MD based on the random-effects model was -12.68 min (95% CI: -70.75 to 45.38), and (Z = 0.43, p = 0.67).
Promethazine in the Second Stage:
Three studies report data for the effect of Promethazine on the second stage duration (67-69). These studies report the second stage duration as the primary outcome. The observed mean differences for these studies ranged from -8.68 min to 7.26 min, with most estimates being negative (77%). The true outcomes appear heterogeneous (Chi² = 5.47, ( p = 0.06); I² = 63%). The estimated combined MD based on the random-effects model was 0.7 min (95% CI: -6.55, 7.96, P=0.85).
Promethazine in the Third Stage:
Only two studies report data for the effect of Promethazine on the third stage duration (68, 69). These studies report the third stage duration as the primary outcome. The observed mean differences for the two studies are -0.03 min to 1.37 min. The true results appear not heterogeneous (Chi² = 1.73, (p = 0.19); I² = 42%). The estimated combined MD based on the fixed-effects model was 0.53 min (95% CI: -0.81, 1.87, p=0.44).
HBB vs Promethazine:
Some RCT studies use HBB and Promethazine in combination with other drugs or alone. The analysis included two studies that compared HBB and promethazine effects on separate groups and met the criteria (3, 68). Studies that combine these drugs or other drugs were excluded from the analysis. These studies report the first stage duration as the primary outcome and include 170 participants. The observed mean for these two studies is -107.40 min and 12.50 min. A hetroginty has appeared between studies (Chi² = 8.24, (p = 0.004); I² = 88%). Considering this, the combined MD was -42.88 min (95% CI: -160.04 to 74.28, P=0.47).
Quality Assessment of the Included Studies:
Based on the Jadad scale, studies get scores from 3 to 8. Most studies (27 studies) have a 6 or 7 score, and two get eight scores. The detailed score for each Study is presented in Table 3 (Supplementary). We considered studies with a score of at least 3 in meta-analysis.
Discussion
Two commonly used drugs to shorten prolonged labor in developing countries are Hyoscine butyl bromide (an anti-spasmodic medicine) and Promethazine (Histamine H1 receptor antagonist). Several RCT studies have investigated these drugs' efficacy in reducing the active phase of labor duration (3, 16, 19, 25, 34-49, 51, 58, 59, 61-66, 69-75). We conduct this systematic review and meta-analyze to determine the benefit of using these drugs for decreasing labor duration. After a systematic search, we selected 30 studies that meet the inclusion criteria. Among studies, 44 studies administered HBB, two used Promethazine, and three used both in different intervention groups to compare their effectiveness.
The studies were conducted in Iran (15 studies), India (8 studies), Nigeria (6 studies), Egypt (6 studies), Iraq (2 studies), Bahrain (1 study), Kenya (1 study), Mexico (1 study), Saudi Arabia (1 study), Spain (1 study), Tanzania (1 study), Turkey (1 study), which all except Spain, are developing countries. The meta-analysis results regarding the effectiveness of HBB on labor stages showed that HBB shortened the first stage of labor by 66.75 min compared to placebo groups. This reduction is 147.02 min for two studies that use 10 mg HBB (36, 54), and 20 mg and 40 mg doses, shortening the labor first stage duration by 58.95 and 71.60 minutes, respectively. However, 10 mg seems more effective, but because only two studies use this dose, we can't tell if the HBB effect is dose-dependent. On the other hand, Promethazine reduces the first stage duration by 12.68, but it isn't statistically significant (Z = 0.43 (p = 0.67)). Among Promethazine studies, Shahmohammadi (69) and Ebrahimzade-Zagami (3) report the highest reduction (81.42 and 78.60 min); however, two studies (67, 68) report an increase in the first stage duration of the intervention group (21.88 min and 65.97 min increase in duration respectively).
The HBB reduces the second and third stages of labor by 3.27 min (Z = 1.93, p = 0.05)) and 0.6 min (Z = 2.27, p = 0.02), which are not statistically nor clinically significant. Promethazine increases the duration of the second (0.7 min increase, Z = 0.19 (p = 0.85)) and third (0.53 min increase, Z = 0.77 (p = 0.44)) stages of labor. However, it's not statistically significant. Indeed, we can see that HBB reduces labor duration mainly by affecting the first stage of labor, so we do a subgroup analysis based on first-stage data. We didn't include its data in further analysis because we couldn't find an overall significant effect of Promethazine in any delivery stages.
Next, we consider the participant's pregnancy history effect on HBB efficacy by analyzing 21 studies that report data per parities (3, 16, 19, 32, 35, 38-40, 44, 45, 48, 50-52, 55, 57, 60, 64, 66, 67, 69). Four studies report data for primipara and multiparous women separately, so we use each group's data in specific subgroups (35, 40, 44, 55). We reviewed 23 studies with 1313 primipara women in the HBB intervention group and 1321 in the control group (3, 16, 19, 32, 35, 38-40, 44, 45, 48, 50-52, 55, 57-60, 64, 66, 67, 69). HBB was found to reduce the duration of the first stage of labor in primipara women by 66.04 min (Z = 9.72 (p < 0.00001)). We use six studies with 336 multiparous women in the HBB intervention group and 324 in the control group for the multiparous subgroup (35, 40, 44, 55, 61, 65). The HBB reduces the first stage duration by 100.61 min (Z = 6.08 (p < 0.00001)). Time reduction in studies that didn't represent separate data for primipara and multiparous women is close to the primipara group (70.37 min, Z = 4.44 (p = 0.00001)). So HBB is more effective in multiparous women compared to primipara women. A recent study by Yousef 2022 found that HBB reduced the duration of the first stage duration in both augmented and non-augmented participants, with a more significant effect on multigravida than primigravida. This study also demonstrated that the average duration of the active first stage of labor was 206.51 minutes in the HBB group compared to 267 minutes in the placebo group (mean difference= 61.44 minutes), which is statistically significant. HBB is an effective and safe drug for reducing the duration of the active first stage of labor (76,77).
One of the main factors in the first stage of labor duration is cervical dilatation; all included studies report the administration time of HBB at 3–4 cm and don't report cervical dilatation rate after administration, so we couldn't involve this factor in the analysis. Two studies use HBB and Promethazine in two separate intervention groups (3, 68). We use these studies to compare HBB and Promethazine directly. The analysis shows that HBB reduces the first stage duration by 42.88 min compared to Promethazine; however, the effect is not statistically significant (Z = 0.72 p = 0.47). More studies are needed to report accurate results in this regard. We have several limitations here; most studies report comprehensive participant data and don't report subgroup data. All studies report participant age as the mean± SD age, and we couldn't include participants' age in the analysis.
Conclusions
HBB administration reduces labor duration mainly by affecting the first stage of labor. HBB is more effective in multiparous women compared to primipara women. Since 20 mg and 40 mg of HBB both have the same effectiveness, we recommend using 20 mg to minimize side effects in the mother and infant. On the other hand, Promethazine does not reduce total labor duration or any stages of labor, so its use is not recommended.
Abbreviations
MD: Mean Difference
SID: Scientific Information Database
CI: Confidence Interval
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses
IG: Intervention Group
CG: Control Group
GA: Gestational Age
HBB: Hyoscine N-Butyl Bromide
Dil: Dilation
FS: First-Stage
SS: Second Stage
TS: Third Stage
PP: Primipara
MP: Multipara
NS: Normal Saline
RCT: Randomized Clinical Trial
HR: Hours
Min: Minutes
IM: Intra Muscular
IV: Intravenously
DW: Distilled Water
NS: Not Specified
HP: Hugo Poin
Acknowledgments
None
Conflicts of interest
The authors declared no conflicts of interest.
Authors' Contributions
MJ, FH, MK, and MA contributed substantially to the design of the study. MJ and FH contributed to data collection. MS had roles in data interpretation. MJ and PY wrote the initial draft and MS critically and substantially revised the final article. All authors reviewed critically and approved the manuscript.
Funding/support
No external or intramural funding was received
Supplementary Material
Table 1: Characteristics of the included studies with Hyoscine N-butyl-bromide intervention
Table 2: Characteristics of the included studies with promethazine intervention
Table 3: Quality assessment of the selected studies was presented according to the Jadad score calculation
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Introduction
Labor is one of the most important events in women's lives; therefore, negative labor experiences can be emotionally and psychologically challenging for mothers and their families (1-3). According to the results of a study, 210 million women get pregnant every year, and of those, 20 million will suffer from pregnancy-related illnesses, and 500,000 will die of complications during pregnancy and childbirth (4). The duration of the active phase of labor is a significant factor associated with maternal and fetal complications (5), so prolonged labor is a common risk factor that influences pregnancy outcomes (6, 7). Additionally, more prolonged labor has many adverse effects on both infants like low Apgar scores, neonatal trauma, sepsis, umbilical artery acidosis, birth asphyxia-related complications, and neonatal intensive care units, and mothers, including chorioamnionitis, early and late postpartum hemorrhage, perineal trauma, episiotomy usage, operative delivery, uterine rupture (8-11). Approximately 3-8% of labors are prolonged, three times higher in nulliparous women than multiparous women (12).
