This systematic review and meta-analysis assessed the effectiveness and safety of camylofin compared with other antispasmodics (drotaverine, hyoscine, valethamate, phloroglucinol, and meperidine) in labor augmentation. A systematic literature search until March 27, 2018, was performed, and data on the cervical dilatation rate (CDR) and duration of stages of labor reported in 39 eligible articles were analyzed using a random-effects model. CDR was significantly higher (0.38 cm/h, 95% confidence interval (CI) 0.10 to 0.67, p = 0.007), and the duration of the first stage of labor was significantly shorter (− 41.21 minutes, 95% CI, − 77.19 to − 5.22, p = 0.02) in women receiving camylofin than those receiving other antispasmodics for labor augmentation. CDR was significantly higher with camylofin compared with valethamate (0.6 cm/h, 95% CI 0.4 to 0.9, p < 0.0001) and hyoscine (20 mg) (0.5 cm/h, 95% CI 0.1 to 0.8, p = 0.02). The duration of the first stage of labor was significantly shorter with camylofin compared with hyoscine (20 mg) (− 59.9 min, 95% CI, − 117.9 to − 1.8, p = 0.04). However, CDR and the duration of first stage of labor were not statistically different between camylofin and drotaverine groups. The percentage of women having nausea and vomiting, cervical/vaginal tear, and postpartum hemorrhage were comparable with all antispasmodics, whereas tachycardia was least reported in women receiving camylofin (3, 2.07%) than those receiving other antispasmodics. This meta-analysis demonstrated the benefit of camylofin in labor augmentation with a faster CDR and reduction in the active first stage of labor in Indian women.
Keywords : Augmentation , Camylofin , Cervical dilatation rate , Duration of first stage , Systematic review and metaanalysis
Prolonged labor is defined as a labor of more than 24 h duration, either due to a prolonged latent phase of > 20 h in a primigravida or > 14 h in a multipara, or due to a “protraction disorder.” [1] The overall rate of obstructed labor, prolonged labor, and failure to progress is 110.4 per 1000 deliveries in developing countries including India [2]. Prolonged labor is often associated with increased chorioamnionitis, perineal lacerations, and birth asphyxia [3–5] and is a leading indication for cesarean sections [6–8]
A cervical dilatation rate (CDR) of < 0.5 to 1 cm/h during the active phase is commonly considered as the slow progress of labor and is an indication for active intervention that includes use of oxytocin, amniotomy, etc. [9]. Slow CDR is an indication for cesarean section; however, cesarean deliveries are not devoid of their share of problems. Therefore, less invasive interventions for augmenting labor might be safer and more effective in preventing risks to mothers and fetuses. Antispasmodic drugs are used in clinical practice to fasten cervical dilation by acting on the smooth muscles of the utero-cervical plexus. Various antispasmodic drugs such as drotaverine hydrochloride (40 mg), camylofin dihydrochloride (50 mg), valethamate bromide (8 mg), and hyoscine butyl bromide (20 and 40 mg) have been evaluated in randomized controlled trials (RCTs). However, the evidence to support their effectiveness in the augmentation of labor is limited [9]. The World Health Organization guidelines for labor augmentation mention the use of antispasmodic agents as an important research priority [9].
Although antispasmodic agents have been used in clinical practice for the last 6 decades, the comparative effectiveness of these agents for cervical dilatation and labor augmentation has not been well-established. Camylofin is safe and effective in shortening the duration of labor compared with other antispasmodic agents such as drotaverine, hyoscine, and valethamate [10]. We conducted a systematic review and network meta-analysis (NMA) to compare the effectiveness and safety of various antispasmodic agents that are widely used for labor augmentation in India.
A protocol was designed to define the objectives, outcomes to be analyzed, and eligibility criteria for guiding the systematic literature search and selection of relevant articles for this NMA. Observational studies and RCTs published in English, in women with term pregnancies (≥ 37 weeks’ gestation), irrespective of parity, receiving an antispasmodic agent or placebo/no intervention (on account of being in the control group) for labor augmentation during any stage, by intramuscular or intravenous route and reporting on at least one of the following outcome measures were considered: duration of labor, CDR, and interval between the first dose of antispasmodic to delivery, i.e., injection to delivery interval (IDI). Studies involving women with obstetric complications and surgical and severe medical complications were excluded.
A systematic literature search was conducted using search terms “antispasmodics,” “effect,” and “augmentation” in PubMed, Cochrane Library, and Embase databases irrespective of the publication date. The search strings with keywords are presented in supplementary material (Box 1). Hand searches from the citation lists of relevant publications,conference proceedings, and studies from clinicaltrials.gov database were also screened.
