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IS ORAL MISOPROSTOL A PROMISING ALTERNATIVE TO STANDARD OXYTOCICSIN THE THIRD STAGE OF LABOUR?
SANJAY B RAO*, M FONSECA**, SACHIN AJMERA***,BHUPESH DHANANJAYAN****, VR BADHWAR*****
*Lecturer; **Associate Professor; ***Resident; ****Intern; *****Head of Department of Obstetrics and Gynaecology, LTMM College and LTM General Hospital, Sion, Mumbai 400 022.
Misoprostol (Cytotec, Searle) is a prostaglandin E1 analogue. Oral misoprostol is rapidly absorbed within two minutes into circulation. It has a rapid onset of action with a uterotonic effect on the postpartum uterus. A single blind non randomised study was conducted in a tertiary hospital to compare oral misoprostol versus standard oxytocics in the third stage of labour including oxytocin, methergin and prostaglandin F2a. The primary outcome was measured in terms of fall in haemoglobin levels postpartum in each of the four study groups. The secondary outcomes evaluated included analysis of the mean duration of third stage, amount of postpartum haemorrhage, and the need for additional oxytocics. A profile of symptomatology in each study group included assessment for nausea, vomiting, diarrhoea, headache and shivering.
This study concludes that misoprostol has the potential of an effective, stable oral oxytocic with a rapid onset of action. It has predictable side effects and a good safety profile. It is as effective as standard oxytocic drugs in preventing atonic post partum haemorrhage.
INTRODUCTION
Postpartum haemorrhage is the leading cause of direct maternal death in developing countries. The incidence of postpartum haemorrhage may vary from less than 5% to more than 10%, though it is difficult to be precisely ascertained. 30% of maternal deaths in developing countries like India occur due to massive haemorrhage. The figures remain at least 100 times higher than those in developed countries.[4,5] Although risk factors may increase a woman’s chances of developing postpartum haemorrhage, two thirds of cases of postpartum haemorrhage occur without any predisposing factors.[6] Hence all pregnant women remain ‘at risk’ for this catastrophic event.
Research has demonstrated that normal blood loss in a vaginal delivery may exceed 500 ml and can range from 500 to 1000 ml.[6,7] Prendiville et al suggested that blood loss in excess of 1000 ml would be a more useful clinical definition.[8] However the problem of blood loss at delivery could remain notoriously inaccurate because it is a subjective visual observation of the obstetrician rather than an objective measurement. Therefore, a decline in haematocrit[9] or haemoglobin is a more reliable estimation of blood loss.
Various comparative trials have been conducted to study the reduction of blood loss through active versus expectant management of labour. They have predominantly focused on blood loss originating from the placental bed. As a part of the physiological adaptation to pregnancy the spinal arteries of the placental bed are denuded of their muscular layer. Active management promptly initiates uterine contractions to compress these spinal arteries as they run among uterine smooth muscle fibres.
Adequate management of the third stage is crucial for the prevention of postpartum bleeding in patients undergoing vaginal delivery. Prendiville et al in the Bristol third stage trial found an incidence of postpartum bleeding of 5.9% in the actively managed group and 17.9% in the physiologically managed group. They concluded that active management had definitely reduced third stage blood loss.[8]
The routine use of oxytocin has been effective in reducing the incidence of postpartum haemorrhage. Though various oxytocics like ergometrine, oxytocin and prostaglandins F2 alpha are available, no single drug has emerged the most superior or ‘drug of choice’. The World Health Organization recommends intramuscular oxytocin in the third stage of labour. Ergometrine is also an effective oxytocic but is frequently associated with nausea, vomiting[11] and hypertension.[8] Both ergometrine and oxytocin require special storage in refrigeration to maintain their potency. They also need to be administered parenterally thus requiring disposable needles and syringes. Oral ergometrine is insufficiently effective for routine use.[12] Intramuscular injections of PGF2a have also been tried successfully in the active management of the third stage.[13]
Misoprostol is a prostaglandin E1, analogue that is additionally methylated at C-16. It does not require storage in refrigeration and has also a shelf life of several years.[14,15] It is widely used in the treatment of peptic ulcer caused by nonsteroidal anti-inflammatory drugs. It is also a potent uterotonic agent. It has a wide range of clinical application in the induction of abortions, cervical ripening and induction of abortion.[16,17]
Oral Misoprostol is absorbed rapidly within two minutes into circulation.[18] It has a rapid onset of action with a uterotonic effect on the postpartum uterus.[19] Therefore oral misoprostol may be a potential alternative to standard oxytocics in preventing atonic postpartum haemorrhage in both low risk and high risk pregnancies.
The purpose of this single blind non randomized controlled trial of oral misoprostol with parenteral oxytocin, ergometrine and PGF2a was to assess the reduction in the third stage blood loss in low risk pregnancies by objective assessment of the difference in pre delivery and post delivery haemoglobin values. Subjective evaluation of symptomatic response to misoprostol in comparison to other standard oxytocics was also done.