There are different types of drugs to shorten prolonged labor (13, 14). Spasmolytic drugs are frequently used in the delivery section to overcome cervical spasms and reduce the duration of labor (15, 16). Hyoscine butyl bromide (HBB) is a parasympatholytic drug, a muscarinic antagonist acting as an anticholinergic drug. The primary mechanism of action of HBB is to block neural impulses in the intramural parasympathetic ganglia of abdominal organs, exerting a spasmolytic action on the smooth muscle of the gastrointestinal, biliary, urinary, and female genital organs, especially the cervix and lower uterine segment that may cause cervical dilatation and effacement (17-19). After intravenous injection, it is rapidly released into the tissue, and final removal takes about 5 hours; its full clearance is 1.2 liters per minute (20).
Promethazine is a Histamine H1 receptor antagonist (HA1RA) derived from phenothiazine, exhibiting sedation, anesthesia, neuroprotection, and antiemetic effects associated with its antimuscarinic properties (21, 22). Promethazine also has anticholinergic effects and central nervous system depression. Therefore, it is prescribed to increase a woman's ability to endure labor pain. Due to its effect on the smooth muscles of the uterus and its ability to reduce anxiety and fear during pregnancy, its use seems to affect the duration of labor (23). On the other hand, some researchers believed that the injection of Hyoscine and Promethazine might prolong the first stage of labor due to the antispasmodic effects of these drugs (3, 19, 20, 24-26). But some studies showed that Hyoscine and Promethazine reduce the duration of the first stage of labor (3, 20, 27).
Several studies have been conducted to evaluate the use of Hyoscine and Promethazine in shortening the phases of labor, with different settings and results. However, no quantitative analysis has been conducted to validate these findings. Thus, the purpose of the present study was to conduct a systematic review of randomized controlled trials assessing Hyoscine-Promethazine's effectiveness in reducing labor phases, ultimately reducing healthcare costs and drug waste.
Materials & Methods
Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this systematic review was conducted in 2021. This present study is a systematic review and meta-analysis of the current research literature on the effectiveness of Hyoscine and Promethazine on the duration of labor. The protocol of this study was accepted in PROSPERO [PROSPERO 2021 CRD42021272783], Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021272783.
Search Strategies:
We conducted an in-depth search in electronic databases included, Science Direct, PubMed Scopus, Google Scholar, MEDLINE, Web of Science, Cochrane Library, PsycINFO, and ProQuest. We also checked Iranian databases consisting of the Scientific Information Database (SID), Magiran, and IranDoc. We searched for terms and keywords including the following: ["Hyoscine" OR "Hyoscine N-Buthyl Bromide," OR "Buscopan"] AND ["Promethazine"] OR " ["labor" OR "duration of labor, "OR "active phase, "OR "shortening of the active phase," OR "reduction of active phase"] AND ["randomized controlled trials" OR "randomized placebo-controlled trials" OR "randomized double-blind controlled trials OR "interventional studies" OR "pilot randomized trials"]. This Study included all Persian and English articles from 2000 to 2021, regardless of their geographical location, journal of published article authors' name, and other bibliographic information of the journals. Notably, the latest search process was performed between July and September 2021 separately by two researchers and then checked by both of them.
Eligibility Criteria and Data Collection:
Following the inclusion and exclusion criteria in relevant studies, we screened the title and abstract of relevant studies separately and obtained the full text. Women who received Promethazine or Hyoscine during labor had singleton pregnancies, vertex presentation, without previous uterine surgery, intact membranes, and spontaneous labor, and mothers with no contraindication for normal vaginal delivery were included in the Study. Exclusion criteria included: Placenta abruption or rupture, placenta previa, women with a history of caesarian delivery, and also studies published in other languages except English and Persian were also excluded from this systematic review.
Type of outcome measure:
The primary outcome measured in this study was a systematic assessment of the interventions regarding the effectiveness of Hyoscine-Promethazine on labor phase duration.
Data Extraction and analysis:
A descriptive table was prepared after carefully reading each article and extracting the information required by FH and MJ, which MA cross-checked. During group discussions, the third author resolved disagreements between the authors. The extracted data included authors' names, publication year, country, age of participants, number of participants in each group, gestational age, duration of labor, intervention, control drug dosage, and gravity of participants.
The means and SDs of outcomes after the intervention were used for the meta-analysis. The summary measures were reported as summary mean difference (MD) with a 95 % confidence interval (CI) using the random-effects model of Der Simonian and Laird. All P-values were considered significant at the level of < 0.05. Results were summarized in a forest plot. Cochran’s Q test and I2 were used to assess between-study heterogeneity. We considered between-study heterogeneity as I2 values of 50% or more. Also, we used a funnel plot to check studies' publication bias (due to the large volume of the article, figures were not reported). In addition, we applied subgroup analysis based on random-effects models to find probable sources of heterogeneity for some variables, including drug dosage and the gravidity of participants in the first stage of labor duration. The data analysis was carried out using Review Manager 5.4.1 Build Date: 21/09/20 19:16 (The Nordic Cochrane Centre 2014, Copenhagen, Denmark).
Assessing the Quality of Selected Articles:
Methodological quality of the clinical trials was assessed using the Jadad score calculation. Jadad's scale consists of two sets of questions: three direct questions and eight indirect questions (28). Three direct questions were asked regarding the Study: whether it appeared to be randomized, whether it was double blinded and whether there were any descriptions of withdrawals or dropouts. As a response to the first direct question, one point was given if the randomization method was described, as well as an additional point if the randomization process was described. Studies in which the randomization method was inappropriate did not receive an additional point. For the second direct question, one point was awarded if blinding was mentioned in the study, and an additional point was awarded if the appropriate method of blinding was described. If the withdrawals or dropouts are described, a point is awarded for the third direct question. According to the first set of questions, the average score ranged from 0 to 5, with higher scores indicating high quality research. Scores ≥3 were considered to be acceptable and appropriate quality studies, while studies scoring <3 were considered to be of weak in quality. There are eight indirect questions in the second section of the Jaded scale regarding the study objectives, obvious outcomes, an explanation of the inclusion and exclusion criteria, an explanation of sample size, a description of the interventions, a description of at least one control group, an explanation of how adverse effects were assessed, and a description of the statistical analysis techniques. The articles selected for this review study were evaluated only in accordance with the three
direct questions outlined above (29-31).
Results
After searching, 170 studies were selected for initial screening. After reading the title and abstract of searched studies, 105 studies were excluded because they did not meet inclusion criteria or were irrelevant to the study objectives. Among the remaining studies, we excluded nonrandomized studies (n=10), compared HBB or Promethazine with another drug without a control group (n=3), compared different concentrations of drugs without a control group (n=2), took the medication orally for some time before labor (n=1), and use the combination of HBB or Promethazine with another drug (n=5). Finally, we selected 44 studies that met all the criteria for analyzing their data (Figure 1).
Labor is one of the most important events in women's lives; therefore, negative labor experiences can be emotionally and psychologically challenging for mothers and their families (1-3). According to the results of a study, 210 million women get pregnant every year, and of those, 20 million will suffer from pregnancy-related illnesses, and 500,000 will die of complications during pregnancy and childbirth (4). The duration of the active phase of labor is a significant factor associated with maternal and fetal complications (5), so prolonged labor is a common risk factor that influences pregnancy outcomes (6, 7). Additionally, more prolonged labor has many adverse effects on both infants like low Apgar scores, neonatal trauma, sepsis, umbilical artery acidosis, birth asphyxia-related complications, and neonatal intensive care units, and mothers, including chorioamnionitis, early and late postpartum hemorrhage, perineal trauma, episiotomy usage, operative delivery, uterine rupture (8-11). Approximately 3-8% of labors are prolonged, three times higher in nulliparous women than multiparous women (12).
There are different types of drugs to shorten prolonged labor (13, 14). Spasmolytic drugs are frequently used in the delivery section to overcome cervical spasms and reduce the duration of labor (15, 16). Hyoscine butyl bromide (HBB) is a parasympatholytic drug, a muscarinic antagonist acting as an anticholinergic drug. The primary mechanism of action of HBB is to block neural impulses in the intramural parasympathetic ganglia of abdominal organs, exerting a spasmolytic action on the smooth muscle of the gastrointestinal, biliary, urinary, and female genital organs, especially the cervix and lower uterine segment that may cause cervical dilatation and effacement (17-19). After intravenous injection, it is rapidly released into the tissue, and final removal takes about 5 hours; its full clearance is 1.2 liters per minute (20).
