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Titrated oral misoprostol for augmenting labour to improve maternal and neonatal outcomes

  1. Joshua P Vogel1,2,*,
  2. Helen M West3,
  3. Therese Dowswell3

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 23 SEP 2013

Assessed as up-to-date: 29 JUL 2013

DOI: 10.1002/14651858.CD010648.pub2


How to Cite

Vogel JP, West HM, Dowswell T. Titrated oral misoprostol for augmenting labour to improve maternal and neonatal outcomes. Cochrane Database of Systematic Reviews 2013, Issue 9. Art. No.: CD010648. DOI: 10.1002/14651858.CD010648.pub2.

Author Information

  1. 1

    World Health Organization, UNDP/UNFPA/UNICEF/WHO/Word Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, Geneva, Switzerland

  2. 2

    University of Western Australia, School of Population Health, Faculty of Medicine, Dentistry and Health Sciences, Perth, Western Australia, Australia

  3. 3

    The University of Liverpool, Cochrane Pregnancy and Childbirth Group, Department of Women's and Children's Health, Liverpool, UK

*Joshua P Vogel, vogeljo@who.int. josh.vogel00@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 23 SEP 2013

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Characteristics of included studies [ordered by study ID]
Bleich 2011

MethodsRandomised trial, two-arm, individual randomisation stratified as either nulliparous or multiparous. Analysed by both intention-to-treat, and as-treated for selected outcomes.


ParticipantsSetting: Single facility in Dallas County, USA.

Period of data collection: December 2008 - January 2011.

Inclusion criteria: Women with spontaneous labour that reached the active phase of labour (defined as cervical dilation of 4 cm or more) but did not progress, maternal age 16 years or older, gestational age 36 weeks or more, singleton, cephalic presentation, reassuring FHR, cervical dilation between 4 and 8 cm, and English or Spanish speaking. Eligible individuals were required to have ruptured membranes with an intrauterine pressure catheter in place confirming the presence of fewer than 200 Montevideo units of uterine activity, the absence of tachysystole, defined as 6 or more contractions in a single 10-min period, and the absence of uterine hypertonus, defined as a single contraction lasting longer than 120 seconds.

Exclusion criteria: non-reassuring FHR pattern, meconium-stained amniotic fluid, previous uterine incision, maternal fever (defined as temperature 38°C or higher), known fetal anomalies, placenta previa or unexplained vaginal bleeding, estimated fetal weight 4500 g or more, abnormal bony pelvis, and parity of 6 or more.

Participants: 439 women met inclusion criteria, of which 350 (79.7%) consented and were randomised. Women recruited were mostly Hispanic (88% Hispanic, 5% White, 7% African American).


InterventionsExperimental group: 75 mcg of oral misoprostol, for up to 2 doses 4 hrs apart. This was prepared by cutting generic 100 mcg misoprostol tablets into one-half and one-quarter tablets. Women were eligible for a second dose of misoprostol if they had a reassuring FHR tracing and did not experience uterine tachysystole or hypertonus after the first dose. All women in the misoprostol arm were assessed for drug failure 2 hrs after administration of the second dose. If they experienced less than 200 Montevideo units and minimal cervical change, IV oxytocin was initiated. If women randomised to the misoprostol arm developed a non-reassuring fetal heart rate (defined as tachycardia, prolonged or late decelerations, moderate to severe variable decelerations (nadir of up to 90 beats per min for more than 30 seconds or a duration of 60 seconds or longer), or any combination of these), uterine tachysystole, or hypertonus before the administration of misoprostol, the study drug was withheld and labour augmented with IV oxytocin.

176 (50.3%) women were randomised to the experimental group, of which 136 (77.30%) received the study drug and 40 (22.7%) did not.

Control group: Women received titrated IV oxytocin according to a hospital protocol of a 6 milliunits/min starting dose, followed by incremental increases of 6 milliunits/min at 40-min intervals, up to a maximum dose of 42 milliunits/min. The protocol also specified use of 3-milliunit/min or 1-milliunit/min doses if tachysystole or hypertonus were encountered. The oxytocin was prepared as a 20 units/L solution in isotonic saline and administered by using calibrated infusion pumps.

