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Drotaverine to improve progression of labor among nulliparous women
International Journal of Gynecology and Obstetrics 124 (2014) 112–117
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CLINICAL ARTICLE
Drotaverine to improve progression of labor among nulliparous women Moustafa I. Ibrahim a, Hazem A. Alzeeniny a, Mohamed I. Ellaithy a,⁎, Ahmed H. Salama a, Mohammed A. Abdellatif b a b
Department of Obstetrics and Gynecology, Ain-shams Faculty of Medicine, Cairo, Egypt Department of Obstetrics and Gynecology, Sohag Teaching Hospital, Sohag, Egypt
a r t i c l e
i n f o
Article history: Received 1 May 2013 Received in revised form 10 August 2013 Accepted 29 October 2013 Keywords: Cervical dilatation rate Drotaverine hydrochloride Nulliparous
a b s t r a c t Objective: To reevaluate the role of the antispasmodic drug drotaverine in shortening the length of the active first stage of labor among nulliparous women. Methods: In a randomized, double-blind, placebo-controlled trial, 422 young nulliparous women admitted to Ain-shams University Maternity Hospital, Cairo, Egypt, in spontaneous labor were initially enrolled between May and December 2012. Drotaverine hydrochloride (40 mg) or placebo was given at the start of the active phase of labor and then repeated every 2 hours (maximum 3 doses). All participants were consistently managed in accordance with the local institutional intrapartum protocol. The primary outcome was the rate of cervical dilation. Results: After excluding women who delivered by cesarean, data were analyzed from 320 women. There was a significant difference in post-treatment labor pain scores, duration of the active phase of labor, and rate of cervical dilatation between the 2 groups (P b 0.001 for all). There was no difference in maternal adverse effects. Kaplan–Meier survival analysis showed a greater probability of faster delivery among patients treated by drotaverine hydrochloride (log rank test; P b 0.001). Conclusion: Drotaverine hydrochloride was used effectively and safely to shorten the duration of the first stage of labor among nulliparous women with active spontaneous labor. ClinicalTrials.gov: NCT01639027. © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Minimizing the duration of labor without compromising fetomaternal wellbeing is a desirable outcome in all labor and delivery units [1]. Prolonged labor has been associated with higher rates of neonatal admission to the intensive care unit [2], and is likely to increase the work burden, especially in busy labor wards, with consequent inadequacy of obstetric care [3]. Hirsch [4] first described the use of antispasmodic drugs to shorten the first stage of labor in 1937: he reported that labor duration could be decreased by 2–4 hours by using an atropine-like drug. Antispasmodic drugs can aid faster cervical dilatation of the cervix during labor via neurotropic and/or musculotropic effects [5]. Drotaverine is a musculotropic agent—an inhibitor of type IV phosphodiesterase (PDE)—that is structurally related to papaverine. It has mild calcium channel blocking activity but no anticholinergic effects and acts directly on smooth muscle cells, inhibiting spasm [6]. A recent Cochrane review [7] found low quality evidence that antispasmodic drugs reduce the duration of first stage of labor and increase the cervical dilatation rate; very low quality evidence that they reduce the total duration of labor; and insufficient evidence to make any conclusion about the safety of these medications. It was ⁎ Corresponding author at: Building 14, Block 14, Alwaha District, Nasr City, Cairo, Egypt. Tel.: +20 1006873417. E-mail addresses: [email protected], [email protected] (M.I. Ellaithy).
therefore advised that large, well-designed, randomized controlled trials are needed to evaluate the role of antispasmodic drugs in the management of labor [7]. The aim of the current study was to reevaluate the safety and efficacy of using the antispasmodic drotaverine to reduce the duration of the active first stage of labor among nulliparous women being managed by a standard intrapartum protocol. 2. Materials and methods The present randomized, double-blind, placebo-controlled trial was conducted among young nulliparous women admitted in spontaneous active labor to the Labor and Delivery Unit of Ain-shams University Maternity Hospital, Cairo, Egypt (annual number of deliveries 12 000–18 000), between May 11 and December 17, 2012. The study was approved by the local institutional ethics and research committee. Written signed informed consent was obtained from all participants before any study-specific procedure was performed. Women were considered eligible to participate in the study if they had a singleton term pregnancy with a vertex presentation, occipitoanterior position, and cervical dilatation of 3–5 cm. The presence of 1 or more of the following was considered sufficient to exclude women from the study: prepartum hemorrhage, placenta previa, prior uterine scar, cephalopelvic disproportion, use of labor-inducing agent, contraindication for vaginal delivery, non-reassuring fetal status, hypersensitivity to drotaverine hydrochloride, prior cervical surgery,
0020-7292/$ – see front matter © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijgo.2013.08.013
M.I. Ibrahim et al. / International Journal of Gynecology and Obstetrics 124 (2014) 112–117
use of antihypertensive therapy, or use of spasmolytic agents within the past 48 hours. Gestational age was calculated at the time of enrollment according to the Naegele rule and confirmed by reviewing early pregnancy ultrasound scans. Active labor was diagnosed by the presence of regular uterine contractions (each lasting for 30 seconds or more) at a rate of at least 3 every 10 minutes, with or without rupture of membranes. Eligible participants were randomly assigned to receive a slow intravenous injection via a syringe prefilled with 2 mL of either drotaverine hydrochloride or placebo during management of the first stage of labor. Randomization was performed via a computer-generated sequence: the randomization list was held in a secure box in the labor ward and the participants were assigned to their groups by using sequentially numbered opaque sealed envelopes that were opened at enrollment. The syringes were masked with black opaque stickers so that the yellowishcolored drotaverine hydrochloride was undistinguishable from the translucent saline solution. Women assigned to the intervention group received intravenously 40 mg of drotaverine hydrochloride (2-mL ampules, 40 mg/ampule; Do-Spa, Alexandria Pharmaceutical and Chemical Industries, Awayed, Alexandria, Egypt), whereas women assigned to the placebo group received intravenously 2 mL of normal saline (0.9% sodium chloride).