Promethazine is a Histamine H1 receptor antagonist (HA1RA) derived from phenothiazine, exhibiting sedation, anesthesia, neuroprotection, and antiemetic effects associated with its antimuscarinic properties (21, 22). Promethazine also has anticholinergic effects and central nervous system depression. Therefore, it is prescribed to increase a woman's ability to endure labor pain. Due to its effect on the smooth muscles of the uterus and its ability to reduce anxiety and fear during pregnancy, its use seems to affect the duration of labor (23). On the other hand, some researchers believed that the injection of Hyoscine and Promethazine might prolong the first stage of labor due to the antispasmodic effects of these drugs (3, 19, 20, 24-26). But some studies showed that Hyoscine and Promethazine reduce the duration of the first stage of labor (3, 20, 27).
Several studies have been conducted to evaluate the use of Hyoscine and Promethazine in shortening the phases of labor, with different settings and results. However, no quantitative analysis has been conducted to validate these findings. Thus, the purpose of the present study was to conduct a systematic review of randomized controlled trials assessing Hyoscine-Promethazine's effectiveness in reducing labor phases, ultimately reducing healthcare costs and drug waste.
Materials & Methods
Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this systematic review was conducted in 2021. This present study is a systematic review and meta-analysis of the current research literature on the effectiveness of Hyoscine and Promethazine on the duration of labor. The protocol of this study was accepted in PROSPERO [PROSPERO 2021 CRD42021272783], Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021272783.
Search Strategies:
We conducted an in-depth search in electronic databases included, Science Direct, PubMed Scopus, Google Scholar, MEDLINE, Web of Science, Cochrane Library, PsycINFO, and ProQuest. We also checked Iranian databases consisting of the Scientific Information Database (SID), Magiran, and IranDoc. We searched for terms and keywords including the following: ["Hyoscine" OR "Hyoscine N-Buthyl Bromide," OR "Buscopan"] AND ["Promethazine"] OR " ["labor" OR "duration of labor, "OR "active phase, "OR "shortening of the active phase," OR "reduction of active phase"] AND ["randomized controlled trials" OR "randomized placebo-controlled trials" OR "randomized double-blind controlled trials OR "interventional studies" OR "pilot randomized trials"]. This Study included all Persian and English articles from 2000 to 2021, regardless of their geographical location, journal of published article authors' name, and other bibliographic information of the journals. Notably, the latest search process was performed between July and September 2021 separately by two researchers and then checked by both of them.
Eligibility Criteria and Data Collection:
Following the inclusion and exclusion criteria in relevant studies, we screened the title and abstract of relevant studies separately and obtained the full text. Women who received Promethazine or Hyoscine during labor had singleton pregnancies, vertex presentation, without previous uterine surgery, intact membranes, and spontaneous labor, and mothers with no contraindication for normal vaginal delivery were included in the Study. Exclusion criteria included: Placenta abruption or rupture, placenta previa, women with a history of caesarian delivery, and also studies published in other languages except English and Persian were also excluded from this systematic review.
Type of outcome measure:
The primary outcome measured in this study was a systematic assessment of the interventions regarding the effectiveness of Hyoscine-Promethazine on labor phase duration.
Data Extraction and analysis:
A descriptive table was prepared after carefully reading each article and extracting the information required by FH and MJ, which MA cross-checked. During group discussions, the third author resolved disagreements between the authors. The extracted data included authors' names, publication year, country, age of participants, number of participants in each group, gestational age, duration of labor, intervention, control drug dosage, and gravity of participants.
The means and SDs of outcomes after the intervention were used for the meta-analysis. The summary measures were reported as summary mean difference (MD) with a 95 % confidence interval (CI) using the random-effects model of Der Simonian and Laird. All P-values were considered significant at the level of < 0.05. Results were summarized in a forest plot. Cochran’s Q test and I2 were used to assess between-study heterogeneity. We considered between-study heterogeneity as I2 values of 50% or more. Also, we used a funnel plot to check studies' publication bias (due to the large volume of the article, figures were not reported). In addition, we applied subgroup analysis based on random-effects models to find probable sources of heterogeneity for some variables, including drug dosage and the gravidity of participants in the first stage of labor duration. The data analysis was carried out using Review Manager 5.4.1 Build Date: 21/09/20 19:16 (The Nordic Cochrane Centre 2014, Copenhagen, Denmark).
Assessing the Quality of Selected Articles:
Methodological quality of the clinical trials was assessed using the Jadad score calculation. Jadad's scale consists of two sets of questions: three direct questions and eight indirect questions (28). Three direct questions were asked regarding the Study: whether it appeared to be randomized, whether it was double blinded and whether there were any descriptions of withdrawals or dropouts. As a response to the first direct question, one point was given if the randomization method was described, as well as an additional point if the randomization process was described. Studies in which the randomization method was inappropriate did not receive an additional point. For the second direct question, one point was awarded if blinding was mentioned in the study, and an additional point was awarded if the appropriate method of blinding was described. If the withdrawals or dropouts are described, a point is awarded for the third direct question. According to the first set of questions, the average score ranged from 0 to 5, with higher scores indicating high quality research. Scores ≥3 were considered to be acceptable and appropriate quality studies, while studies scoring <3 were considered to be of weak in quality. There are eight indirect questions in the second section of the Jaded scale regarding the study objectives, obvious outcomes, an explanation of the inclusion and exclusion criteria, an explanation of sample size, a description of the interventions, a description of at least one control group, an explanation of how adverse effects were assessed, and a description of the statistical analysis techniques. The articles selected for this review study were evaluated only in accordance with the three
direct questions outlined above (29-31).
Results
After searching, 170 studies were selected for initial screening. After reading the title and abstract of searched studies, 105 studies were excluded because they did not meet inclusion criteria or were irrelevant to the study objectives. Among the remaining studies, we excluded nonrandomized studies (n=10), compared HBB or Promethazine with another drug without a control group (n=3), compared different concentrations of drugs without a control group (n=2), took the medication orally for some time before labor (n=1), and use the combination of HBB or Promethazine with another drug (n=5). Finally, we selected 44 studies that met all the criteria for analyzing their data (Figure 1).
Fig. 1. PRISMA flow diagram
The total samples in intervention and control groups were 3083 and 3084, respectively. The mean age in intervention and control groups were 25.50 ± 4.30 and 25.67 ± 4.12, respectively. All studies had equal or almost equal sample sizes in two groups, and the mean age of participants in both groups was the same. Thirty-nine studies only used HBB in intervention groups ADDIN EN.CITE.DATA (16, 19, 20, 27, 32-66), two studies only used Promethazine (26, 67), and three studies used both to compare their effectiveness (3, 68, 69).
A Summary of the Included Studies is Presented in the Supplementary:
The studies' publication dates ranged from 2001(26) to 2021 (57). Studies were conducted in several countries, fifteen studies in Iran (3, 26, 32, 45, 48, 51, 58-60, 62, 64, 65, 67-69), eight studies in India (20, 33, 34, 36, 44, 46, 54, 61), six studies in Nigeria (27, 43, 47, 49, 55, 57), six studies in Egypt (16, 38, 39, 50, 52, 63), two studies in Iraq (35, 37), one study in Bahrain(66), one study in Kenya (41), one study in Mexico (42), one study in Saudi Arabia (19), one study in Spain (53), one study in Tanzania (56), and one study in Turkey (40). In total, 6167 women participated in these studies (3083 women intervention groups, 3086 women control groups). Three studies that have used both HBB and Promethazine intervention groups use one control group, so we use this control group for both interventions (3, 68, 69). In one study, 8 mg of dexamethasone was administrated six hours before induction, then 40 mg HBB was injected at the active phase for the intervention group (50). Participants in intervention groups get HBB in 10, 20, or 40 mg doses by injection (IM or IV) or suppository. Promethazine intervention groups get 1, 25, or 50 mg doses by injection. Control group’s participants get a placebo or have no intervention.
HBB:
In total, 42 RCT studies' data were included in this
meta-analysis to determine HBB efficacy in reducing labor duration ADDIN EN.CITE.DATA (3, 16, 19, 20, 27, 32-66, 68, 69). The sample size of the included trials varied from 40 to 382 in both the intervention and the control groups. In total, 5907 women with a gestational age of 37–42 weeks enrolled in the studies, 2953 women in the intervention, and 2954 women in the control or placebo group. The timeframe of publication was between 2004 and 2021.
Stages of Labor:
All studies that represent labor duration as the primary outcome were included in the meta-analysis. All 42 studies represented the first stage of labor duration ADDIN EN.CITE.DATA (3, 16, 19, 20, 27, 32-66, 68, 69), 31 reported first and second stage duration (16, 19, 20, 27, 34, 35, 37-39, 41-45, 48-50, 52, 53, 55-62, 64, 65, 68, 69), and 21 represented first, second, and third stage duration (16, 20, 27, 35, 37-39, 41, 44, 48, 50, 55-57, 59-61, 64, 65, 68, 69). We analyze these subgroups to determine the HBB administration effect on each stage separately.