 

174 (49.7%) randomised to the control group, of which 143 (82.2%) women received the control drug and 31 (17.8%) did not.


OutcomesPrimary outcome: incidence of uterine tachysystole, hypertonus, or both in a 10-min period.

Secondary outcomes:

  • Uterine tachysystole in a 20-min interval (defined as 6 contractions in 2 consecutive 10-min periods).
  • Birthweight.
  • Apgar score less than 4 at 5 mins of life.
  • Umbilical cord artery pH less than 7.1.
  • Admission to the NICU.
  • Chorioamnionitis (defined as a temperature of 38°C or higher in the absence of other sources of infection).
  • Maternal blood transfusion for hypovolaemia.
  • Mode of delivery elapsed time from start of labour augmentation to complete cervical dilatation.
  • Elapsed time from the start of labour augmentation to delivery.
  • Maximum number of Montevideo units.
  • Diagnosis of non-reassuring FHR were evaluated.


Also reported on other outcomes:

  • Tachystole in a 10-min period.
  • Hypertonus in a 10-min period.
  • Tachysystole, hypertonus, or both associated with non-reassuring FHR.
  • Caesarean for dystocia.
  • Caesarean for non-reassuring FHR.
  • Epidural analgesia.
  • Time from admission to study drug (min).
  • Duration of second stage (min).
  • Maximum oxytocin doses (milliunits/min).


NotesSeveral continuous outcomes were reported as median (interquartile range) rather than mean (standard deviation).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation sequence.

Allocation concealment (selection bias)Low riskOn enrolment, an opaque envelope corresponding to the participant’s enrolment number was opened.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskWomen and care staff were not blinded to treatment allocation once it has been assigned, suggesting a high risk of bias. However, it is unclear what (if any) effect this may have had on most outcomes, but the risk of bias is likely to be high for the epidural analgesia outcome.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskOutcome assessors were blinded for judgements of FHR traces and uterine hyperstimulation - low risk of bias for these outcomes only. However, outcome assessment was not blinded for other outcomes but it is unclear what (if any) effect this may have had.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk20.3% of study participants overall (22.7% in experimental group and 17.8% in control group) did not receive study drugs - reasons were reported, however the authors did not explain why the proportion attributable to progression to 8 cm prior to initiation of augmentation differed between groups (18/40 women in experimental group and 30/31 in control group). It is also unclear how many women randomised to misoprostol arm eventually received oxytocin due to drug failure, as per study protocol.

Selective reporting (reporting bias)Unclear riskThe study reported on 5 additional secondary outcomes (uterine tachysystole in a 20-min interval, birthweight, elapsed time from the start of labour augmentation to delivery, maximum number of Montevideo units, diagnosis of non-reassuring FHR) compared to the outcomes stated in the clinical trial protocol registration, and did not report on one of the stated clinical trial protocol outcomes (maternal metritis). The reason for these changes was not stated and it is unclear what effect this may have had on conclusions.

Other biasUnclear risk20% of women declined participation when approached; the reason for this is unclear.

Ho 2010

MethodsRandomised trial with two arms and individual randomisation.

Analysed by intention-to-treat.


ParticipantsSetting: single facility in Taiwan, China.

Period of data collection: March 2008-December 2009 

Inclusion criteria:

  • Pregnancy between 36 and 42 weeks of gestation.
  • Live singleton fetus in cephalic presentation.
  • No history of uterine surgery.
  • Spontaneous onset of active labour with regular contractions.
  • An effaced cervix dilated between 3 cm and 9 cm.
  • A reassuring FHR pattern.
  • Inadequate uterine contractions (2 or fewer every 10 mins).


Exclusion criteria:

  • Non-reassuring FHR pattern.
  • Parity greater than 5.
  • Any contraindication to labour or vaginal delivery or both.
  • Epidural  analgesia.
  • Significant maternal cardiac, renal or hepatic disease.
  • Hypersensitivity to misoprostol or prostaglandin analogues.