After screening the various databases, full text articles of seemingly eligible studies were retrieved and reviewed by two independent reviewers who finalized the set of articles to be included in the NMA through a consultative process. Data on study characteristics (study design, number of participants, and demographic characteristics), effectiveness parameters (CDR, duration of first, second, and third stages of labor, and IDI), and adverse events (AEs) (tachycardia, nausea, vomiting, flushing of the face, postpartum hemorrhage [PPH], cervical or vaginal tear, fetal tachycardia, fetal bradycardia, and fetal distress) were extracted from the eligible studies by two independent extractors and were matched to resolve discrepancies. The risk of bias assessment was performed using the Cochrane Handbook for Systematic Interventions Reviews [11]. The selected studies were assessed for following areas of bias: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias; the risks were classified as low, high, and unclear.
Following data extraction, a meta-analysis using Review Manager 5.3 (The Cochrane Collaboration, Copenhagen) and NMA using SAS ® version 9.4 was performed. Both the studies aimed at comparing the effectiveness of camylofin with other antispasmodics (valethamate, drotaverine, hyoscine, phloroglucinol, meperidine, placebo, and expectant management or no intervention [henceforth referred to as the “control” arm]) on the parameters of CDR, duration of labor (first, second, and third stage and overall duration), and IDI. The random-effects model was adopted because of clinical heterogeneity between the studies. The mean difference and 95% confidence intervals (95% CIs) were estimated for all the parameters across both the arms. For the analysis, a study using other adjuncts with camylofin was considered under the camylofin arm with the assumption that the control group of ‘expectant management’ might have used the same analgesics and tranquilizers, as well as amniotomy except for camylofin, which would have balanced the confounding effect; [12]. Similarly, studies using valethamate bromide with hyoscine were considered under the valethamate arm, considering its widespread use as an adjunct [13, 14]. Ten studies not reporting standard deviations (SDs) for the means of effectiveness parameters could not be included in the quantitative analysis. Primarily, available data on primigravida women, when reported separately for all outcomes of interest were, included in the analysis; data reported exclusively for multiparous women were excluded to minimize the bias due to comparatively shorter duration of labor in them. One such study reporting data only for multiparous women was excluded from the NMA. The studies wherein data were not reported separately for primigravida and multiparous women were included in the analysis. The safety parameters were summarized across the different antispasmodics.
A literature search conducted on March 27, 2018, yielded 467 citations. Thirty-nine full text articles were included in this NMA (Fig. 1).
Among the 39 studies, 27 were conducted in India. The antispasmodics used in the intervention groups were camylofin (5 studies) [12, 14–17], drotaverine hydrochloride (19 studies) [13, 15, 18–34], valethamate bromide (13 studies) [13, 14, 19, 20, 24–26, 29, 31, 35–38], and hyoscine butyl bromide (10 studies) [16, 22, 33, 34, 39–44]. Seven studies [30, 45–50] evaluated other antispasmodics such as pethidine, phloroglucinol, and tramadol that are not widely used in India. Other adjunct treatments for analgesia and augmentation of labor were reported in 9 studies, which mainly included hyoscine, opioid analgesia, and oxytocin (Table 1). Women receiving camylofin for labor augmentation received maximum 1 dose; those receiving drotaverine and valethamate were given a maximum of 3 doses.
Figure 2 shows the risk of bias assessment for the included studies. Nineteen of 39 studies had a “high risk” of bias. Eleven studies had a high risk of bias because there was no randomization of the participants or blinding of the participants, investigators, or outcomes. Nine studies had a high risk of bias because of the incomplete data and/or selective reporting of the outcomes. The risk was unclear for one or more parameters for the remaining studies.
This NMA assessed the comparative effectiveness of antispasmodics widely used in women for labor augmentation. Rohwer et al, in their systematic review and meta-analysis reported a significant reduction in the total duration and the duration of the first stage of labor, and increased CDR with the use of antispasmodics compared with the no medication/ placebo/sodium chloride, however, the evidence was of low quality [51]. We performed a meta-analysis to compare the effects and safety of camylofin with other antispasmodics. The stress of labor releases catecholamines, which may lead to prolonged labor and compromised fetal oxygenation [52]. Prolonged labor is associated with increased risks for obstetric intervention and poor fetal outcomes [53]. Increased catecholamine secretion can be reduced by the synergistic use of analgesics and antispasmodics in the active phase of labor [52]. Camylofin has both musculotropic and neurotrophic effects, whereby it relaxes smooth muscle by inhibiting the acetylcholine-muscarinic receptor binding. Camylofin primarily acts on the cervical smooth muscles. Although camylofin possesses a musculotropic action, it does not interfere with uterine contractility because of its phosphodiesterase IV isoenzyme selectivity. Because of this unique preferential cervical dilating action, camylofin accelerates the first stage of labor. Camylofin has a prompt action that begins in 15 to 20 min and lasts until 4 to 5 h [17, 54].