HBB in the First Stage: Dilation and Fetal Descent:
A total of 42 studies report the first stage duration average for the intervention, and control groups were included in the analysis ADDIN EN.CITE.DATA (3, 16, 19, 32-66, 68, 69). These studies observed MD ranging from -171.60 min to 78.47 min, with most estimates being negative (87.8 %). The accurate outcomes appear to be heterogeneous (I² = 95%, p <0.0001) so to find sources of heterogeneity, we performed group analysis based on HBB dosage and the parity of participants and used the random effect model. Based on the random-effects model, the estimated combined MD was -66.75 (95% CI: -80.22 to -53.28) (Z = 9.71 P < 0.001) HBB in any given dose (10, 20, or 40 mg) decreased the first stage duration by 66.75 min. A forest plot showing the observed outcomes and the estimate based on the random-effects model is shown in Figure 2. The forest plot indicated the combined MD (Figure 2).
A Summary of the Included Studies is Presented in the Supplementary:
The studies' publication dates ranged from 2001(26) to 2021 (57). Studies were conducted in several countries, fifteen studies in Iran (3, 26, 32, 45, 48, 51, 58-60, 62, 64, 65, 67-69), eight studies in India (20, 33, 34, 36, 44, 46, 54, 61), six studies in Nigeria (27, 43, 47, 49, 55, 57), six studies in Egypt (16, 38, 39, 50, 52, 63), two studies in Iraq (35, 37), one study in Bahrain(66), one study in Kenya (41), one study in Mexico (42), one study in Saudi Arabia (19), one study in Spain (53), one study in Tanzania (56), and one study in Turkey (40). In total, 6167 women participated in these studies (3083 women intervention groups, 3086 women control groups). Three studies that have used both HBB and Promethazine intervention groups use one control group, so we use this control group for both interventions (3, 68, 69). In one study, 8 mg of dexamethasone was administrated six hours before induction, then 40 mg HBB was injected at the active phase for the intervention group (50). Participants in intervention groups get HBB in 10, 20, or 40 mg doses by injection (IM or IV) or suppository. Promethazine intervention groups get 1, 25, or 50 mg doses by injection. Control group’s participants get a placebo or have no intervention.
HBB:
In total, 42 RCT studies' data were included in this
meta-analysis to determine HBB efficacy in reducing labor duration ADDIN EN.CITE.DATA (3, 16, 19, 20, 27, 32-66, 68, 69). The sample size of the included trials varied from 40 to 382 in both the intervention and the control groups. In total, 5907 women with a gestational age of 37–42 weeks enrolled in the studies, 2953 women in the intervention, and 2954 women in the control or placebo group. The timeframe of publication was between 2004 and 2021.
Stages of Labor:
All studies that represent labor duration as the primary outcome were included in the meta-analysis. All 42 studies represented the first stage of labor duration ADDIN EN.CITE.DATA (3, 16, 19, 20, 27, 32-66, 68, 69), 31 reported first and second stage duration (16, 19, 20, 27, 34, 35, 37-39, 41-45, 48-50, 52, 53, 55-62, 64, 65, 68, 69), and 21 represented first, second, and third stage duration (16, 20, 27, 35, 37-39, 41, 44, 48, 50, 55-57, 59-61, 64, 65, 68, 69). We analyze these subgroups to determine the HBB administration effect on each stage separately.
HBB in the First Stage: Dilation and Fetal Descent:
A total of 42 studies report the first stage duration average for the intervention, and control groups were included in the analysis ADDIN EN.CITE.DATA (3, 16, 19, 32-66, 68, 69). These studies observed MD ranging from -171.60 min to 78.47 min, with most estimates being negative (87.8 %). The accurate outcomes appear to be heterogeneous (I² = 95%, p <0.0001) so to find sources of heterogeneity, we performed group analysis based on HBB dosage and the parity of participants and used the random effect model. Based on the random-effects model, the estimated combined MD was -66.75 (95% CI: -80.22 to -53.28) (Z = 9.71 P < 0.001) HBB in any given dose (10, 20, or 40 mg) decreased the first stage duration by 66.75 min. A forest plot showing the observed outcomes and the estimate based on the random-effects model is shown in Figure 2. The forest plot indicated the combined MD (Figure 2).
Fig. 2. Forest plot showing the observed outcomes and the estimate of the random-effects model for the duration of the first stage of labor in 10, 20, and 40 mg HBB RCTs
To explore potential sources of heterogeneity, a sensitivity analysis was conducted by removing studies. By eliminating 20 studies(16, 20, 35-37, 39, 40, 42, 43, 45, 47-49, 52, 54, 55, 58-60, 68) (including the entire 10 mg subgroup), A significant statistical difference was still found regarding the effect of HBB on the first stage of labor despite a reduction in heterogeneity to 42%
(p = 0.02) (Z=15.78, p = 0.001). We couldn't find any common feature between the eliminated studies. A funnel plot of the estimated Study's bias is shown in Figure 3.
Fig. 3. Forest plot showing the observed outcomes and the estimate of the random-effects model for the duration of the second stage of labor in HBB RCTs
HBB in the Second Stage: Delivery of the Infant:
Among the selected studies, 31 of them represent both first and second stages duration data (16, 19, 20, 27, 34, 35, 37-39, 41-45, 48-50, 52, 53, 55-62, 64, 65, 68, 69). Those studies were included in the analysis to determine the HBB effect on the second stage of labor. The observed MD of these studies ranged from -63.30 min to 17 min, with most estimates being negative (87%). The true outcomes appear heterogeneous (I² = 97%, p < 0.001). Based on the random-effects model, the estimated MD was -3.27 min (95% CI -6.58 to 0.04), (Z= 1.93, p = 0.05) and HBB in any given concentration (10, 20, or 40 mg) did not affect the second stage of labor duration. A forest plot showing the observed outcomes and the estimate based on the random-effects model is shown in Figure 3.
HBB in the Third Stage: Delivery of the Placenta:
We include 21 studies that report all three stages of labor duration in the analysis for this section (16, 20, 27, 35, 37-39, 41, 44, 48, 50, 55-57, 59-61, 64, 65, 68, 69). We use the third-stage duration data to observe the HBB effect on this stage of labor. The observed MD of analyzed studies ranged from -3.60 min to 2.40 min, with most estimates being negative (62%). Based on the random-effects model, the estimated combined MD was -0.60 min (95% CI: -1.13 to -0.08) and (Z = 2.27, p = 0.02). So HBB in any given dose (10, 20, or 40 mg) did not affect the third stage of labor duration. A forest plot showing the observed outcomes and the estimate based on the random-effects model is shown in Figure 4. The true outcomes appear to be heterogeneous (I² = 86%); Chi² = 141.74, df = 20 (p < 0.001).
Among the selected studies, 31 of them represent both first and second stages duration data (16, 19, 20, 27, 34, 35, 37-39, 41-45, 48-50, 52, 53, 55-62, 64, 65, 68, 69). Those studies were included in the analysis to determine the HBB effect on the second stage of labor. The observed MD of these studies ranged from -63.30 min to 17 min, with most estimates being negative (87%). The true outcomes appear heterogeneous (I² = 97%, p < 0.001). Based on the random-effects model, the estimated MD was -3.27 min (95% CI -6.58 to 0.04), (Z= 1.93, p = 0.05) and HBB in any given concentration (10, 20, or 40 mg) did not affect the second stage of labor duration. A forest plot showing the observed outcomes and the estimate based on the random-effects model is shown in Figure 3.
HBB in the Third Stage: Delivery of the Placenta:
We include 21 studies that report all three stages of labor duration in the analysis for this section (16, 20, 27, 35, 37-39, 41, 44, 48, 50, 55-57, 59-61, 64, 65, 68, 69). We use the third-stage duration data to observe the HBB effect on this stage of labor. The observed MD of analyzed studies ranged from -3.60 min to 2.40 min, with most estimates being negative (62%). Based on the random-effects model, the estimated combined MD was -0.60 min (95% CI: -1.13 to -0.08) and (Z = 2.27, p = 0.02). So HBB in any given dose (10, 20, or 40 mg) did not affect the third stage of labor duration. A forest plot showing the observed outcomes and the estimate based on the random-effects model is shown in Figure 4. The true outcomes appear to be heterogeneous (I² = 86%); Chi² = 141.74, df = 20 (p < 0.001).