Participants: 827 women met the inclusion criteria, of which 712 (86.1%) consented. Of these, 231 (32.4%) developed inadequate uterine contractions and were randomised.


InterventionsExperimental group:

One 200-mcg tablet of misoprostol was completely dissolved in 200 mL of tap water with stirring bar in a medicine bottle by the duty nurse. The misoprostol solution was stored in a medicine bottle at the nurses’ station and used completely within 24 hrs after preparation or discarded. Women were given 1 basal unit of 20 mL of misoprostol solution (1 mcg/mL, 20 mcg total). Misoprostol was initially administered at a dose of 20 mcg/h, until adequate uterine contractions (defined as 3 or more in 10-min over 30-min windows) were achieved. If contractions did not occur after 4 hrs (4 doses), the dosage was increased to 40 mcg and repeated every hr until uterine contractions occurred. Nothing by mouth, except medication, was allowed during the active phase of labour. Once uterine activity was adequate over 1 hr, no further misoprostol was given. If contractions subsequently became inadequate, hourly doses of misoprostol solution were started at 10 mcg/h and could be increased to 20 mcg/h and to as much as 40 mcg/h based on uterine responsiveness. This process was repeated until adequate uterine contractions occurred. A maximum cumulative dose of 1,600 mcg of misoprostol was permitted.
118 women (51.10%) were randomised to receive the titrated oral misoprostol regimen.

Control group:

Women received IV oxytocin by pump initially set to deliver 1 milliunit/min for 20 mins, and then increase the rate by 1 milliunit/min every 20 mins until adequate uterine contractions were attained.

Maximum dosing rate permitted was 20 milliunits/min of oxytocin.

113 (48.9%) women were randomised to receive titrated IV oxytocin.

Women in both groups had FHR and uterine activity monitored continuously throughout augmentation. IV magnesium sulfate (4 g over 30 mins) could be given at the discretion of the physician if uterine hyperstimulation occurred. Cesarean delivery was offered to all patients after failure of labour to progress or when non-reassuring FHR occurred.


OutcomesPrimary outcomes:

  • Interval from the start of augmentation to vaginal delivery.
  • Percentage of women who delivered their newborns vaginally within 12 hrs of this interval.
  • Percentage of women who delivered their newborns vaginally within 24 hrs of this interval.
  • Incidence of tachysystole.
  • Incidence of hypertonus.
  • Incidence of uterine hyperstimulation.
  • Incidence of non-reassuring FHR.


Secondary outcomes:

  • Total dosage of oxytocin or misoprostol.
  • Rates of caesarean births.
  • Failure to progress.
  • Apgar score less than 7 at 5 mins.
  • Admittance to the NICU.
  • Occurrence of treatment side-effects (not specified; however reported on nausea, vomiting, diarrhoea, shivering, pyrexia).


Also reported on other outcomes:

  • Vaginal delivery.
  • Apgar score less than 7 at 1 min.
  • Active phase interval (h).
  • Birthweight of newborn (g).


NotesSeveral continuous outcomes were reported as median (interquartile range) rather than mean (standard deviation).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe treatment arm allocation was determined using a computer-generated table of random numbers.

Allocation concealment (selection bias)Low riskThe randomisation assignments were placed into opaque, sealed envelopes. When inadequate uterine contractions occurred, the envelope was opened by the patient’s obstetrician to determine the treatment allocation.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskAuthors stated it was not possible to blind the study participants and personnel from knowledge of which intervention a participant received because the two methods were clearly different. However, it is unclear to what extent this may have affected outcomes.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAs above. It is unclear to what extent this may have affected outcomes.

Incomplete outcome data (attrition bias)
All outcomes
Low risk3 women did not receive intended treatment (2 in experimental group - 1 woman asked for epidural and 1 underwent emergency caesarean section due to non-reassuring FHR; 1 in control group, due to non-reassuring FHR). They were included in the analysis by intention-to-treat.

