Objective: To comparatively evaluate the efficacy and safety of Drotaverine hydrochloride and Valethamate bromide in shortening first stage of labour in a primi mother.
Method : The study was conducted over 300 selected uncomplicated primi gravidae, with term pregnancy, in established labour at 3-4 cm cervical dilatation with adequate uterine contraction. In group D, 100 cases were given Injection Drotaverine 40mg intramuscularly, every 2 hours, for a maximum 3 doses. In group V, 100 cases were given Injection Valethamate 8mg intravenously, every half hour, for a maximum of 3 doses. In group C, 100 cases underwent labour without the administration of any smooth muscle relaxants. Duration of first, second and third stage of labour, rate of cervical dilatation, number of injections required and any maternal or neonatal adverse outcomes were noted.
Results : The rate of cervical dilatation was significantly increased in Drotaverine group, when compared with control group (p=0.0001) and Valethamate group (p=0.0006). Both drotaverine and valethamate reduced duration of first stage of labour when compared with control group, the difference being statistically significant. Drotaverine was found to be more effective than valethamate and the difference was statistically significant (p-value 0.0022). There were no serious maternal or neonatal adverse effects in any group.
Conclusion : The reduction of the duration of first stage of labour was observed with both Drotaverine and Valethamate, with Drotaverine being more effective. Both drugs were found to be safe with minimal or no adverse effects on the mother and the fetus.
labour, drotaverine, valethamate, cervical dilatation, stages of labour
Onset of labour represents the culmination of a series of biochemical changes in the uterus and cervix. These result from endocrine and paracrine signals emanating from both mother and fetus. The first stage of labour starts from the onset of true labour pain and ends with full dilatation of the cervix. Its average duration is 12 hours in primigravidae and 6 hours in multiparae and unlikely to last more than 18 hours. There are several labour abnormalities that interfere with the orderly progression to spontaneous delivery. These are referred to as dystocia and it is characterized by abnormally slow labour progress. Protaction disorders are more commonly seen in primigravida women as compared to multigravida.
These days active management of labour is the norm, rather than the exception. In view of this, search for methods to reduce the duration of labour and thus decrease the incidence of complications arising due to prolonged labour is a must.
As shown in studies conducted in India and elsewhere,, antispasmodics could be used as accelerators of labour. Drotaverine hydrochloride and valethamate bromide are two such newer agents that are being employed or to be employed for this purpose, without having any deleterious effects on the mother and fetus.
This was a prospective interventional study conducted over 1.5 years at M. R. Bangur Hospital from September 2013 to March 2015.
The number of patients calculated for this study was 300.17 ∼ 300 with power 86% (Proportion of primi gravida among the pregnant women who underwent vaginal delivery was 39.4% out of the total patients that attended Obstetrics and Gynaecology Department at M. R. Bangur hospital i.e. p= 0.394 as per the hospital record). The formula used for sample size calculation was as follows ñ n = 4pq/L2
Where, n= Required sample size ; p= Proportion of cases ; q = 1 ñ p ; L = Loss %
300 primi gravida mothers who fulfilled the inclusion criteria and with exclusion criteria ruled out were included in the study. Only booked cases were included in the study. Patient evaluation was done according to the designed proforma, that included detailed demographic, social, and obstetric histories.
Following inclusion and exclusion criteria were considered for selection of uncomplicated patients.
Inclusion Criteria : 1. Singleton pregnancy in primigravida women with no antenatal medical/surgical/obstetric risk factors.
2. Informed consent
3. Cephalic presentation
4. Spontaneous onset of labour
5. Women in active phase of labour with uterine contractions of at least 3 every 10 minutes, with each contraction lasting for at least 30 seconds
6. Cervical dilatation of 3-4 cms and effacement 70 - 80%
7. Intact foetal membranes
8. Gestational period of 37 to 42 weeks
9. Age group 20 to 30 yrs.
Exclusion Criteria : 1. Cephalopelvic disproportion
2. History of cervical / uterine surgery in the past
3. Known hypersensitivity or contraindications to the use of Drotaverine and / or Valethamate
4. Use of any other agent augmenting labour and / or affecting cervical dilatation
5. Induced labour
6. Evidence of maternal or fetal compromise
After obtaining a homogenous group based on inclusion criteria, 100 cases each were randomly assigned by computer generated number to group D (Drotaverine), group V (Valethamate) and group C (Control). Group D constituted those who were administered Inj. Drotaverine 40mg intramuscularly, every 2 hours, for a maximum of 3 doses. Group V were administered Inj. Valethamate bromide 8mg intravenously every half an hour, for a maximum of 3 doses. Group C was the Control group who underwent labour without administration of any smooth muscle relaxants.