Fig. 4. Forest plot showing the observed outcomes and the estimate of the random effects model for the duration of the third stage of labor in HBB RCTs
HBB Concentration:
Different concentrations of HBB have been administrated in reviewed studies. In 2 studies, women in the intervention group get 10 mg (36, 54), 30 studies get 20 mg(3, 20, 32-35, 38-47, 49-51, 56-61, 63-65, 68, 69), and 10 studies get 40 mg(16, 19, 27, 37, 48, 52, 53, 55, 62, 66) HBB by injection (39 studies) or rectal suppository (3 studies)(36, 54, 64). Since HBB only reduces the first stage of labor duration significantly, we use these subgroups' data to investigate whether the HBB effect on the first stage duration is concentration-dependent or not. The result indicated that there is a hetroginty between studies so we used the random effects model; I² = 95%; Chi² 800.74, df = 41 (p < 0.00001).
10-mg HBB:
In 2 studies researchers used 10 mg of HBB in the intervention group (36, 54); these two studies were included in the analysis. These studies' observed MD ranged from -154.29 min to -139.70 min, and all estimates have been negative (100%). The estimated standardized combined MD based on the random-effects model was -147.02 min (95% CI: -161.32 to -132.73) and (Z = 20.15, p = 0.001. So, 10 mg of HBB decreased the first stage of labor duration by 147.02 min. A forest plot showing the observed outcomes and the estimate based on the random-effects model is shown in Figure 2.
20-mg HBB:
In most studies (30 studies), the concentration of 20 mg of HBB has been administrated (3, 20, 32-35, 38-47, 49-51, 56-61, 63-65, 68, 69). These studies' observed MD ranged from -146.00 min to 78.47 min, with most of the estimates being negative (83%). Based on this model, the estimated combined MD was -58.95 min (95% CI: -74.55 to -43.35), (Z = 7.41, p < 0.001). So this results showed that 20 mg HBB decreased the first stage of labor duration by 58.95 min. A forest plot showing the observed outcomes and the estimate based on the random-effects model is shown in Figure 2.
40-mg HBB:
The highest concentration of HBB used in reviewed studies is 40 mg; in 10 studies, this concentration was administrated (16, 19, 27, 37, 48, 52, 53, 55, 62, 66). The observed mean differences of these studies ranged from -171.60 min to -27.20 min, with all estimates being negative. The estimated combined MD based on the random-effects model was -71.60 min (95% CI: -99.83 to -43.37) (Z = 4.97, p = 0.001). According to this combined MD, 40 mg of HBB decreased the first stage of labor duration by 71.60 min. Moreover, these results were shown in Figure 2.
Different concentrations of HBB have been administrated in reviewed studies. In 2 studies, women in the intervention group get 10 mg (36, 54), 30 studies get 20 mg(3, 20, 32-35, 38-47, 49-51, 56-61, 63-65, 68, 69), and 10 studies get 40 mg(16, 19, 27, 37, 48, 52, 53, 55, 62, 66) HBB by injection (39 studies) or rectal suppository (3 studies)(36, 54, 64). Since HBB only reduces the first stage of labor duration significantly, we use these subgroups' data to investigate whether the HBB effect on the first stage duration is concentration-dependent or not. The result indicated that there is a hetroginty between studies so we used the random effects model; I² = 95%; Chi² 800.74, df = 41 (p < 0.00001).
10-mg HBB:
In 2 studies researchers used 10 mg of HBB in the intervention group (36, 54); these two studies were included in the analysis. These studies' observed MD ranged from -154.29 min to -139.70 min, and all estimates have been negative (100%). The estimated standardized combined MD based on the random-effects model was -147.02 min (95% CI: -161.32 to -132.73) and (Z = 20.15, p = 0.001. So, 10 mg of HBB decreased the first stage of labor duration by 147.02 min. A forest plot showing the observed outcomes and the estimate based on the random-effects model is shown in Figure 2.
20-mg HBB:
In most studies (30 studies), the concentration of 20 mg of HBB has been administrated (3, 20, 32-35, 38-47, 49-51, 56-61, 63-65, 68, 69). These studies' observed MD ranged from -146.00 min to 78.47 min, with most of the estimates being negative (83%). Based on this model, the estimated combined MD was -58.95 min (95% CI: -74.55 to -43.35), (Z = 7.41, p < 0.001). So this results showed that 20 mg HBB decreased the first stage of labor duration by 58.95 min. A forest plot showing the observed outcomes and the estimate based on the random-effects model is shown in Figure 2.
40-mg HBB:
The highest concentration of HBB used in reviewed studies is 40 mg; in 10 studies, this concentration was administrated (16, 19, 27, 37, 48, 52, 53, 55, 62, 66). The observed mean differences of these studies ranged from -171.60 min to -27.20 min, with all estimates being negative. The estimated combined MD based on the random-effects model was -71.60 min (95% CI: -99.83 to -43.37) (Z = 4.97, p = 0.001). According to this combined MD, 40 mg of HBB decreased the first stage of labor duration by 71.60 min. Moreover, these results were shown in Figure 2.
Fig. 5. Forest plot showing the observed outcomes and the estimate of the random-effects model for the duration of the first stage of labor in Primipara, Multiparous, and Primipara and Multiparous women
We investigate the effects of previous pregnancy on HBB efficacy in reducing labor duration. A total of 24 studies report data for primipara women and six studies for multiparous women. Studies that didn't specify participants' status were excluded.
Primipara Women:
In 24 studies (3, 16, 19, 32, 35, 38-40, 44, 45, 48, 50-52, 55, 57-60, 64, 66, 69), data for primipara women were reported separately; these studies were included in the analysis. The observed MD of included studies ranged from -146.00 min to 54.49 min, with most estimates being negative (96%). According to the Cochran’s Q test. A hetroginty was appeared in studies (Chi² = 254.35, (p < 0.00001); I² = 92%). The estimated combined MD based on this model was -66.04 min (95% CI: -79.36 to -52.73) and (Z = 9.72, p < 0.001.) According to the results were summarized in Figure 5, HBB decreased the first stage of labor duration by 66.04 min in primipara women.
Multiparous Women:
A total of 6 studies (35, 40, 44, 55, 61, 65) that reported data for multiparous women were included in the analysis. The observed MD ranged from -153.96 min to -32.40 min, with most estimates being negative (100%). The true outcomes appear to be heterogeneous (Tau² = 1372.18; Chi² = 77.41, df = 5 (p < 0.00001); I² = 94%). Based on the random-effects model, the estimated combined MD was -100.61 min (95% CI: -133.04 to -68.18 and p<0.001). So, HBB decreased the first stage of labor duration by 100.61 min in multiparous women (Figure 5).
Promethazine
Promethazine in the First Stage:
A total of 5 RCT studies that use Promethazine to reduce labor duration and met criteria were included in the analysis (3, 26, 67-69). These studies report the first stage duration as the primary outcome. The observed mean differences for these studies ranged from -81.42 min to 65.97 min, with most estimates being negative (60%). The true outcomes appear to be heterogeneous (Tau² = 3974.01; Chi² = 62.01, df = 4 ( p < 0.00001); I² = 94%). The estimated combined MD based on the random-effects model was -12.68 min (95% CI: -70.75 to 45.38), and (Z = 0.43, p = 0.67).
Promethazine in the Second Stage:
Three studies report data for the effect of Promethazine on the second stage duration (67-69). These studies report the second stage duration as the primary outcome. The observed mean differences for these studies ranged from -8.68 min to 7.26 min, with most estimates being negative (77%). The true outcomes appear heterogeneous (Chi² = 5.47, ( p = 0.06); I² = 63%). The estimated combined MD based on the random-effects model was 0.7 min (95% CI: -6.55, 7.96, P=0.85).
Promethazine in the Third Stage:
Only two studies report data for the effect of Promethazine on the third stage duration (68, 69). These studies report the third stage duration as the primary outcome. The observed mean differences for the two studies are -0.03 min to 1.37 min. The true results appear not heterogeneous (Chi² = 1.73, (p = 0.19); I² = 42%). The estimated combined MD based on the fixed-effects model was 0.53 min (95% CI: -0.81, 1.87, p=0.44).
HBB vs Promethazine:
Some RCT studies use HBB and Promethazine in combination with other drugs or alone. The analysis included two studies that compared HBB and promethazine effects on separate groups and met the criteria (3, 68). Studies that combine these drugs or other drugs were excluded from the analysis. These studies report the first stage duration as the primary outcome and include 170 participants. The observed mean for these two studies is -107.40 min and 12.50 min. A hetroginty has appeared between studies (Chi² = 8.24, (p = 0.004); I² = 88%). Considering this, the combined MD was -42.88 min (95% CI: -160.04 to 74.28, P=0.47).
Quality Assessment of the Included Studies:
Based on the Jadad scale, studies get scores from 3 to 8. Most studies (27 studies) have a 6 or 7 score, and two get eight scores. The detailed score for each Study is presented in Table 3 (Supplementary). We considered studies with a score of at least 3 in meta-analysis.