Enrollment
An injection was given at the start of the active phase of labor and repeated every 2 hours for a maximum of 3 doses if full cervical dilatation did not happen. All participants were consistently managed according to the local institutional intrapartum protocol and received identical monitoring and supportive care. Before being enrolled, all participants were thoroughly assessed to confirm eligibility and to exclude allergy to drotaverine hydrochloride and/or any contraindication for vaginal delivery. The presence of normal fetal heart rate pattern and assessment of uterine activity were assured via cardiotocography for 30 minutes before the intervention was started. Intrapartum fetal monitoring was performed via intermittent auscultation for low-risk women and continuous electronic fetal monitoring for high-risk women. Vaginal examination was performed every 2 hours, unless clinically indicated, to define the progress of cervical dilatation. Artificial rupture of fetal membranes was considered for women with intact membranes if there was poor progress of labor (cervical dilatation, b1 cm/hour). Oxytocin, if needed, was begun 2 hours after rupture of fetal membranes via a low-dose titration approach with a starting dose of 2 mU/minute and increments of 2 mU/minute every 15 minutes until adequate uterine contractions were achieved
Assessed for eligibility (n=1126) Nulliparous women admitted in labor during the study period
Excluded (n=704) Contraindication to vaginal delivery (n=141) Induced labor (n=223) Cervical dilatation >5 cm (n=87) Gestational age <37 weeks (n=103) Twins (n=21) Others (n=129)
Eligible women (n=422)
Excluded (n=70) Declined to participate
Allocation Received drotaverine (n=176)
Received placebo (n=176)
Analysis Analyzed (n=161) Excluded from analysis (cesarean delivery before full cervical dilatation) (n=15)
113
Analyzed (n=159) Excluded from analysis (cesarean delivery before full cervical dilatation) (n=17)
Fig. 1. Flow of participants through the study.
114
M.I. Ibrahim et al. / International Journal of Gynecology and Obstetrics 124 (2014) 112–117
or the maximum dose (32 mU/minute) was reached. The intrapartum fetal heart rate pattern and uterine contractions were interpreted in accordance with ACOG guidelines [8,9]. A partogram was used to document the progress of labor and the duration of the first stage of labor to determine the study endpoints. The primary outcome was the rate of cervical dilation; secondary outcomes included the duration of the active first stage of labor (from first injection to full cervical dilatation), mode of delivery, Apgar score of less than 7 at 1 and 5 minutes, maternal drug adverse effect, and pain assessment via visual analog scale recorded before and after the injected solution at 30, 60, and 120 minutes. The required study sample size was estimated via G*Power version 3.1.0 (Institut für Experimentelle Psychologie, Heinrich Heine Universität, Düsseldorf, Germany). The study sample size was calculated on the basis of the duration of the first stage of labor because this calculation yielded the highest sample size; this powered the study sufficiently to assess many outcomes, including the primary outcome of the study, which was the rate of cervical dilatation. It was estimated that a sample size of 160 women in each group would have a power of 80% to detect an effect size (d) of 0.3. The test used was the 2-sample t-test and significance was targeted at an α error of 0.05. The sample size was increased by 10% to compensate for post-randomization exclusions related to performing cesarean delivery in the first stage of labor. Statistical analysis was done via SPSS version 19 (IBM, Armonk, NY, USA). Quantitative variables were described as mean ± SD or median (interquartile range; IQR) as appropriate. Qualitative variables were described as number and percentage. Qualitative variables were compared between the 2 groups by χ2 test; quantitative variables were compared by an independent sample t-test for parametric data and by Mann–Whitney test for non-parametric data. A P value of less than 0.05 was considered to be statistically significant. A Kaplan–Meier survival analysis was used to detect the probabilities of faster delivery with the use of drotaverine hydrochloride and placebo. The 2 curves were compared via a log rank test. 3. Results During the study period, 422 young nulliparous women were eligible for participation in the study. Seventy women refused consent; as a result, 176 women were allocated to the drotaverine group and 176 to the placebo group. After excluding women who delivered by cesarean, the final statistical analysis included 320 women (Fig. 1). The mean maternal age of participants was 23.8 ± 3.6 years, and the mean gestational age at the time of enrollment was 38.5 ± 1.1 weeks. The mean duration of the active phase was 160.3 ± 66.4 minutes, and the median rate of cervical dilatation was 2.11 cm/hour (IQR, 1.75–2.67). The median Apgar score at 1 minute was 8 (IQR, 8–9), the median Apgar at 5 minutes was 9 (IQR, 9–9). In the drotaverine group, the median number of doses administered was 2 (IQR, 1–2).
Table 2 Comparison of study outcomes between the drotaverine and placebo groups.a Outcome
Oxytocin augmentation Meperidine hydrochloride Labor pain (VAS) after 30 min Labor pain (VAS) after 60 min Labor pain (VAS) after 120 min Cervical dilatation rate, cm/h First-stage duration, min Second-stage duration, min Third-stage duration, min Normal vaginal delivery Ventouse-assisted delivery Forceps-assisted delivery Second-stage cesarean delivery Blood loss, mL Cervical lacerations Fetal distress Apgar score at 1 mi Apgar score at 5 min Meconium-stained liquor NICU admission Neonatal birth weight, g
Study group
P value
Drotaverine (n = 161)
Placebo (n = 159)
101 (62.7) 96 (59.6) 5 (4–7) 3 (2–5) 8 (6–9) 2.7 (2.4–3.0) 120.7 ± 53.2 42.2 ± 22.3 9.1 ± 1.5 145 (90.1) 4 (2.5) 2 (1.2) 10 (6.2) 349 ± 97 3 (1.9) 4 (2.5) 8 (8–9) 9 (9–9) 5 (3.1) 4 (2.5) 2903 ± 354
96 (60.4) 113 (71.1) 9 (7–9) 9 (8–10) 10 (9–10) 1.8 (1.6–2.0) 200.8 ± 79.8 38.7 ± 20.8 8.9 ± 1.6 144 (90.1) 5 (3.1) 1 (0.6) 9 (5.7) 367 ± 88 2 (1.3) 6 (3.8) 8 (8–9) 9 (8–9) 4 (2.5) 4 (2.5) 2876 ± 298
0.73 0.035 b0.001 b0.001 b0.001 b0.001 b0.001 0.15 0.25 N0.99 0.75 N0.99 N0.99 0.083 N0.99 0.54 0.6 0.44 N0.99 N0.99 0.46
Abbreviations: NICU, neonatal intensive care unit; VAS, visual analog scale. a Values are given as mean ± SD, median (interquartile range), or number (percentage) unless stated otherwise.