For all participants, assessment of cervical dilatation was done every two hours and supportive management in the form of adequate hydration, nutrition and bed rest was provided. Progress of labour was plotted on partogram. Blood pressure and pulse rate measured hourly and half-hourly respectively.
The duration of first stage (specifically the active phase of labour), second and third stages of labour was noted for all the women. Total duration of labour and rate of cervical dilatation were calculated. The mode of delivery, spontaneous or instrumental was noted. Any woman who had to be taken for caesarean section for maternal or fetal indication or cephalopelvic disproportion was excluded from the study.
In the Drotaverine and Valethamate groups any woman who reported any discomfort or specific complaints such as headache, nausea, vomiting, dryness of mouth were managed accordingly and the complaint as such, was noted under side effects of the drug administered.
For all the women in all three groups, maternal adverse outcomes in the post partum period were evaluated by assessing for blood loss, and exploration of cervix and vagina was done to note any tears or lacerations that required repair. These were managed appropriately under the watchful guidance of senior obstetrician.
For assessment of fetal well being in the intrapartum period, for all three groups, fetal heart rate was monitored every half an hour and noted in the partograph.
The colour of liquor (in cases where the membrane had ruptured spontaneously during the course of labour) was noted and if found to be meconium stained, was accordingly managed under the watchful guidance of senior obstetricians. Amniotomy was not done in the present study, as it is a well established method of augmentation of labour and use of additional modalities to induce or augment labour would have excluded the parturient from this study.
Neonatal well being was evaluated by calculating APGAR scores at 1 minute and 5 minutes of birth respectively for all the neonates, irrespective of the maternal groups. A score of < 7 was considered an adverse neonatal event, and managed accordingly under the supervision of senior paediatricians.
Finally, all the data that was collected from the study was compiled, and further analysis was carried out to reach a conclusion.
Statistical Analysis :
Statistical Analysis was performed with help of Epi Info (TM) 3.5.3 which is a trademark of the Centers for Disease Control and Prevention (CDC). Using this software, mean and standard deviations (S.D.) were calculated and basic crosstabulation and frequency distributions were prepared. Test was used to test the association of different study variables with the study groups. t-test was used to compare the means and Test of proportion (Z-test) i.e. Standard Normal Deviate was used to test the difference between two proportions. p = 0.05 was considered statistically significant.
Results and Observations :
In the present study, epidemiological factors of all participants were the same. The groups were statistically matched for age, socio-economic status and gestational age.
Table 1:Number of injections.
|No. of injections||Drotaverine(n=100)||Valethamate(n=100)||Total|
Most of the subjects of the Drotaverine Group require single dose 74% or 2(24%) injections.
Most of the subjects of Valethamate Group require 3 doses(98%).
Table-2:Comparison of duration of active phase (in minutes)
|Comparison of groups||t ||p-value|
|Control vs Drotaverine||9.59||< 0.00001*|
|Control vs Valethamate||7.34||< 0.0001*|
|Drotaverine vs Valethamate||1.18||0.23NS|
*Significant at 1% level of significance; NS- Not Significant
The main duration of active phase (mean ± SD) of the control, Drotaverine and Valethamate groups were 252.25 ± 37.87, 188.00 ± 55.24 and 210.25 ± 42.86 minutes respectively. The main duration of active phase of Drotaverine group and Valethamate group were significantly lower than that of control (p< 0.01). Though main duration of active phase of Drotaverine group was shorter than that of Valethamate group but it was statistically significant.
Table-3: Comparison of duration of stage I of labour(in minutes)
|Comparison of groups||t ||p-value|
|Control vs Drotaverine||7.20||< 0.0001*|
|Control vs Valethamate||4.67||< 0.001*|
|Drotaverine vs Valethamate||3.10||0.0022*|
*Significant at 1% level of significance.