Discussion
Two commonly used drugs to shorten prolonged labor in developing countries are Hyoscine butyl bromide (an anti-spasmodic medicine) and Promethazine (Histamine H1 receptor antagonist). Several RCT studies have investigated these drugs' efficacy in reducing the active phase of labor duration (3, 16, 19, 25, 34-49, 51, 58, 59, 61-66, 69-75). We conduct this systematic review and meta-analyze to determine the benefit of using these drugs for decreasing labor duration. After a systematic search, we selected 30 studies that meet the inclusion criteria. Among studies, 44 studies administered HBB, two used Promethazine, and three used both in different intervention groups to compare their effectiveness.
The studies were conducted in Iran (15 studies), India (8 studies), Nigeria (6 studies), Egypt (6 studies), Iraq (2 studies), Bahrain (1 study), Kenya (1 study), Mexico (1 study), Saudi Arabia (1 study), Spain (1 study), Tanzania (1 study), Turkey (1 study), which all except Spain, are developing countries. The meta-analysis results regarding the effectiveness of HBB on labor stages showed that HBB shortened the first stage of labor by 66.75 min compared to placebo groups. This reduction is 147.02 min for two studies that use 10 mg HBB (36, 54), and 20 mg and 40 mg doses, shortening the labor first stage duration by 58.95 and 71.60 minutes, respectively. However, 10 mg seems more effective, but because only two studies use this dose, we can't tell if the HBB effect is dose-dependent. On the other hand, Promethazine reduces the first stage duration by 12.68, but it isn't statistically significant (Z = 0.43 (p = 0.67)). Among Promethazine studies, Shahmohammadi (69) and Ebrahimzade-Zagami (3) report the highest reduction (81.42 and 78.60 min); however, two studies (67, 68) report an increase in the first stage duration of the intervention group (21.88 min and 65.97 min increase in duration respectively).
The HBB reduces the second and third stages of labor by 3.27 min (Z = 1.93, p = 0.05)) and 0.6 min (Z = 2.27, p = 0.02), which are not statistically nor clinically significant. Promethazine increases the duration of the second (0.7 min increase, Z = 0.19 (p = 0.85)) and third (0.53 min increase, Z = 0.77 (p = 0.44)) stages of labor. However, it's not statistically significant. Indeed, we can see that HBB reduces labor duration mainly by affecting the first stage of labor, so we do a subgroup analysis based on first-stage data. We didn't include its data in further analysis because we couldn't find an overall significant effect of Promethazine in any delivery stages.
Next, we consider the participant's pregnancy history effect on HBB efficacy by analyzing 21 studies that report data per parities (3, 16, 19, 32, 35, 38-40, 44, 45, 48, 50-52, 55, 57, 60, 64, 66, 67, 69). Four studies report data for primipara and multiparous women separately, so we use each group's data in specific subgroups (35, 40, 44, 55). We reviewed 23 studies with 1313 primipara women in the HBB intervention group and 1321 in the control group (3, 16, 19, 32, 35, 38-40, 44, 45, 48, 50-52, 55, 57-60, 64, 66, 67, 69). HBB was found to reduce the duration of the first stage of labor in primipara women by 66.04 min (Z = 9.72 (p < 0.00001)). We use six studies with 336 multiparous women in the HBB intervention group and 324 in the control group for the multiparous subgroup (35, 40, 44, 55, 61, 65). The HBB reduces the first stage duration by 100.61 min (Z = 6.08 (p < 0.00001)). Time reduction in studies that didn't represent separate data for primipara and multiparous women is close to the primipara group (70.37 min, Z = 4.44 (p = 0.00001)). So HBB is more effective in multiparous women compared to primipara women. A recent study by Yousef 2022 found that HBB reduced the duration of the first stage duration in both augmented and non-augmented participants, with a more significant effect on multigravida than primigravida. This study also demonstrated that the average duration of the active first stage of labor was 206.51 minutes in the HBB group compared to 267 minutes in the placebo group (mean difference= 61.44 minutes), which is statistically significant. HBB is an effective and safe drug for reducing the duration of the active first stage of labor (76,77).
One of the main factors in the first stage of labor duration is cervical dilatation; all included studies report the administration time of HBB at 3–4 cm and don't report cervical dilatation rate after administration, so we couldn't involve this factor in the analysis. Two studies use HBB and Promethazine in two separate intervention groups (3, 68). We use these studies to compare HBB and Promethazine directly. The analysis shows that HBB reduces the first stage duration by 42.88 min compared to Promethazine; however, the effect is not statistically significant (Z = 0.72 p = 0.47). More studies are needed to report accurate results in this regard. We have several limitations here; most studies report comprehensive participant data and don't report subgroup data. All studies report participant age as the mean± SD age, and we couldn't include participants' age in the analysis.
Conclusions
HBB administration reduces labor duration mainly by affecting the first stage of labor. HBB is more effective in multiparous women compared to primipara women. Since 20 mg and 40 mg of HBB both have the same effectiveness, we recommend using 20 mg to minimize side effects in the mother and infant. On the other hand, Promethazine does not reduce total labor duration or any stages of labor, so its use is not recommended.
Abbreviations
MD: Mean Difference
SID: Scientific Information Database
CI: Confidence Interval
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses
IG: Intervention Group
CG: Control Group
GA: Gestational Age
HBB: Hyoscine N-Butyl Bromide
Dil: Dilation
FS: First-Stage
SS: Second Stage
TS: Third Stage
PP: Primipara
MP: Multipara
NS: Normal Saline
RCT: Randomized Clinical Trial
HR: Hours
Min: Minutes
IM: Intra Muscular
IV: Intravenously
DW: Distilled Water
NS: Not Specified
HP: Hugo Poin
Acknowledgments
None
Conflicts of interest
The authors declared no conflicts of interest.
Authors' Contributions
MJ, FH, MK, and MA contributed substantially to the design of the study. MJ and FH contributed to data collection. MS had roles in data interpretation. MJ and PY wrote the initial draft and MS critically and substantially revised the final article. All authors reviewed critically and approved the manuscript.
Funding/support
No external or intramural funding was received
Supplementary Material
Table 1: Characteristics of the included studies with Hyoscine N-butyl-bromide intervention
Table 2: Characteristics of the included studies with promethazine intervention
Table 3: Quality assessment of the selected studies was presented according to the Jadad score calculation
Type of Study: orginal article |
Subject:
Medical Informatics
References
1. Waters BL, Raisler J. Ice massage for the reduction of labor pain. J Midwifery Womens Health 2003;48(5):317-21. [DOI:10.1016/S1526-9523(03)00277-0] [PMID]
2. Aziz M. Effect of rectal Hyoscine Butylbromide suppositories on the first stage of labor. Int J Adv Res 2014;2(4):128-35. [URL]
3. Ebrahimzadeh Zagami S, Golmakani N, Saadatjoo SA-R, Dadgar S, Baghbani B. Comparison of effects of hyoscine n-butyl bromide and promethazine on length of active phase of first stage of labor. Iran J Obstet Gynecol Infertil 2012;15(6):16-21. [Google Scholar]
4. McCarthy M. What's going on at the World Health Organization? Lancet 2002;360(9340):1108-10. [DOI:10.1016/S0140-6736(02)11243-8] [PMID]
5. Neilson J, Lavender T, Quenby S, Wray S. Obstructed labour: reducing maternal death and disability during pregnancy. Br Med Bull 2003;67(1):191-204. [DOI:10.1093/bmb/ldg018] [PMID]
6. Laughon SK, Berghella V, Reddy UM, Sundaram R, Lu Z, Hoffman MK. Neonatal and maternal outcomes with prolonged second stage of labor. Obstet Gynecol 2014;124(1):57. [DOI:10.1097/AOG.0000000000000278] [PMID] []