There were no significant differences regarding maternal age, gestational age at time of enrollment, baseline cervical dilatation, initial labor pain score, or Apgar scores measured at 1 minute and 5 minutes (Table 1). However, the 2 groups differed in post-treatment labor pain scores, duration of the active phase of labor, and rate of cervical dilatation (P b 0.001) (Table 2). There was no significant difference between the 2 groups in maternal adverse events: tachycardia and palpitation were reported for 7 women (4.3%) and 8 women (5.0%) in the drotaverine and placebo groups, respectively, whereas headache was reported for 6 women (3.7%) and 6 women (3.8%), respectively. Hypotension was reported for 5 women (3.1%) and 6 women (3.8%) in the drotaverine and placebo groups, respectively, whereas nausea was reported for 6 women (3.7%) and 6 women (3.8%), respectively. Dry mouth, flushing, unsteadiness, photophobia, and retention of urine were not reported for women in either group. Neonatal adverse events, including fetal distress rate, median Apgar scores at 1 and 5 minutes, meconium-stained liquor rate, and rate of admission to the neonatal intensive care unit did not differ significantly between the 2 groups (Table 2).
Table 1 Comparison of baseline parameters between the drotaverine and placebo groups.a Baseline parameter
Maternal age, y BMI on admission Gestational age, wk Cervical dilatation, cm Bishop score b10 Initial labor pain score (VAS)
Study group
P value
Drotaverine (n = 161)
Placebo (n = 159)
23.8 ± 3.8 30.1 ± 5.1 38.6 ± 1.1 4.3 ± 0.8 73 (47.2) 7 (6–9)
23.8 ± 3.4 29.9 ± 4.9 38.5 ± 1.1 4.3 ± 0.8 68 (42.8) 7 (6–9)
0.92 0.72 0.38 0.69 0.65 0.92
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); VAS, visual analog scale. a Values are given as mean ± SD, median (interquartile range), or number (percentage) unless stated otherwise.
Fig. 2. Kaplan–Meier curves showing the probability of faster delivery among women treated by drotaverine hydrochloride and placebo.
Nulliparas (n = 150) low risk Cx 4 cm Mixed parity (n = 300) low risk Cx 4 cm Nulliparas (n = 100) low risk Cx 3–6 cm Mixed parity (n = 200) low risk Cx ≥3 cm Mixed parity (n = 150) low/high risk Cx N3 cm Mixed parity (n = 150) low risk Cx 4 cm Nulliparas (n = 320) low risk Cx 3–5 cm
Sharma et al., 2001 [13]
Drotaverine HCl 40 mg/2 h IMI versus valethamate bromide 8 mg/h IMI (maximum of 3 doses) Drotaverine HCl 40 mg/2 h IMI versus valethamate bromide 8 mg/30 min IMI (maximum of 3 doses) Drotaverine HCl 40 mg IMI (second injection if no progress after 4 h)
Drotaverine HCl 40 mg IVI
Drotaverine HCl 40 mg/2 h IMI versus hyoscine butylbromide 20 mg/30 min IVI (maximum of 3 doses) Drotaverine HCl 40 mg/h IMI versus valethamate bromide 8 mg/h IMI (maximum of 3 doses) Drotaverine HCl 40 mg/2 h IVI (maximum of 3 doses)
Duration of first stage of labor; delivery within 6 h; cervical dilatation rate Duration of first stage of labor
Duration of first stage of labor
Duration of first stage of labor
Duration of first stage of labor; cervical dilatation rate
Duration of first stage of labor; cervical dilatation rate
Duration of whole labor; pain in labor
Intervention
Main outcome measures
Abbreviations: Cx, cervical dilatation; IMI, intramuscular injection; IVI, intravenous injection; RCT, randomized controlled trial.
Current study, 2013
Madhu et al., 2010 [12]
Gupta et al., 2008 [11]
Roy et al., 2007 [15]
Singh et al., 2004 [14]
Khosla et al., 2003 [10]
Population
Study
Table 3 Summary of data from previous trials of drotaverine hydrochloride.
Placebo
Placebo
None
None
Placebo
None
None
Control
Shorter duration of first stage of labor; faster cervical dilatation
Shorter duration of first stage of labor; faster cervical dilatation
Shorter duration of first stage of labor, more effective in multigravida and when given in more dilated cervix No difference
Strictly defined labor management protocol; largest participant number
Unclear labor management protocol; women were not stratified according to their parity
Unclear labor management protocol (labor onset was not defined); women with prior cesarean were included
Methods not clearly stated
Unclear labor management protocol; augmentation after 8 h of dysfunctional labor
First stage of labor was not defined
Shorter duration of first stage of labor
Shorter duration of labor in the subgroup randomized at 4 cm dilatation
Unclear labor management protocol; first -stage duration was not defined
Comments
Shorter duration of first stage of labor; faster cervical dilatation
Results
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Fig. 2 shows the Kaplan–Meier survival analysis; a significant difference was observed in the probability of faster delivery among patients who were treated by drotaverine hydrochloride compared with those who were treated by placebo (log rank test, P b 0.001).