The mean duration of stage 1 (mean ± SD)of the Control, Drotaverine and Valethamate groups were 285.70 ± 54.59, 220.20 ± 72.69 and 248.85 ± 56.92 minutes respectively. t-test showed that mean duration of first stage of Drotaverine group and Valethamate group were significantly shorter than that of Control group(p< 0.01).
Table-4: Comparison of duration of Second Stage of labour (in minutes)
|Comparison of groups||t ||p-value|
|Control vs Drotaverine||1.58||0.11 NS|
|Control vs Valethamate||0.32||0.74 NS|
|Drotaverine vs Valethamate||1.41||0.16 NS|
The mean duration of Second Stage of labour (mean ± S.D.) of the Control, Drotaverine and Valethamate groups were 46.09 ± 9.19, 44.33 ± 6.29 and 45.71 ± 7.49 minutes respectively. t-test showed that mean duration of second stage of Drotaverine Group and Valethamate Group were shorter than that of Control Group, but not statistically significant (p > 0.01). Duration of second stage of labour was shorter in Drotaverine group than that in Valethamate group, but the difference was not statistically significant (p > 0.01).
Table-5: Comparison of duration of Third stage (in minutes)
|Comparison of groups||t ||p-value|
|Control vs Drotaverine||1.53||0.1276 NS|
|Control vs Valethamate||0.99||0.3234 NS|
|Drotaverine vs Valethamate||0.56||0.5761 NS|
The mean duration of Third stage of labour (mean ± S.D.) of the Control, Drotaverine and Valethamate groups were 5.17 ± 0.76, 5.02 ± 0.61 and 5.07 ± 0.65 minutes respectively. The mean duration of Third stage of labour of Drotaverine Group and Valethamate Group were shorter than the control group, but the difference was not statistically significant.
Table-6: Comparison of rate of cervical dilatation (in minutes)
|Comparison of groups||t ||p-value|
|Control vs Drotaverine||9.03||p=0.0001*|
|Control vs Valethamate||6.80||p=0.0001*|
|Drotaverine vs Valethamate||3.56||p=0.0006*|
* Significant at 1% level of significance.
The mean rate of cervical dilatation (mean ± S.D.) of the Drotaverine, Valethamate and Control groups was 2.09 ± 0.67 cm/hr, 1.80 ± 0.46 cm/hr and 1.45 ± 0.23 cm/hr respectively. t-test showed that mean rate of cervical dilatation of Drotaverine Group and valethamate group were significantly higher than that of Control group (p< 0.01). Also, Drotaverine group had significantly higher rate of cervical dilatation when compared to valethamate group.
Distribution of APGAR score at 1 minute.
|APGAR score at 1min.||Control group(n=100)||Drotaverine Group(n=100)||Valethamate Group(n=100)||TOTAL|
x2=1.04; p=0.59; NS: Not Significant
Corrected Chi-square(x2) test showed that there was no significant association between Apgar score at 1 minute and group of pateints (p=0.59). APGAR score calculated at 5 minutes was found to be =7 in all the neonates and in all the groups.
Table 8: Side Effects.
a- fetal heart rate; b-trancient material tachycardia.
In the Drotaverine group none of the parturients had FHR variation, 3(3%) had TMT and 5(5%) had vomiting whereas in the valithamate group 1 subject(1%) had FHR variation, 5(5%) had TMT and none of the participants had vomiting. Test of proportion showed that there was no significant difference in the proportiob of different side effects of the three groups(p> 0.05).
Table 9: Distributions of complications.
a- Post partum haemorrhage; x2=1.31; p=0.51; NS: Not significant
Corrected Chi-square (x2) test showed that there was no significant association between complications and group of the patients (p=0.51).
Various studies have been conducted over the last two decades to determine the efficacy of antispasmodics, particularly drotaverine hydrochloride and valethamate bromide in shortening the first stage of labour. Drotaverine hydrochloride is a novel smooth muscle antispasmodic which acts by inhibition of phoshodiesterase-4 enzyme (PDE-4). It is an isoquinolone derivative which binds to the surface of smooth muscle cells and changes their membrane potential and permeability. Valethamate bromide is a synthetic compound, belonging to the anticholinergic group of drugs. It is a tertiary amine. It acts as a visceral antispasmodic and also helps hasten the rate of cervical dilatation.