7. Zipori Y, Grunwald O, Ginsberg Y, Beloosesky R, Weiner Z. The impact of extending the second stage of labor to prevent primary cesarean delivery on maternal and neonatal outcomes. Am J Obstet Gynecol 2019;220(2):e1-e7. [DOI:10.1016/j.ajog.2018.10.028] [PMID]
8. Myles TD, Santolaya J. Maternal and neonatal outcomes in patients with a prolonged second stage of labor. Obstet Gynecol 2003;102(1):52-8. [DOI:10.1016/S0029-7844(03)00400-9] [PMID]
9. Allen VM, O'Connell CM, Baskett TF. Maternal and perinatal morbidity of caesarean delivery at full cervical dilatation compared with caesarean delivery in the first stage of labour. BJOG: Int J Obstet Gynaecol 2005;112(7):986-90. [DOI:10.1111/j.1471-0528.2005.00615.x] [PMID]
10. Allen VM, Baskett TF, O'Connell CM, McKeen D, Allen AC. Maternal and perinatal outcomes with increasing duration of the second stage of labor. Obstetr Gynecol 2009;113(6):1248-58. [DOI:10.1097/AOG.0b013e3181a722d6] [PMID]
11. Sandström A, Altman M, Cnattingius S, Johansson S, Ahlberg M, Stephansson O. Durations of second stage of labor and pushing, and adverse neonatal outcomes: a population-based cohort study. J Perinatol 2017;37(3):236-42. [DOI:10.1038/jp.2016.214] [PMID] []
12. Kolås T, Hofoss D, Daltveit AK, Nilsen ST, Henriksen T, Häger R, et al. Indications for cesarean deliveries in Norway. Am J Obstet Gynecol 2003;188(4):864-70. [DOI:10.1067/mob.2003.217] [PMID]
13. Mollart LJ, Adam J, Foureur M. Impact of acupressure on onset of labour and labour duration: A systematic review. Women Birth 2015;28(3):199-206. [DOI:10.1016/j.wombi.2015.03.007] [PMID]
14. Ranjbaran M, Khorsandi M, Matourypour P, Shamsi M. Effect of massage therapy on labor pain reduction in primiparous women: A systematic review and meta-analysis of randomized controlled clinical trials in Iran. Iran J Nurs Midwifery Res 2017;22(4):257. [DOI:10.4103/ijnmr.IJNMR_109_16] [PMID] []
15. Shwetha B, Subramanian S, Solanke P. A study of the effects of drotaverine hydrochloride and hyoscine butylbromide in the acceleration of the first stage of labour in primigravidae at SMIMS. J Evid Based Med Healthc 2016;3:1166. [DOI:10.18410/jebmh/2016/267] [PMID]
16. Kandil MA, Sayyed TM, El-Mallah EM, Rezk MA, Zidan HM. Hyoscine butylbromide for shortening of the first stage of labor in primigravid women. Menoufia Medical Journal. 2017;30(2):350. [DOI:10.4103/1110-2098.215455]
17. Weiser T, Just S. Hyoscine butylbromide potently blocks human nicotinic acetylcholine receptors in SH-SY5Y cells. Neurosci Lett 2009;450(3):258-61. [DOI:10.1016/j.neulet.2008.12.004] [PMID]
18. Aggarwal P, Zutshi V, Batra S. Role of hyoscine N-butyl bromide (HBB, buscopan®) as labor analgesic. Ind J Med Sci 2008. [DOI:10.4103/0019-5359.40982] [PMID]
19. Al Qahtani NH, Al Hajeri F. The effect of hyoscine butylbromide in shortening the first stage of labor: a double blind, randomized, controlled, clinical trial. Ther Clin Risk Manag 2011;7:495. [DOI:10.2147/TCRM.S16415] [PMID] []
20. Gupta B, Nellore V, Mittal S. Drotaverine hydrochloride versus hyoscine-N-butylbromide in augmentation of labor. Int J Gynaecol Obstet 2008;100(3):244-7. [DOI:10.1016/j.ijgo.2007.08.020] [PMID]
21. Ashmawi HA, Braun LM, Sousa AM, Posso IdP. Analgesic effects of H1 receptor antagonists in the rat model of formalin-induced pain. Rev Bras Anestesiol 2009;59:461-70. [DOI:10.1590/S0034-70942009000400008] [PMID]
22. Southard BT, Al Khalili Y. Promethazine. StatPearls [Internet]. 2021. [] [PMID]
23. Saat SS, Haji AM, Basirat Z, Nazari R, Beheshti Z. Comparison of atropine-promethazine combination and pethidine effects on active phase of labor. J Babol Univ Med Sci 2007. [Google Scholar]
24. Kashanian M, Shahali S. Effects of acupressure at the Sanyinjiao point (SP6) on the process of active phase of labor in nulliparas women. J Matern Fetal Neonatal Med 2010;23(7):638-41. [DOI:10.3109/14767050903277662]
25. Payandeh M, Nahidi F, Nasiri M, Fouladi A. Comparing the effects of transcutaneous electrical nerve stimulation and pharmaceutical hyoscine-promethazine compound on duration of second phase of labor. Iran J Obstetr Gynecol Infertil 2019;22(8):19-25. [DOI:10.34172/mj.2019.042]
26. Rabiei S, Shabani M. A comparative study of the effect of atropine and promethazine on the labor process. J Sabzevar Univ Med Sci 2001. [URL]
27. Ibrahim R, Nwobodo E, Tunau K, Burodo A, Sulaiman B, Garba J, et al. The effect of hyoscine butyl bromide in shortening the duration of first stage of labor: A single blind randomized control study. Trop J Obstet Gynaecol 2019;36(1):28-32. [DOI:10.4103/TJOG.TJOG_57_18]
28. Halpern SH, Douglas MJ. Appendix: Jadad scale for reporting randomized controlled trials. Evidence-based Obstetric Anesthesia Oxford, UK: Blackwell Publishing Ltd. 2005:237-8. [DOI:10.1002/9780470988343.app1]
29. Berger VW, Alperson SY. A general framework for the evaluation of clinical trial quality. Rev Recent Clin Trials 2009;4(2):79-88. [DOI:10.2174/157488709788186021] [PMID] []
30. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17(1):1-12. [DOI:10.1016/0197-2456(95)00134-4] [PMID]
31. Oremus M, Wolfson C, Perrault A, Demers L, Momoli F, Moride Y. Interrater reliability of the modified Jadad quality scale for systematic reviews of Alzheimer's disease drug trials. Dement Geriatr Cogn Disord 2001;12(3):232-6. [DOI:10.1159/000051263] [PMID]
32. Iravani M, Bekhradi Nasab H. Study of the effects of intravenous injection of hyoscine on parturition (labor). SSU_J 2006;13(5):59-64. [Google Scholar]
33. Samuels LA, Christie L, Roberts-Gittens B, Fletcher H, Frederick J. The effect of hyoscine butylbromide on the first stage of labour in term pregnancies. BJOG: Int J Obstet Gynaecol 2007;114(12):1542-6. [DOI:10.1111/j.1471-0528.2007.01497.x] [PMID]
34. Abdullah SCKN, Kant B, Azhar T. The effect of hyoscine butylbromide on 1st stage of labour in term pregrencacy. Pak Armed Forces Med J 2010;60(2):278-81. [Google Scholar]
35. Al-Khishali W, Rasheed F, Hussain S. The effect of 20 mg hyoscine butylbromide on Normal labor in Iraqi Primi-and multi-gravida women. J Adv Sci Res 2012;3(4):70e3. [Google Scholar]
36. Kirmani SA, Malla MS. Efficacy of drotaverine in comparison to hyoscine butylbromide in augmentation of labour. J Med Sci 2012;15(1):39-43. [DOI:10.33883/jms.v15i1.107]
37. Alani H, Salim RT. The effect of hyoscine N-butyl bromide on the duration of active phase of labor. Zanco J Med Sci 2013;17(3):549-55. [DOI:10.15218/zjms.2013.0047]
38. Nagi M, Mostafa M, Farid E, Abbas M. Does hyoscine butylbromide (spasmocin) shorten the first stage of labour in term pregnancies? J Evid-Based Women Health J Soc 2014;4(1):52-4. [DOI:10.1097/01.EBX.0000440889.54205.68]
39. Edessy M, EL-Darwish A, Nasr A, Ali A, El-Katatny H, Tammam M. Different modalities in first stage enhancement of labor. Gen Health Med Sci 2015;2(1):1-4. [Google Scholar]
40. Kirim S, Asicioglu O, Yenigul N, Aydogan B, Bahat N, Bayrak M. Effect of intravenous hyoscine-N-butyl bromide on active phase of labor progress: a randomized double blind placebo controlled trial. J Matern-Fetal Neonatal Med 2015;28(9):1038-42. [DOI:10.3109/14767058.2014.942628] [PMID]
41. Srivastava K, Sinha P, Sharma R, Gupta U. A comparative study of the effect of drotaverine hydrochloride with hyoscine butylbromide in first stage of labor. Int J Basic Clin Pharmacol 2015;4(3):488-91. [DOI:10.18203/2319-2003.ijbcp20150025]
42. Treviño-Salinas EM, Castillo-Martín del Campo GE, Ayuzo-del Valle C, Guzmán-López A, Soria-López JA, Iglesias-Benavides JL, et al. Effect of hyoscine butylbromide on cervical dilation during labor. Medicina Universitaria 2015;17(66):30-3. [DOI:10.1016/j.rmu.2015.01.001]
43. Akinbile To. Effects of Intravenous Hyoscine Butylbromide On Labour Outcome And Its Safety Among Parturients In Lautech Teaching Hospital Ogbomoso, Nigeria. Nigeria Fac Obstetr Gynaecol 2016.