Appears that all participants were followed up; however, this is not explicitly stated.

Selective reporting (reporting bias)Unclear riskTrial data were recent and all declared outcomes were reported, even if insignificant. However, Apgar scores less than 7 at 1 min and 5 mins were both reported, despite only Apgar score less than 7 at 5 mins being prespecified. The study also reported on an additional primary outcome (interval from the start of augmentation to vaginal delivery) and several additional secondary outcomes, compared to the original clinical trial protocol. The reasons for these changes were not reported. There were no outcomes reported on maternal mortality/severe morbidity, nor on perinatal mortality.

Other biasUnclear riskNo obvious other bias.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Patel 2000Women were randomised to receive IV oxytocin or vaginal (rather than oral) misoprostol every 4 hrs. The inclusion criteria included women who had been induced, rather than women in spontaneous labour only.

 
Characteristics of ongoing studies [ordered by study ID]
Aalami-Harandi 2009

Trial name or titleComparison of the effect of oral misoprostol versus oxytocin on labour augmentation in pregnant women.

MethodsRandomised, non-blinded trial, two arms.

ParticipantsSetting: Shohada Tajrish Hospital, Islamic Republic Of Iran.

Period of data collection: January 2009 to January 2011.

Inclusion criteria:

- Pregnancy between 36 and 42 weeks of gestation.

- A live singleton fetus in cephalic presentation.

- No history of uterine surgery.

- Spontaneous onset of active labour with regular contractions.

- An effaced cervix dilated between 3 cm and 9 cm.

- A reassuring fetal heart rate pattern.

- Maternal age 16 to 45 years of age.

Exclusion criteria:

- Non-reassuring fetal heart rate pattern.

- Parity greater than 5.

- Any contraindication to labour or vaginal delivery or both.

- Epidural analgesia.

- Significant maternal cardiac, renal or hepatic disease.

- Hypersensitivity to misoprostol or prostaglandin analogues.

InterventionsExperimental group:

In the misoprostol group, a tablet of 200 mcg misoprostol dissolved in 200 cc of water and 25 cc was administered every 2 hrs for up to 24 hrs. The maximum dose was 300 mcg. Fetal heart monitoring and uterine contraction were recorded. Adequate uterine contractions were defined as 3 or more in 10 mins over 30-min windows. Once uterine activity was adequate over 1 hr, no further misoprostol was given.

Control group:

In the oxytocin group, infusion rate of 2 mIU/min was prescribed for induction and gradually increased by 2 mIU/min every 15 mins to a maximum dose of 36 mIU/min. In presence of any tachysystole (5 contractions in a 10-min interval) or hypertonus (single contractions lasting 2 mins or longer), or changes in fetal heart rate associated with tachysystole or hypertonus, infusion rate was decreased or stopped

OutcomesPrimary outcomes:

- The time from augmentation to vaginal delivery, 12 and 24 hrs during labour.

- Mode of delivery, 12 and 24 hrs during labour.

Secondary outcomes:

- Fetal and neonatal status in 'peri labor phase'.

- Maternal complications in 'peri labour phase'.

Starting date1st August, 2008

Contact informationAssistant Professor Rezvan Aalami-Harandi

Department of Obstetrics and Gynecology, Shahid Beheshti University of Medical Science
Tehran, Islamic Republic of Iran
mahmaz2002@yahoo.com

Dr Seyed Jalaledin Khoshnevis

Shahid Beheshti University of Medical Science

Tehran, Islamic Republic of Iran

jkhosh20012002@yahoo.com

Dr Aida Moeini

Department of Obstetrics and Gynecology, Shahid Beheshti University of Medical Science

Tehran, Islamic Republic of Iran

a.moeini64@gmail.com

Study co-ordinators emailed on 29th May, 2013 for request for further information on trial and outcomes.