MATERIAL AND METHODS
This study was conducted at a 1416 bedded tertiary municipal hospital which cares for approximately 6500 deliveries each year. 160 low risk term pregnant women were included in four study groups from 1st Jan. 2001 to 25th Feb. 2001. Group A (40 patients) received 400 mg Misoprostol orally immediately after birth of the baby and clamping of the umbilical cord. The Group B (40 patients) received 10 IU intramuscular oxytocin at the delivery of anterior shoulder and Group C (40 patients) received intravenous methyl ergometrine 0.5 mg. Group D (40 patients) received 125 mg intramuscular PGF2a. The placentae were delivered by controlled cord traction.
Exclusion criteria
Patients undergoing caesarean section were not included in this study. Patients with Hb < 8 gm%, pregnancy induced hypertension, grand multiparae, multiple pregnancy, malpresentations, coagulation abnormalities or medical disorders were excluded from this study.
The primary outcome was objective assessment of blood loss. The haemoglobin concentration was recorded by Sahli’s method before delivery. A second Hb estimation was done 24 hours postpartum. Baseline maternal characteristics were noted. These included age, height, weight and parity. Significant obstetric history, if any was recorded. The blood pressure levels were noted before and after delivery. Other variables included agents used for augmentation of labour, use of epidural analgesics and mode of delivery with birth weight. Any traumatic causes for post partum haemorrhage were recorded.
Differences in haemoglobin concentration pre and postpartum were estimated in each group. Blood loss was also quantified in a kidney tray immediately following clamping of and division of the umbilical cord. The secondary outcomes which were evaluated included nausea, vomiting, diarrhoea, shivering and headache.
OBSERVATION
TABLE 1
Demographic variables of patientsMisoprostol Oxytocin Methergin PG F2 a Parameters (N=40) (N=40) (N=40) (N=40) Mean Age (yrs) 23.6 ± 2.9 24.1 ± 3.1 22.8 ± 3.8 24.2 ± 3.9 Mean height (cms) 147.2 ± 8.9 146.8 ± 7.8 147.3 ± 6.36 144.7 ± 6.01 Mean weight (kg) 51.9 ± 6.4 9.2 ± 5.3 50.7 ± 7.11 53.2 ± 6.91 Mean period (wk) of gestation 37.2 ± 2.4 38.1 ± 3.11 37.4 ± 2.9 37.2 ± 3.08 Student’s test p > 0.05 Not Significant
TABLE 2
Events in labourMisoprostol Oxytocin Methergin PGF2 a (N=40) (N=40) (N=40) (N=40) Labour Spontaneous 34 37 (92%) 36 (90%) 36 (90%) Labour induced 6 (15) 3 (8%) 4 (10%)s 4 (10%) Augmentation with oxytocin 5 (12.5%) 13 11 (27.5%) 14 (35%) Use of Epidural analgesia 0 3 0 2 Mean Duration of 1st Stage (Hours) 6.6 6.4 6.3 6.41 Mean Duration of IInd stage (minutes) 45 40 42 43 Mean Duration of III stage in (min) 6.1 6.3 6.2 6.4 Mean Difference in Pre and post delivery BP Systolic mmHg ± 8 ± 10 ± 10 ± 12 Diastolic mmHg ± 10 ± 6 ± 12 ± 8
TABLE 3
Events in the 3rd stage of labourMisoprostol Oxytocin Methergin PG F2a Blood loss > 500 ml 6 (15%) 7 (17.5%) 4 (10%) 5 (12.5%) Use of additional Oxytocics 6 7 4 5 Average blood loss 260 280 360 220
TABLE 4
Profile of symptomatology in all study groupsSymptom Misoprostol Oxytocin Methergin PG F2a P No % No % No % No % Nausea 2 5 3 (7.5) 14 (35.0) 10 (25.0) P < 0.05 Vomiting 2 5 2 (5.0) 13 (32.5) 14 (35.0) P < 0.05 Shivering 13 32.5 6 (15.0) 3 (7.5) 04 (10.0) P < 0.05 Diarrhoea 2 5 0 - 0 - 21 (52.5) P < 0.05 Headache 2 5 0 — 4 (10) 05 (12.5) NS Temperature 38oC 6 15 0 — 0 0 2 5 NS (Chi-square test) - NS - Not significant P < 0.05 – significant
TABLE 5
Comparison of changes in haemoglobin levels between all the groupsMean Haemoglobin (Gms%) x ‘ SD Groups Pre-delivery Post-delivery Misoprostol 10.4 ± 1.2 9.8 ± 0.92 Oxytocin 10.5 ± 1.1 9.9 ± 1.01 Methergin 10.6 ± 0.9 10.01 ± 0.90 PG F2a 10.2 ± 1.0 9.7 ± 0.85 Student’s ‘t’ test - P > 0.05 Not Significant; (x = mean)
TABLE 6
Comparison of average blood loss between all the groupsGroups Mean Blood loss (ml) Misoprostol 260.8 ± 41.4 Oxytocin 280.4 ± 47.5 Methergin 258.9 ± 39.5 PG F2a 221.4 ± 40.6 (By Student’s ‘t’ test) - P > 0.05 not significant
RESULTS
This prospective study evaluated 40 patients each in four study groups.