In the present study, 74% of the Drotaverine group required only 1 injection and 98% of the Valethamate group required 3 injections to achieve satisfactory cervical dilatation. The above results were comparable with those of Jayashree S,Virupaksha Ajjammanavar, Sujatha M.S. (2013).
Active phase of labour was found to be shortest with Drotaverine, followed by Valethamate. It was the longest in the control group. Mean duration of the active phase was significantly shorter with Drotaverine and Valethamate when compared with Control group. The difference in duration of active phase with Drotaverine and Valethamate was not statistically significant. In the present study, there was no significant reduction in the duration of second and third stages of labour with the administration of drotaverine or valethamate when compared with control group. These results were comparable with Singh KC et al (2004) and Tripti N, Jyoti J (2009).
Six studies (Jayshree S et al, Madhu C et al, Tripti N et al, Kaur D et al, Mishra et al and Sharma JB et al) reported on the rate of cervical dilatation. In the present study, the rate of cervical dilatation was significantly higher in Drotaverine group when compared with Control and Valethamate groups. The results were comparable with Mishra SL et al and Sharma JB et al.
Duration of active phase (in minutes) in different groups in various studies :
|Study||Drotaverine Group||Valethamate Group||Control Group|
|DAHAL P et al||178.31 +/- 73.412 min||254.29 +/- 96.621 min||346.31 +/- 123.351min|
|MADHU C et al||183.2 +/- 78.8 min||206.5 +/- 69.7 min||245 +/- 70.9 min|
|SHARMA JB et al||193.96 min||220.68 min||412.84 min|
|PRESENT STUDY||188.00 +/- 55.24 min||210.25 +/- 42.86 min||252.25 +/- 37.87 min|
In the present study, there was no significant reduction in the duration of second and third stages of labour with the administration of drotaverine or valethamate when compared with control group. These results were comparable with Singh KC et al (2004) and Tripti N, Jyoti J (2009).
Six studies (Jayshree S et al, Madhu C et al, Tripti N et al, Kaur D et al, Mishra et al and Sharma JB et al) reported on the rate of cervical dilatation. In the present study the rate of cervical dilatation was significantly higher in Drotaverine group when compared with Control and Valethamate groups. The results were comparable with Mishra SL et al and Sharma JB et al.
Rate of cervical dilatation in various studies :
|Control Group||Drotaverine Group||Valethamate Group|
|Jayshree et al (2013)||0||3.31 cm/hr||2.58 cm/hr|
|Tripti N et al (2009)||0||2.89 cm/hr||2.01 cm/hr|
|Kaur D et al (2003)||0||3.18 cm/hr||2.41 cm/hr|
|Mishra SL et al (2002)||0||2.05 cm/hr||1.53 cm/hr|
|Sharma JB et al (2001)||1.01 cm/hr||2.04 cm/hr||1.86 cm/hr|
|PRESENT STUDY||1.45 cm/hr||2.09 cm/hr||1.80 cm/hr|
In the present study APGAR score at 1" was < 7 in 6 neonates born to mothers of the control group, 5 neonates from Drotaverine group and 3 neonates from Valethamate group. These findings were not statistically significant. All the neonates from all three groups had APGAR score > 7 at 5 minutes of birth.
In the present study, the most common side effects noted in Drotaverine group was vomiting and transient maternal tachycardia, while those in Valethamate group showed maternal tachycardia more commonly. The most common post partum complications, that occurred were post partum haemorrhage and cervical tear/lacerations requiring repair. None of these complications were found to be statistically significant.
Conclusion : The above findings have important implications in a developing nation such as ours, where expert anaesthesiologists to perform epidural analgesia on mothers in labour are not available at many centres and cost remains a limiting factor. In such a scenario, antispasmodics such as Drotaverine hydrochloride and Valethamate bromide provide an alternative and cost effective method to alleviate the pain associated with labour and also effectively reduce the duration of labour, without causing any maternal or neonatal adverse events or altering the rate of uncomplicated vaginal deliveries.
However, as per the WHO recommendation for augmentation of labour (2014), the use of antispasmodic agents for treatment of delay in labour remains a research priority.