In this NMA, the duration of the first stage of labor was significantly shorter by 60 min with camylofin than with hyoscine (20 mg). This reduction was much greater than the 11.7 min observed in the RCT comparing camylofin and hyoscine (20 mg) [16]. The duration of the first stage of labor was also observed to be shorter with camylofin than with high-dose hyoscine (40 mg) and valethamate; however, the differences were not statistically significant. Camylofin performed better than drotaverine in shortening the third stage of labor, although the result was not statistically significant.
In previous reports, CDR was better with camylofin (1.92 cm/h) compared with valethamate-hyoscine combination (0.69 cm/h) [14]. Our results mirrored the trend and demonstrated that camylofin fared better in increasing the CDR compared with valethamate, hyoscine (20 mg). Although not statistically significant, a CDR faster by about 2 mm (0.2 cm)/h was observed with camylofin than with drotaverine. After excluding the study involving the camylofin-drotaverine combination, we found that the duration of the first stage of labor was shorter for camylofin by 21 min than that for drotaverine. The results were similar in a RCT comparing camylofin with drotaverine with significantly better CDR and IDI in the camylofin group [15]. CDR with camylofin was faster by 0.4 cm/h, and the duration of the first stage of labor and IDI were shorter by approximately 40 min compared with other antispasmodics (considered as 1 group) in the present meta-analysis.
As per a recent pan-Indian observational study, labor augmentation occurred in nearly half of the women (44.7%) in primary health centers [55]. Similarly, in Rajasthan, labor augmentation was common (53.5% to 93.0%) [56]. Antispasmodics like drotaverine and valethamate were commonly used drugs after oxytocin and misoprostol for labor augmentation [55, 56]. Our findings showed that the performance of camylofin and drotaverine in augmenting labor was comparable, which might be attributed to the same mechanism of action. Moreover, camylofin is cost-effective as only a single injection is recommended for labor augmentation compared with multiple doses of other antispasmodics [10].
The common AEs with camylofin included nausea and vomiting. Compared with other antispasmodics, camylofin was safer with a low rate of AEs such as tachycardia, dryness of mouth, and PPH in mothers.
Overall, our results show that camylofin was beneficial in labor augmentation, especially in increasing CDR and reducing the active first stage of labor in comparison with all other antispasmodics currently available in India. The duration of the first stage of labor is expected to be reduced with camylofin because of its specific mode of action. Hence, our results may have applicability, especially for primigravida women, in whom the duration of the first stage of labor is often prolonged. The safety profile of camylofin was comparable with that of other antispasmodics.
The major limitation of this NMA was that most studies were from resource-limited settings, conducted in a realworld scenario, and hence had a high risk of bias. The studies were predominantly from India. Since the antispasmodics were used as a part of the active management of labor protocol with a lack of systematic study design, there was a large heterogeneity across studies. Furthermore, few studies did not report data separately for primigravida women. Although a trend towards the benefit of camylofin in reducing the total duration of labor was observed, the inclusion of some mixed data (from primigravida and multiparous women) may have led to this statistically inconclusive result. We used a random-effects model for meta-analysis to minimize the possibility of bias in the results. Pregnancy outcomes are reported in very few studies. Moreover, among the studies, which have reported the pregnancy outcomes, the reasons for cesarean section deliveries and fetal distress are not clearly reported; hence, the failure of augmentation and fetal safety could not be assessed quantitatively. Additionally, safety is underreported in many studies. Nonetheless, the NMA showed a statistically significant reduction in CDR because of camylofin. Although not statistically significant, it has also shown favorable effects of camylofin over other antispasmodics in reducing the total duration of labor, predominantly in primigravida women. These results may help in clinical decision-making practices of obstetricians when using an antispasmodic for augmentation of labor.
Camylofin Versus other Antispasmodics
Figure 3 presents the results of the random-effect meta-analysis comparing camylofin and other antispasmodics.