Table 1 shows four demographic variables including mean age, mean height in centimeters, mean body weight in kilograms and mean period of gestation in weeks. There were no statistically significant differences in any of these variables, indicating that baseline characteristics of patients selected remained similar in all four arms of the trial (p > 0.05 not significant).
Table 2 shows that events during labour were comparable in all four groups before administration of the oxytocic drug. Labour occurred spontaneously in 85% of patients in the misoprostol group, 92% of patient of oxytocin group and 90% of patients each in methergin groups and PGF2a group respectively. The percentage of patients who underwent augmentation with oxytocin in group B, C, D ranged from 27% to 35%. 12.5% of patients in group A had undergone augmentation of labour. There were only three and two patients in group B and Group D respectively who were given epidural analgesia.
Table 3 shows that the incidence of post partum haemorrhage (blood loss > 500 ml) was 15% each in group A and 12.5% in group D. 15% of patients receiving methergin had postpartum haemorrhage. This difference was not statistically significant. All patients from group A,B,C who had postpartum haemorrhage had received an intravenous infusion containing 20 IU of oxytocin and 250 mgs intramuscular injection. Two patients in group B also had traumatic causes for postpartum blood loss-cervical tears and vaginal lacerations. However none required blood transfusions.
Table 4 reveals that in all groups predelivery haemoglobin levels were in a comparable range with a mean Hb between 10.2 and 10.6 (range 9.2 to 11.5 gm%). The mean Hb reduction was in the range of 5% to 6% in all four groups. A profile of the symptomatology in Table 5 showed that in group A 32.5% patients receiving misoprostol experienced shivering which was significantly higher when analysed by Chi-square test (p < 0.05) as compared to other groups. In patients receiving methergin, nausea and vomiting were noted more frequently (32-35%). In group D patients receiving PG-F2a, nausea, vomiting and diarrhoea occurred in 25-50% of the patients.
DISCUSSION
Prophylactic administration of oxytocic agents in the third stage of labour could significantly reduce the rate of postpartum haemorrhage from 18% to 5%.[2,20] In addition, the need for therapeutic oxytocic drugs is reduced from 30% to 6% and the duration of the third stage is reduced from 15 minutes to 5 minutes.[2,20]
The present comparative study has shown that orally administered misoprostol with its rapid onset of action is as effective as oxytocin, methergin and prostaglandin F2 in terms of minimization of blood loss in the third stage.
Misoprostol has many advantages. It is cheap, storable at room temperature and absorbed rapidly. It does not cause significant hypertension unlike methergin. It does not have a bronchoconstrictory effect unlike PG F2a. It has an acceptable safety profile.
A review of literature showed that oral misoprostol has been compared with a control group[21] or to a placebo.[22] A study by Bamigboye et al compared rectal misoprostol with synometrine for the management of third stage of labour. In the present study, the average duration of the third stage was 6.2 minutes in the misoprostol group and ranged between 6.2 and 6.4 minutes with other oxytocins. There was no statistically significant difference in the mean blood loss between the misoprostol group and the oxytocics used, as analysed by the student’s t test in Table 3. Only 15% of patients in the misoprostol group had blood loss exceeding 50 ml. This was comparable to other oxytocics used in the study series. None of the patients in the misoprostol group needed blood transfusion. In the three other groups there were two patients in group B, who required one unit of blood transfusion.
E1Rafaey et al also reported no significant differences between misoprostol and oxytocin. When comparing the drop in haemoglobin concentration.[23] In the present study also a reassuring primary outcome was that the maximum of haemoglobin between all four groups was in the range of 5 to 6 percent.
In the present series, analysis of symptomatology shows that shivering was most frequently seen in the misoprostol group. This was an undesirable side-effect, though it was self-limiting and responded to chlorpheniramine or tramadol. Both shivering and pyrexia occurring with use of misoprostol is likely to be a prostaglandin E, effect on central thermoregulatory centres. Lumbiganol et al report that though this may be of limited clinical concern, it can make the obstetrician suspicious of infection and cause unnecessary tests or initiation of antibiotic therapy.[24] They also report a dose-related modest difference of 15% reduction in shivering when 400 mg is used instead of 600 mg.[24] Nausea and vomiting were more common in the methergin and prostaglandin F2a groups. All these patients needed metaclopramide injections for symptomatic relief. Diarrhoea was a unpleasant side-effect occurring frequently in the PGF2a group. Chua S et al also report a statistically significant increase in the incidence of profuse frequent diarrhoea with the use of PGF2a. In their randomized controlled study they concluded that use of 125 mg PFG2a had the disadvantage of higher cost and diarrhoea.[25]
CONCLUSION
This study concludes that Misoprostol has the potential of an effective, stable oral oxytocic with a rapid onset of action. It has predictable side effect and a good safety profile. It is as effective as standard oxytocic drugs in preventing atomic postpartum haemorrhage. Though the study was limited to low risk patients. However, misoprostol has scope for use even in high-risk patients of bronchial asthma, pregnancy induced hypertension and Rh negative blood groups where other oxytocics are contraindicated. Moreover, it holds promise for the obstetrician in rural areas to tide over, the "Unforgiving stage of labour", by effectively controlling blood loss.
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