4. Discussion Although the potential role of drotaverine hydrochloride in enhancing the progress of the first stage of labor has been investigated in few trials [10–15], most of those trials had an unclear labor management protocol with conflicting results and heterogeneous populations and interventions (Table 3). In the current study, drotaverine was associated with improved progress of the first stage of labor without increasing the fetomaternal compromise among nulliparous women. The precise mechanism by which drotaverine can speed up cervical dilatation is not clear. Drotaverine hydrochloride is a potent antispasmodic agent, which is devoid of anticholinergic activity; it acts mainly by inhibiting type IV PDE, leading to an increase in intracellular cyclic AMP and cyclic GMP, smooth muscle relaxation, and cervical dilatation [12]. It has no significant fetal adverse effects because it does not cross the human placenta. Drotaverine is excreted via a non-renal route and its half-life is 7–12 hours. Its metabolites are much more potent in inhibiting type IV PDE isoenzymes than is drotaverine itself. Its maternal adverse effects are generally mild and occur mainly when the drug is given by rapid intravenous administration [16,17]. Modern labor management protocols contain interventions that can directly or indirectly affect the duration of labor, such as epidural analgesia, amniotomy, and oxytocin administration [3]. Unlike amniotomy and oxytocin augmentation, drotaverine hydrochloride does not enhance myometrial contractility; hence, it does not induce uterine hyperstimulation or compromise fetomaternal outcomes. Although drotaverine is a smooth muscle relaxant that reduces uterine muscle contraction and subsequently improves uterine perfusion in the non-pregnant uterus [18], hindrance of uterine contractions is not a problem during labor. Leroy et al. [16] reported that there is a higher concentration of type IV PDE in the human myometrium in the third trimester and near term. This predominance suggests its potential role in labor. The presence of high-risk maternal and/or fetal conditions would adversely affect conclusions on the potential beneficial role of drotaverine on the progress of labor; as a result, apart from the study of Gupta et al. [11], which included women who had prior cesarean delivery, the current trial and other previous trials [10,12–15] included only women with low-risk pregnancies. Because the problem of dystocia and prolonged labor are more commonly encountered among nulliparous women, the current study and 2 previous studies [13,14] included only nulliparous women. Other studies included both nulliparous and multiparous women [10–12,15]. Use of cervical ripening agents would alter the cervical status and potentially alter the responsiveness to antispasmodic drugs; as a result, the current study and most previous trials [10,12–15] included only women with spontaneous labor. One study did not specify whether its participants were in spontaneous labor or not [11]. In previous studies, the duration of labor was the primary outcome measure [10–15]. Although the duration of the first stage of labor was the primary endpoint of the current study, the rate of dilatation was used as the primary outcome measure because women were randomized at different dilatation levels to make the comparison between groups feasible. In keeping with previous studies [10–15], only women who completed the first stage of labor were considered in calculating the mean duration of the first stage of labor and the cervical dilatation rate, and women who delivered via cesarean in the first stage of labor were excluded. The current study reported significantly faster cervical dilatation rates among women receiving drotaverine; these
findings are in agreement with previous reports [12,13] but in contrast to the results of Gupta et al. [11]. Unexpectedly, the current study has documented a beneficial effect of drotaverine hydrochloride in relieving labor pains. Apart from Singh et al. [14], no previous trials evaluated the effect of drotaverine on pain relief [10–13,15]. Singh et al. [14] reported no effect of drotaverine on pain relief. In the current study, drotaverine had no overall significant effect on the normal delivery rate; this finding is in agreement with previous data [10–14]. Neurotropic antispasmodic agents function by antagonizing acetylcholine at muscarinic receptors, whereas musculotropic antispasmodic drugs act directly on smooth muscle cells with no anticholinergic effects [5]. Although there was no significant difference between the 2 groups in maternal and neonatal adverse events in the present study, maternal tachycardia, dry mouth, and flushing have been reported to be significantly higher in previous multi-interventional studies; however, it should be mentioned that such adverse effects were reported in the patient subgroups receiving neurotropic agents not drotaverine [10–13]. Other adverse events, including maternal headache [12,13], unsteadiness [12,13], and bleeding [14], were not found to be significantly higher among women receiving drotaverine; in addition, the rates of fetal distress [13] and NICU admission [11] were not significantly higher among women receiving drotaverine. In addition to the current study, 2 other studies used drotaverine as the only intervention controlled by placebo [14] or no treatment [15]. Other studies used multiple interventions controlled by placebo [12] or no treatment [10,11,13]. To the best of our knowledge, this is the largest trial to investigate the potential role of drotaverine in shortening the first stage of labor; other merits include the use of a standard labor management protocol and the study design of a double-blind placebo-controlled trial. The study is limited by its inability to evaluate maternal satisfaction. In conclusion, drotaverine hydrochloride can be considered as an effective and safe pharmaceutical agent to shorten the duration of the first stage of spontaneous labor among nulliparous women. Conflict of interest The authors have no conflicts of interest. References [1] Cheng YW, Shaffer BL, Bryant AS, Caughey AB. Length of the first stage of labor and associated perinatal outcomes in nulliparous women. Obstet Gynecol 2010;116(5):1127–35. [2] Waldenström U, Borg IM, Olsson B, Sköld M, Wall S. The childbirth experience: a study of 295 new mothers. Birth 1996;23(3):144–53. [3] Cromi A, Ghezzi F, Agosti M, Uccella S, Piazza N, Serati M, et al. Use of an antispasmodic (rociverine) to shorten the length of labor: a randomized, placebo-controlled trial. Acta Obstet Gynecol Scand 2011;90(12):1371–8. [4] Hirsch FE. Anti-spasmodic drugs in Labour. BMJ 1937;2:559–60. [5] Samuels LA. Pharmacotherapy Update: Hyoscine butylbromide in the treatment of abdominal spasms. Clinical Medicine Insights. Therapeutics 2009;1:647–55. [6] Romics I, Molnár DL, Timberg G, Mrklic B, Jelakovic B, Köszegi G, et al. The effect of drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU Int 2003;92(1):92–6. [7] Rohwer AC, Khondowe O, Young T. Antispasmodics for labour. Cochrane Database Syst Rev 2013;6:CD009243. [8] American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 106: Intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. Obstet Gynecol 2009;114(1):192–202. [9] ACOG Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 107: Induction of labor. Obstet Gynecol 2009;114(2 Pt 1):386–97. [10] Khosla AH, Bala I, Dahiya K, Sangwan K. A comparative study of the efficacy of valethamate bromide with drotaverine in normal labor. J Obstet Gynecol Ind 2003;53:568–70. [11] Gupta B, Nellore V, Mittal S. Drotaverine hydrochloride versus hyoscine-Nbutylbromide in augmentation of labor. Int J Gynecol Obstet 2008;100(3):244–7. [12] Madhu C, Mahavarkar S, Bhave S. A randomised controlled study comparing Drotaverine hydrochloride and valethamate bromide in the augmentation of labour. Arch Gynecol Obstet 2010;282(1):11–5. [13] Sharma JB, Pundir P, Kumar A, Murthy NS. Drotaverine hydrochloride vs. valethamate bromide in acceleration of labor. Int J Gynecol Obstet 2001;74(3):255–60.
M.I. Ibrahim et al. / International Journal of Gynecology and Obstetrics 124 (2014) 112–117 [14] Singh KC, Jain P, Goel N, Saxena A. Drotaverine hydrochloride for augmentation of labor. Int J Gynecol Obstet 2004;84(1):17–22. [15] Roy A, Patra KK, Mukhopadhyay S, Guha S. Study of drotaverine on first stage of labour and pregnancy outcome. J Indian Med Assoc 2007;105(8):450–2. [16] Leroy MJ, Lugnier C, Merezak J, Tanguy G, Olivier S, Le Bec A, et al. Isolation and characterization of the rolipram-sensitive cyclic AMP-specific phosphodiesterase (type IV PDE) in human term myometrium. Cell Signal 1994;6(4):405–12.