The difference in the mean duration of the first stage of labor (41.21 minutes, 95% CI, − 77.19 to − 5.22, p = 0.02), IDI (− 38.75 minutes, 95% CI, 78.18 to 0.69), and CDR (0.38 cm/h, 95% CI 0.10 to 0.67, p = 0.007) between women receiving camylofin and those receiving other antispasmodics significantly favored Camylofin for labor augmentation.
Comparative Effectiveness of Antispasmodics
The number of studies analyzed for each effectiveness parameter are summarized in Table 2.
The network diagrams of various comparisons of antispasmodics are shown in Fig. 4a, b. The results of NMA for 4 antispasmodics available in India are presented in Fig. 5. The results of NMA for all antispasmodics are shown in supplementary Tables 2 to 7.
The difference in mean CDR significantly favored camylofin over valethamate (0.6 cm/h, 95% CI 0.4 to 0.9, p < 0.0001) and hyoscine (20 mg) (0.5 cm/h, 95% CI 0.1 to 0.8, p = 0.02). The CDR results favored camylofin over drotaverine. The difference in the mean duration of the first stage of labor between camylofin and hyoscine (20 mg) (− 59.9 min, 95% CI, − 117.9 to − 1.8, p = 0.04) significantly favored camylofin. There was no statistically significant difference in the mean duration of the first stage of labor between drotaverine and camylofin (9.5 minutes, 95% CI, − 42.5 to 61.5, p = 0.70).
The difference in the mean total duration of labor favored camylofin over hyoscine (20 mg) (− 18.1 min, 95% CI − 342.8 to 306.7, p = 0.60) and drotaverine (− 25.8 min, 95% CI, − 96.7 to 45.1, p = 0.32).
The differences in the mean duration of the third stage of labor between camylofin and drotaverine (− 3.3 min, 95% CI − 5.45 to − 1.10, p = 0.006), valethamate (− 3.6 min, 95% CI, − 6.52 to − 0.77, p = 0.02), and hyoscine (20 mg) (− 2.9 min, 95% CI, − 5.43 to − 0.38, p = 0.03) significantly favored camylofin. The differences in the mean duration of the second stage of labor and IDI were comparable across all the four antispasmodics.
One of the studies included in the NMA, Bachani and Topden 2005, had a sample size of 700 women in the intervention arm and thus could have skewed the results. Moreover the other adjunct treatment(s) used with the camylofin arm might have also confounded the results [12]. Thus, a sensitivity analysis excluding this study was performed. The sensitivity analysis also showed a similar trend as that of the primary analysis except for the mean difference in the duration of the first stage of labor, which favored camylofin over drotaverine (− 21.3 minutes, 95% CI, − 93.83 to 51.26, p = 0.55) (Supplementary Tables 8-12).
Safety of AntispasmodicsA qualitative summary of frequently reported maternal and fetal AEs is presented in Table 3.
Maternal OutcomesA total of 145 events of tachycardia were reported in the selected studies. The incidence of tachycardia was most commonly reported in women receiving valethamate (106/145, 73.10%) and least reported in women receiving camylofin (3/145, 2.07%). Similarly, dryness of mouth was reported most frequently with valethamate (103/140, 73.57%) and least frequently with hyoscine (10/140, 7.14%). Nausea and vomiting (21/110, 19.09%), cervical/vaginal tear (3/20, 15.00%), and postpartum hemorrhage (2/13, 15.38%) were other events reported with camylofin use.
AEs reported with camylofin were comparatively lower (42 events in 963 women) than reported with drotaverine (80 events in 1069 women), hyoscine (27 events in 476 women), and valethamate (235 events in 770 women). Nausea and vomiting (21/42 events, 50%) and dryness of mouth (13/42, events, 31%) were most frequently reported AEs in women receiving camylofin. Tachycardia was commonly reported in women receiving hyoscine (12/27, 44.4%) and valethamate (106/235, 45.1%). Postpartum hemorrhage and cervical/ vaginal tear (2 and 3 events in 963 women, respectively) were rarely reported events in women receiving camylofin compared with women receiving drotaverine (6 and 8 events in 1069 women, respectively).
Fetal Outcomes
Fetal distress was the most commonly observed AE among babies born to women receiving camylofin (238/270, 85.30%). A majority of these events (235) were reported in 1 study having a high risk of bias, which used drotaverine or tramadol along with camylofin in the intervention arm [12]. Abnormal fetal heart rate (tachycardia/bradycardia) and neonatal morbidities observed with other antispasmodics were not observed with camylofin.
Conflict of interest The authors express that there is no conflict of interest.
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