Notes

 
Comparison 1. Titrated misoprostol (20 mcg dose) vs intravenous oxytocin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Uterine hyperstimulation with non-reassuring heart rate changes1231Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.14, 6.68]

2 Duration of labour (e.g.: 3 cm dilatation to delivery), in minutes00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 3 Caesarean section1231Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.42, 1.85]

 4 Incidence of tachysystole1231Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.17, 0.91]

 5 Incidence of hypertonus1231Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Vaginal delivery within 12 hours of commencement of augmentation1231Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.80, 1.03]

 7 Vaginal delivery within 24 hours of commencement of augmentation1231Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.93, 1.11]

 8 Apgar < 7 at 5 minutes1231Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Admission to neonatal intensive care unit (NICU)1231Risk Ratio (M-H, Fixed, 95% CI)2.39 [0.47, 12.09]

 10 Non pre-specified outcome: Rate of failure to progress1231Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.36, 1.77]

 11 Non pre-specified outcome: Maternal side-effects: nausea1231Risk Ratio (M-H, Fixed, 95% CI)2.87 [0.12, 69.82]

 12 Non pre-specified outcome: Maternal side-effects: vomiting1231Risk Ratio (M-H, Fixed, 95% CI)2.87 [0.12, 69.82]

 13 Non pre-specified outcome: Maternal side-effects: diarrhoea1231Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 14 Non pre-specified outcome: Maternal side-effects: shivering1231Risk Ratio (M-H, Fixed, 95% CI)2.87 [0.12, 69.82]

 15 Non pre-specified outcome: Maternal side-effects: pyrexia1231Risk Ratio (M-H, Fixed, 95% CI)2.87 [0.12, 69.82]

16 Non pre-specified outcome: Total dosage of oxytocin or misoprostol00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 17 Non pre-specified outcome: Apgar score < 7 at 1 minute1231Risk Ratio (M-H, Fixed, 95% CI)4.79 [0.23, 98.69]

18 Non pre-specified outcome: Active phase interval00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

19 Non pre-specified outcome: Birthweight of newborn00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. Titrated misoprostol (75 mcg dose) vs intravenous oxytocin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Uterine hyperstimulation (tachysystole, hypertonus or both) associated with fetal heart changes1350Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.88, 1.80]

2 Duration of labour (from start of augmentation to delivery), in minutes00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 3 Caesarean section1350Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.57, 1.92]

4 Duration of second stage00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 5 Maternal blood transfusion for hypovolemia1350Risk Ratio (M-H, Fixed, 95% CI)2.97 [0.61, 14.49]

 6 Caesarean for non-reassuring fetal heart rate (i.e. fetal distress)1350Risk Ratio (M-H, Fixed, 95% CI)1.58 [0.53, 4.74]

 7 Forceps delivery1350Risk Ratio (M-H, Fixed, 95% CI)1.98 [0.37, 10.66]

 8 Caesarean section for dystocia (i.e. prolonged labour)1350Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.39, 1.82]

 9 Uterine tachysystole, hypertonus, or both in 10-minute period (hyperstimulation of labour)1350Risk Ratio (M-H, Fixed, 95% CI)1.17 [1.02, 1.35]

 10 Uterine tachysystole in a 20-minute interval1350Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.84, 1.72]

 11 Chorioamnionitis1350Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.55, 1.37]

 12 Umbilical cord artery pH < 7.11350Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.17, 3.26]

 13 Admission to neonatal intensive care unit (NICU)1350Risk Ratio (M-H, Fixed, 95% CI)2.97 [0.12, 72.31]

 14 Non pre-specified outcome: Apgar score < 4 at 5 minutes1350Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 15 Non pre-specified outcome: Spontaneous vaginal delivery1350Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.91, 1.06]

 16 Non pre-specified outcome: Epidural analgesia1350Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.84, 1.01]

 17 Non pre-specified outcome: Birthweight1350Mean Difference (IV, Random, 95% CI)-22.0 [-117.96, 73.96]

18 Non pre-specified outcome: Maximum number of Monteovideo units00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

19 Non pre-specified outcome: Maximum oxytocin dose00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

20 Non pre-specified outcome: Admission to study drug (minutes)00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]