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[17] Bolaji OO, Onyeji CO, Ogundaini AO, Olugbade TA, Ogunbona FA. Pharmacokinetics and bioavailability of drotaverine in humans. Eur J Drug Metab Pharmacokinet 1996;21(3):217–21. [18] Pareek A, Chandurkar NB, Patil RT, Agrawal SN, Uday RB, Tambe SG. Efficacy and safety of aceclofenac and drotaverine fixed-dose combination in the treatment of primary dysmenorrhoea: a double-blind, double-dummy, randomized comparative study with aceclofenac. Eur J Obstet Gynecol Reprod Biol 2010;152(1):86–90.
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Drotaverine to improve progression of labor among nulliparous women Moustafa I. Ibrahim a, Hazem A. Alzeeniny a, Mohamed I. Ellaithy a,⁎, Ahmed H. Salama a, Mohammed A. Abdellatif b a b
Department of Obstetrics and Gynecology, Ain-shams Faculty of Medicine, Cairo, Egypt Department of Obstetrics and Gynecology, Sohag Teaching Hospital, Sohag, Egypt
a r t i c l e
i n f o
Article history: Received 1 May 2013 Received in revised form 10 August 2013 Accepted 29 October 2013 Keywords: Cervical dilatation rate Drotaverine hydrochloride Nulliparous
a b s t r a c t Objective: To reevaluate the role of the antispasmodic drug drotaverine in shortening the length of the active first stage of labor among nulliparous women. Methods: In a randomized, double-blind, placebo-controlled trial, 422 young nulliparous women admitted to Ain-shams University Maternity Hospital, Cairo, Egypt, in spontaneous labor were initially enrolled between May and December 2012. Drotaverine hydrochloride (40 mg) or placebo was given at the start of the active phase of labor and then repeated every 2 hours (maximum 3 doses). All participants were consistently managed in accordance with the local institutional intrapartum protocol. The primary outcome was the rate of cervical dilation. Results: After excluding women who delivered by cesarean, data were analyzed from 320 women. There was a significant difference in post-treatment labor pain scores, duration of the active phase of labor, and rate of cervical dilatation between the 2 groups (P b 0.001 for all). There was no difference in maternal adverse effects. Kaplan–Meier survival analysis showed a greater probability of faster delivery among patients treated by drotaverine hydrochloride (log rank test; P b 0.001). Conclusion: Drotaverine hydrochloride was used effectively and safely to shorten the duration of the first stage of labor among nulliparous women with active spontaneous labor. ClinicalTrials.gov: NCT01639027. © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Minimizing the duration of labor without compromising fetomaternal wellbeing is a desirable outcome in all labor and delivery units [1]. Prolonged labor has been associated with higher rates of neonatal admission to the intensive care unit [2], and is likely to increase the work burden, especially in busy labor wards, with consequent inadequacy of obstetric care [3]. Hirsch [4] first described the use of antispasmodic drugs to shorten the first stage of labor in 1937: he reported that labor duration could be decreased by 2–4 hours by using an atropine-like drug. Antispasmodic drugs can aid faster cervical dilatation of the cervix during labor via neurotropic and/or musculotropic effects [5]. Drotaverine is a musculotropic agent—an inhibitor of type IV phosphodiesterase (PDE)—that is structurally related to papaverine. It has mild calcium channel blocking activity but no anticholinergic effects and acts directly on smooth muscle cells, inhibiting spasm [6]. A recent Cochrane review [7] found low quality evidence that antispasmodic drugs reduce the duration of first stage of labor and increase the cervical dilatation rate; very low quality evidence that they reduce the total duration of labor; and insufficient evidence to make any conclusion about the safety of these medications. It was ⁎ Corresponding author at: Building 14, Block 14, Alwaha District, Nasr City, Cairo, Egypt. Tel.: +20 1006873417. E-mail addresses: [email protected], [email protected] (M.I. Ellaithy).
therefore advised that large, well-designed, randomized controlled trials are needed to evaluate the role of antispasmodic drugs in the management of labor [7]. The aim of the current study was to reevaluate the safety and efficacy of using the antispasmodic drotaverine to reduce the duration of the active first stage of labor among nulliparous women being managed by a standard intrapartum protocol. 2. Materials and methods The present randomized, double-blind, placebo-controlled trial was conducted among young nulliparous women admitted in spontaneous active labor to the Labor and Delivery Unit of Ain-shams University Maternity Hospital, Cairo, Egypt (annual number of deliveries 12 000–18 000), between May 11 and December 17, 2012. The study was approved by the local institutional ethics and research committee. Written signed informed consent was obtained from all participants before any study-specific procedure was performed. Women were considered eligible to participate in the study if they had a singleton term pregnancy with a vertex presentation, occipitoanterior position, and cervical dilatation of 3–5 cm. The presence of 1 or more of the following was considered sufficient to exclude women from the study: prepartum hemorrhage, placenta previa, prior uterine scar, cephalopelvic disproportion, use of labor-inducing agent, contraindication for vaginal delivery, non-reassuring fetal status, hypersensitivity to drotaverine hydrochloride, prior cervical surgery,
0020-7292/$ – see front matter © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijgo.2013.08.013
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use of antihypertensive therapy, or use of spasmolytic agents within the past 48 hours. Gestational age was calculated at the time of enrollment according to the Naegele rule and confirmed by reviewing early pregnancy ultrasound scans. Active labor was diagnosed by the presence of regular uterine contractions (each lasting for 30 seconds or more) at a rate of at least 3 every 10 minutes, with or without rupture of membranes. Eligible participants were randomly assigned to receive a slow intravenous injection via a syringe prefilled with 2 mL of either drotaverine hydrochloride or placebo during management of the first stage of labor. Randomization was performed via a computer-generated sequence: the randomization list was held in a secure box in the labor ward and the participants were assigned to their groups by using sequentially numbered opaque sealed envelopes that were opened at enrollment. The syringes were masked with black opaque stickers so that the yellowishcolored drotaverine hydrochloride was undistinguishable from the translucent saline solution. Women assigned to the intervention group received intravenously 40 mg of drotaverine hydrochloride (2-mL ampules, 40 mg/ampule; Do-Spa, Alexandria Pharmaceutical and Chemical Industries, Awayed, Alexandria, Egypt), whereas women assigned to the placebo group received intravenously 2 mL of normal saline (0.9% sodium chloride).