44. Changede PR, Tank P. The effect of Hyoscine butyl bromide on the duration and course of labor. Indian J Obstet Gynecol Res 2016;3(2). [DOI:10.5958/2394-2754.2016.00041.2]
45. Jamilian M, Karamali M, Sadeghi B, Ghazi Mirsaeed M. The effect of intramuscular administration of atropine and hyoscine combination on labor progress and maternal and neonatal outcomes in primigravid women. Iranian Journal of Neonatology Iran J Nurs 2016;7(1):13-8. [Google Scholar]
46. Narappagari SR. Effect of hyoscine butylbromide (buscopan) as cervical spasmolytic agent in labour. J Evol Med Dent Sci 2016;5(90):6670-5. [DOI:10.14260/Jemds/2016/1509]
47. Imaralu JO, Kuti O, Badejoko OO, Loto OM, Olaleye A. Effect of hyoscine butyl-bromide on the duration of active phase of labor: A randomized-controlled trial. Taiwan J Obstet Gynecol 2017;56(6):725-30. [DOI:10.1016/j.tjog.2017.10.003] [PMID]
48. Pahlavani-Sheikhi Z, Razavi M. Hyoscine-N-butylbromide effect on the acceleration of labor and postpartum hemorrhage in primigravida women. Feyz J 2017;21(3):218-23. [Google Scholar]
49. Barau DD, Agida ET, Onafowokan O, Adebayo FO. Effect of Hyoscine Butyl Bromide on the Course of Labour. Open J Obstetr Gynecol 2018;08(12):1102-8. [DOI:10.4236/ojog.2018.812111]
50. El-Sherbini M, Helal O, Zaki M, Sherif S. The Effect of Intramuscular Administration of Dexamethasone Alone or in Combination with Hyoscine Butylbromide in Shortening the duration of Induced Labor in Primigravidas. Med J Cairo Univ 2018;86(September):2335-40. [DOI:10.21608/mjcu.2018.57534]
51. Maddady SM, Mohammad-Alizadeh-Charandabi S, Shafaei FS, Mirghafourvand M. Comparing the effects of hot shower and intravenous injection of hyoscine on the pain intensity and duration of active phase of labour in nulliparous women. J Clin Diagn Res 2018;12(8):QC07-QC11. [DOI:10.7860/JCDR/2018/35508.11950]
52. Maged AM, Mosaad M, AbdelHak AM, Kotb MM, Salem MM. The effect of hyoscine butylbromide on the duration and progress of labor in primigravidae: a randomized controlled trial. J Matern Fetal Neonatal Med 2018;31(22):2959-64. [DOI:10.1080/14767058.2017.1359828] [PMID]
53. Laura Tarrats IN, Isabel Paez, Sandra Cabrera. Hyoscine Butylbromide for Cervical Rigidity in the First Stage of Labor: Randomized Clinical Trial. Gynecol Obstetr 2019;9(3):6. [URL]
54. Namdeo TA, Jeevitha KJ, Ganapathy P. Effect of hyoscine-nbutyl bromide (Buscopan) rectal suppository in active phase of labour in primigravida. Obs Gyne Review: J Obstetr Gynecol 2019;5(3):2-6. [DOI:10.17511/joog.2019.i03.04]
55. Ejikeme TB, Eleje GU, Igberase GO, Ugwu EO, Ikwuka DC, Okpala BC. A double-blind placebo-controlled randomized trial on the effect of hyosine n-butyl bromide for improving duration of labor in term pregnancies. J Obstet Gynaecol Res 2020;46(6):890-8. [DOI:10.1111/jog.14251] [PMID]
56. Kinyina A, Chamos S, Lyimo GS. Effect of Hyoscine Butylbromide in Shortening the Active Phase of the First Stage of Labor in Term Pregnant Women. 2020. [DOI:10.38124/IJISRT20AUG570]
57. Akiseku AK, Jagun OE, Akadri AA, Imaralu JO, Olatunji AO, Sule-Odu AO. Effect of hyoscine-N-butylbromide on labor duration among nullipara in a southwestern Nigerian teaching hospital: A randomized controlled trial. Int J Gynaecol Obstet 2021;153(2):254-9. [DOI:10.1002/ijgo.13444] [PMID]
58. Namazian E, Mokhtari F. The effect of hyoscine in labor process of primiparous women (A Clinical Trial Study). Iran J Obstet Gynecol Infertil 2017;19(38):57-65. [Google Scholar]
59. Azary M, Nasiri E, Molod S, Manavi M, Azezzadh R. The Effect of combination atropine and hyoscine progress of delivery in primiparous women in Ardabil-Alavi hospital 2008. J Ardabil Univ Med Sci 2008;8(4):351-5. [Google Scholar]
60. Topraghlou SB, Shafaie FS, Mirghafourvand M, Salehi N. Comparing the Effects of Acupressure at the Hugo Point and Hyoscine on the Duration of Labor Stages and Fetalneonatal Outcomes in Nulliparous Women: A Controlled Randomized Clinical Trial. Int J Womens Health Reprod 2009;7(3):393-9. [DOI:10.15296/ijwhr.2019.64]
61. Kausar U, Siddiqui N. To compare the efficacy of Drotaverine Hydrochloride with Hyoscine Butyl bromide for increasing the rate of cervical dilatation. Int J Reprod Contracept Obstet Gynecol 2017;6(4):1615. [DOI:10.18203/2320-1770.ijrcog20171438]
62. Shirazi M, Shahbazi F, Akhavan S, Sharifi Taskooh M, Azadi F. Hyoscine-N-Butylbromide and Progression of Labor at Different Stages. J Obstet Gynecol Cancer Res 2016;1(3):0-0. [DOI:10.17795/ojcr-9532]
63. Bashir S, Mushtaq R. Effect of hyosine butylbromide on first stage of labour in term pregnancy. Pak Armed Forces Med J 2016;66(4):485-89. [Google Scholar]
64. Makvandi S, Tadayon M, Abbaspour M. Effect of hyoscine-N-butyl bromide rectal suppository on labor progress in primigravid women: randomized doubleblind placebo-controlled clinical trial. Croat Med J 2011;52(2):159-63. [DOI:10.3325/cmj.2011.52.159] [PMID] []
65. Sekhavat L, Karbasi S, Fallah R, Mirowliai M. Effect of hyoscine butylbromide first stage of labour in multiparus women. Afr Health Sci 2012;12(4):408-11. [DOI:10.4314/ahs.v12i4.1] [PMID] []
66. Akleh HE, Al-Jufairi ZA. Effect of Hyoscine-N-Butyl Bromide (Buscopan) in accelerating first stage of labor. J Bahrain Med Soc 2010;22(3):103-7. [Google Scholar]
67. Delaram M, Aein F, Nasimi A, Forouzandeh N, Danesh A. The effect of Atropine and Promethazine on the labor process and Apgar score of infants. J Shahrekord Univ Med Sci 2002. [Google Scholar]
68. Mortazavi F, Rakhshani M. The effect of Atropine, Hyoscine and Promethazine on the duration of labor stages and rate of labor progress in multiparous women. J Gorgan Univ Med Sci 2004;6(2):92-6. [Google Scholar]
69. Shahmohammadi F. The effect of intramascular Hyoscine and Hyoscine-Promethazine on the duration of labour and delivery outcomes to nulliparous pregnant women (triple-blind randomize control trial): Tabriz University of Medical Sciences, School of Nursing and Midwifery; 2016. [PMID]
70. Tytgat GN. Hyoscine butylbromide - a review on its parenteral use in acute abdominal spasm and as an aid in abdominal diagnostic and therapeutic procedures. Curr Med Res Opinion 2008;24(11):3159-73. [DOI:10.1185/03007990802472700] [PMID]
71. Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw 2010;36(3):47. [DOI:10.18637/jss.v036.i03]
72. Viechtbauer W, Cheung MW. Outlier and influence diagnostics for meta-analysis. Res Synth Methods 2010;1(2):13. [DOI:10.1002/jrsm.11] [PMID]
73. Riley RD, Higgins JP, Deeks JJ. Interpretation of random effects meta-analyses. Br Med J 2011;342. [DOI:10.1136/bmj.d549] [PMID]
74. Fardiazar Z, Niknami F, Mashayekhi S, Ghojazadeh M. Hyoscine-N-butylbromide versus atropine as labour accelerant and analgesic: a randomized clinical trial. Pak J Biol Sci 2013;16(9):443-5. [DOI:10.3923/pjbs.2013.443.445] [PMID]
75. Golmakani N, Ebrahimzade S, Saadatjoo A, Dadgar S, Baghani B. Comparative effect of Hyoscine and Promethazine. Q Horiz Med Sci 2013;18(5):266-7. [Google Scholar]
76. Yadollahi P, Taghizdeh Z, Ebadi A, Khormaei F. Development and validation of the perception of labor pain questionnaire among Iranian women. Int J Comm Based Nurs Midwifery 2019;7(2):128. [PMID]
77. Yousuf S. Is Hyosine Butylbromide a Good Choice for Shortening Labour Duration? J Soc Obstet Gynaecol Pak 2022;12(3):215. [Google Scholar]
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