Enrollment
An injection was given at the start of the active phase of labor and repeated every 2 hours for a maximum of 3 doses if full cervical dilatation did not happen. All participants were consistently managed according to the local institutional intrapartum protocol and received identical monitoring and supportive care. Before being enrolled, all participants were thoroughly assessed to confirm eligibility and to exclude allergy to drotaverine hydrochloride and/or any contraindication for vaginal delivery. The presence of normal fetal heart rate pattern and assessment of uterine activity were assured via cardiotocography for 30 minutes before the intervention was started. Intrapartum fetal monitoring was performed via intermittent auscultation for low-risk women and continuous electronic fetal monitoring for high-risk women. Vaginal examination was performed every 2 hours, unless clinically indicated, to define the progress of cervical dilatation. Artificial rupture of fetal membranes was considered for women with intact membranes if there was poor progress of labor (cervical dilatation, b1 cm/hour). Oxytocin, if needed, was begun 2 hours after rupture of fetal membranes via a low-dose titration approach with a starting dose of 2 mU/minute and increments of 2 mU/minute every 15 minutes until adequate uterine contractions were achieved
Assessed for eligibility (n=1126) Nulliparous women admitted in labor during the study period
Excluded (n=704) Contraindication to vaginal delivery (n=141) Induced labor (n=223) Cervical dilatation >5 cm (n=87) Gestational age <37 weeks (n=103) Twins (n=21) Others (n=129)
Eligible women (n=422)
Excluded (n=70) Declined to participate
Allocation Received drotaverine (n=176)
Received placebo (n=176)
Analysis Analyzed (n=161) Excluded from analysis (cesarean delivery before full cervical dilatation) (n=15)
113
Analyzed (n=159) Excluded from analysis (cesarean delivery before full cervical dilatation) (n=17)
Fig. 1. Flow of participants through the study.
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or the maximum dose (32 mU/minute) was reached. The intrapartum fetal heart rate pattern and uterine contractions were interpreted in accordance with ACOG guidelines [8,9]. A partogram was used to document the progress of labor and the duration of the first stage of labor to determine the study endpoints. The primary outcome was the rate of cervical dilation; secondary outcomes included the duration of the active first stage of labor (from first injection to full cervical dilatation), mode of delivery, Apgar score of less than 7 at 1 and 5 minutes, maternal drug adverse effect, and pain assessment via visual analog scale recorded before and after the injected solution at 30, 60, and 120 minutes. The required study sample size was estimated via G*Power version 3.1.0 (Institut für Experimentelle Psychologie, Heinrich Heine Universität, Düsseldorf, Germany). The study sample size was calculated on the basis of the duration of the first stage of labor because this calculation yielded the highest sample size; this powered the study sufficiently to assess many outcomes, including the primary outcome of the study, which was the rate of cervical dilatation. It was estimated that a sample size of 160 women in each group would have a power of 80% to detect an effect size (d) of 0.3. The test used was the 2-sample t-test and significance was targeted at an α error of 0.05. The sample size was increased by 10% to compensate for post-randomization exclusions related to performing cesarean delivery in the first stage of labor. Statistical analysis was done via SPSS version 19 (IBM, Armonk, NY, USA). Quantitative variables were described as mean ± SD or median (interquartile range; IQR) as appropriate. Qualitative variables were described as number and percentage. Qualitative variables were compared between the 2 groups by χ2 test; quantitative variables were compared by an independent sample t-test for parametric data and by Mann–Whitney test for non-parametric data. A P value of less than 0.05 was considered to be statistically significant. A Kaplan–Meier survival analysis was used to detect the probabilities of faster delivery with the use of drotaverine hydrochloride and placebo. The 2 curves were compared via a log rank test. 3. Results During the study period, 422 young nulliparous women were eligible for participation in the study. Seventy women refused consent; as a result, 176 women were allocated to the drotaverine group and 176 to the placebo group. After excluding women who delivered by cesarean, the final statistical analysis included 320 women (Fig. 1). The mean maternal age of participants was 23.8 ± 3.6 years, and the mean gestational age at the time of enrollment was 38.5 ± 1.1 weeks. The mean duration of the active phase was 160.3 ± 66.4 minutes, and the median rate of cervical dilatation was 2.11 cm/hour (IQR, 1.75–2.67). The median Apgar score at 1 minute was 8 (IQR, 8–9), the median Apgar at 5 minutes was 9 (IQR, 9–9). In the drotaverine group, the median number of doses administered was 2 (IQR, 1–2).
Table 2 Comparison of study outcomes between the drotaverine and placebo groups.a Outcome
Oxytocin augmentation Meperidine hydrochloride Labor pain (VAS) after 30 min Labor pain (VAS) after 60 min Labor pain (VAS) after 120 min Cervical dilatation rate, cm/h First-stage duration, min Second-stage duration, min Third-stage duration, min Normal vaginal delivery Ventouse-assisted delivery Forceps-assisted delivery Second-stage cesarean delivery Blood loss, mL Cervical lacerations Fetal distress Apgar score at 1 mi Apgar score at 5 min Meconium-stained liquor NICU admission Neonatal birth weight, g
Study group
P value
Drotaverine (n = 161)
Placebo (n = 159)
101 (62.7) 96 (59.6) 5 (4–7) 3 (2–5) 8 (6–9) 2.7 (2.4–3.0) 120.7 ± 53.2 42.2 ± 22.3 9.1 ± 1.5 145 (90.1) 4 (2.5) 2 (1.2) 10 (6.2) 349 ± 97 3 (1.9) 4 (2.5) 8 (8–9) 9 (9–9) 5 (3.1) 4 (2.5) 2903 ± 354
96 (60.4) 113 (71.1) 9 (7–9) 9 (8–10) 10 (9–10) 1.8 (1.6–2.0) 200.8 ± 79.8 38.7 ± 20.8 8.9 ± 1.6 144 (90.1) 5 (3.1) 1 (0.6) 9 (5.7) 367 ± 88 2 (1.3) 6 (3.8) 8 (8–9) 9 (8–9) 4 (2.5) 4 (2.5) 2876 ± 298
0.73 0.035 b0.001 b0.001 b0.001 b0.001 b0.001 0.15 0.25 N0.99 0.75 N0.99 N0.99 0.083 N0.99 0.54 0.6 0.44 N0.99 N0.99 0.46
Abbreviations: NICU, neonatal intensive care unit; VAS, visual analog scale. a Values are given as mean ± SD, median (interquartile range), or number (percentage) unless stated otherwise.
There were no significant differences regarding maternal age, gestational age at time of enrollment, baseline cervical dilatation, initial labor pain score, or Apgar scores measured at 1 minute and 5 minutes (Table 1). However, the 2 groups differed in post-treatment labor pain scores, duration of the active phase of labor, and rate of cervical dilatation (P b 0.001) (Table 2). There was no significant difference between the 2 groups in maternal adverse events: tachycardia and palpitation were reported for 7 women (4.3%) and 8 women (5.0%) in the drotaverine and placebo groups, respectively, whereas headache was reported for 6 women (3.7%) and 6 women (3.8%), respectively. Hypotension was reported for 5 women (3.1%) and 6 women (3.8%) in the drotaverine and placebo groups, respectively, whereas nausea was reported for 6 women (3.7%) and 6 women (3.8%), respectively. Dry mouth, flushing, unsteadiness, photophobia, and retention of urine were not reported for women in either group. Neonatal adverse events, including fetal distress rate, median Apgar scores at 1 and 5 minutes, meconium-stained liquor rate, and rate of admission to the neonatal intensive care unit did not differ significantly between the 2 groups (Table 2).
Table 1 Comparison of baseline parameters between the drotaverine and placebo groups.a Baseline parameter
Maternal age, y BMI on admission Gestational age, wk Cervical dilatation, cm Bishop score b10 Initial labor pain score (VAS)
Study group
P value
Drotaverine (n = 161)
Placebo (n = 159)
23.8 ± 3.8 30.1 ± 5.1 38.6 ± 1.1 4.3 ± 0.8 73 (47.2) 7 (6–9)
23.8 ± 3.4 29.9 ± 4.9 38.5 ± 1.1 4.3 ± 0.8 68 (42.8) 7 (6–9)
0.92 0.72 0.38 0.69 0.65 0.92
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); VAS, visual analog scale. a Values are given as mean ± SD, median (interquartile range), or number (percentage) unless stated otherwise.
Fig. 2. Kaplan–Meier curves showing the probability of faster delivery among women treated by drotaverine hydrochloride and placebo.
Nulliparas (n = 150) low risk Cx 4 cm Mixed parity (n = 300) low risk Cx 4 cm Nulliparas (n = 100) low risk Cx 3–6 cm Mixed parity (n = 200) low risk Cx ≥3 cm Mixed parity (n = 150) low/high risk Cx N3 cm Mixed parity (n = 150) low risk Cx 4 cm Nulliparas (n = 320) low risk Cx 3–5 cm
Sharma et al., 2001 [13]
Drotaverine HCl 40 mg/2 h IMI versus valethamate bromide 8 mg/h IMI (maximum of 3 doses) Drotaverine HCl 40 mg/2 h IMI versus valethamate bromide 8 mg/30 min IMI (maximum of 3 doses) Drotaverine HCl 40 mg IMI (second injection if no progress after 4 h)
Drotaverine HCl 40 mg IVI
Drotaverine HCl 40 mg/2 h IMI versus hyoscine butylbromide 20 mg/30 min IVI (maximum of 3 doses) Drotaverine HCl 40 mg/h IMI versus valethamate bromide 8 mg/h IMI (maximum of 3 doses) Drotaverine HCl 40 mg/2 h IVI (maximum of 3 doses)
Duration of first stage of labor; delivery within 6 h; cervical dilatation rate Duration of first stage of labor
Duration of first stage of labor
Duration of first stage of labor
Duration of first stage of labor; cervical dilatation rate
Duration of first stage of labor; cervical dilatation rate
Duration of whole labor; pain in labor
Intervention
Main outcome measures
Abbreviations: Cx, cervical dilatation; IMI, intramuscular injection; IVI, intravenous injection; RCT, randomized controlled trial.
Current study, 2013
Madhu et al., 2010 [12]
Gupta et al., 2008 [11]
Roy et al., 2007 [15]
Singh et al., 2004 [14]
Khosla et al., 2003 [10]
Population
Study
Table 3 Summary of data from previous trials of drotaverine hydrochloride.
Placebo
Placebo
None
None
Placebo
None
None
Control
Shorter duration of first stage of labor; faster cervical dilatation
Shorter duration of first stage of labor; faster cervical dilatation
Shorter duration of first stage of labor, more effective in multigravida and when given in more dilated cervix No difference
Strictly defined labor management protocol; largest participant number
Unclear labor management protocol; women were not stratified according to their parity
Unclear labor management protocol (labor onset was not defined); women with prior cesarean were included
Methods not clearly stated
Unclear labor management protocol; augmentation after 8 h of dysfunctional labor
First stage of labor was not defined
Shorter duration of first stage of labor
Shorter duration of labor in the subgroup randomized at 4 cm dilatation
Unclear labor management protocol; first -stage duration was not defined
Comments
Shorter duration of first stage of labor; faster cervical dilatation
Results
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Fig. 2 shows the Kaplan–Meier survival analysis; a significant difference was observed in the probability of faster delivery among patients who were treated by drotaverine hydrochloride compared with those who were treated by placebo (log rank test, P b 0.001).
4. Discussion Although the potential role of drotaverine hydrochloride in enhancing the progress of the first stage of labor has been investigated in few trials [10–15], most of those trials had an unclear labor management protocol with conflicting results and heterogeneous populations and interventions (Table 3). In the current study, drotaverine was associated with improved progress of the first stage of labor without increasing the fetomaternal compromise among nulliparous women. The precise mechanism by which drotaverine can speed up cervical dilatation is not clear. Drotaverine hydrochloride is a potent antispasmodic agent, which is devoid of anticholinergic activity; it acts mainly by inhibiting type IV PDE, leading to an increase in intracellular cyclic AMP and cyclic GMP, smooth muscle relaxation, and cervical dilatation [12]. It has no significant fetal adverse effects because it does not cross the human placenta. Drotaverine is excreted via a non-renal route and its half-life is 7–12 hours. Its metabolites are much more potent in inhibiting type IV PDE isoenzymes than is drotaverine itself. Its maternal adverse effects are generally mild and occur mainly when the drug is given by rapid intravenous administration [16,17]. Modern labor management protocols contain interventions that can directly or indirectly affect the duration of labor, such as epidural analgesia, amniotomy, and oxytocin administration [3]. Unlike amniotomy and oxytocin augmentation, drotaverine hydrochloride does not enhance myometrial contractility; hence, it does not induce uterine hyperstimulation or compromise fetomaternal outcomes. Although drotaverine is a smooth muscle relaxant that reduces uterine muscle contraction and subsequently improves uterine perfusion in the non-pregnant uterus [18], hindrance of uterine contractions is not a problem during labor. Leroy et al. [16] reported that there is a higher concentration of type IV PDE in the human myometrium in the third trimester and near term. This predominance suggests its potential role in labor. The presence of high-risk maternal and/or fetal conditions would adversely affect conclusions on the potential beneficial role of drotaverine on the progress of labor; as a result, apart from the study of Gupta et al. [11], which included women who had prior cesarean delivery, the current trial and other previous trials [10,12–15] included only women with low-risk pregnancies. Because the problem of dystocia and prolonged labor are more commonly encountered among nulliparous women, the current study and 2 previous studies [13,14] included only nulliparous women. Other studies included both nulliparous and multiparous women [10–12,15]. Use of cervical ripening agents would alter the cervical status and potentially alter the responsiveness to antispasmodic drugs; as a result, the current study and most previous trials [10,12–15] included only women with spontaneous labor. One study did not specify whether its participants were in spontaneous labor or not [11]. In previous studies, the duration of labor was the primary outcome measure [10–15]. Although the duration of the first stage of labor was the primary endpoint of the current study, the rate of dilatation was used as the primary outcome measure because women were randomized at different dilatation levels to make the comparison between groups feasible. In keeping with previous studies [10–15], only women who completed the first stage of labor were considered in calculating the mean duration of the first stage of labor and the cervical dilatation rate, and women who delivered via cesarean in the first stage of labor were excluded. The current study reported significantly faster cervical dilatation rates among women receiving drotaverine; these
findings are in agreement with previous reports [12,13] but in contrast to the results of Gupta et al. [11]. Unexpectedly, the current study has documented a beneficial effect of drotaverine hydrochloride in relieving labor pains. Apart from Singh et al. [14], no previous trials evaluated the effect of drotaverine on pain relief [10–13,15]. Singh et al. [14] reported no effect of drotaverine on pain relief. In the current study, drotaverine had no overall significant effect on the normal delivery rate; this finding is in agreement with previous data [10–14]. Neurotropic antispasmodic agents function by antagonizing acetylcholine at muscarinic receptors, whereas musculotropic antispasmodic drugs act directly on smooth muscle cells with no anticholinergic effects [5]. Although there was no significant difference between the 2 groups in maternal and neonatal adverse events in the present study, maternal tachycardia, dry mouth, and flushing have been reported to be significantly higher in previous multi-interventional studies; however, it should be mentioned that such adverse effects were reported in the patient subgroups receiving neurotropic agents not drotaverine [10–13]. Other adverse events, including maternal headache [12,13], unsteadiness [12,13], and bleeding [14], were not found to be significantly higher among women receiving drotaverine; in addition, the rates of fetal distress [13] and NICU admission [11] were not significantly higher among women receiving drotaverine. In addition to the current study, 2 other studies used drotaverine as the only intervention controlled by placebo [14] or no treatment [15]. Other studies used multiple interventions controlled by placebo [12] or no treatment [10,11,13]. To the best of our knowledge, this is the largest trial to investigate the potential role of drotaverine in shortening the first stage of labor; other merits include the use of a standard labor management protocol and the study design of a double-blind placebo-controlled trial. The study is limited by its inability to evaluate maternal satisfaction. In conclusion, drotaverine hydrochloride can be considered as an effective and safe pharmaceutical agent to shorten the duration of the first stage of spontaneous labor among nulliparous women. Conflict of interest The authors have no conflicts of interest. References [1] Cheng YW, Shaffer BL, Bryant AS, Caughey AB. Length of the first stage of labor and associated perinatal outcomes in nulliparous women. Obstet Gynecol 2010;116(5):1127–35. [2] Waldenström U, Borg IM, Olsson B, Sköld M, Wall S. The childbirth experience: a study of 295 new mothers. Birth 1996;23(3):144–53. [3] Cromi A, Ghezzi F, Agosti M, Uccella S, Piazza N, Serati M, et al. Use of an antispasmodic (rociverine) to shorten the length of labor: a randomized, placebo-controlled trial. Acta Obstet Gynecol Scand 2011;90(12):1371–8. [4] Hirsch FE. Anti-spasmodic drugs in Labour. BMJ 1937;2:559–60. [5] Samuels LA. Pharmacotherapy Update: Hyoscine butylbromide in the treatment of abdominal spasms. Clinical Medicine Insights. Therapeutics 2009;1:647–55. [6] Romics I, Molnár DL, Timberg G, Mrklic B, Jelakovic B, Köszegi G, et al. The effect of drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU Int 2003;92(1):92–6. [7] Rohwer AC, Khondowe O, Young T. Antispasmodics for labour. Cochrane Database Syst Rev 2013;6:CD009243. [8] American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 106: Intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. Obstet Gynecol 2009;114(1):192–202. [9] ACOG Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 107: Induction of labor. Obstet Gynecol 2009;114(2 Pt 1):386–97. [10] Khosla AH, Bala I, Dahiya K, Sangwan K. A comparative study of the efficacy of valethamate bromide with drotaverine in normal labor. J Obstet Gynecol Ind 2003;53:568–70. [11] Gupta B, Nellore V, Mittal S. Drotaverine hydrochloride versus hyoscine-Nbutylbromide in augmentation of labor. Int J Gynecol Obstet 2008;100(3):244–7. [12] Madhu C, Mahavarkar S, Bhave S. A randomised controlled study comparing Drotaverine hydrochloride and valethamate bromide in the augmentation of labour. Arch Gynecol Obstet 2010;282(1):11–5. [13] Sharma JB, Pundir P, Kumar A, Murthy NS. Drotaverine hydrochloride vs. valethamate bromide in acceleration of labor. Int J Gynecol Obstet 2001;74(3):255–60.
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