SAFETY AND EFFICACY OF MISOPROSTOL AND DINOPROSTONE AS CERVICAL RIPENING AGENTS .

1. SAFETY AND EFFICACY OF MISOPROSTOL AND DINOPROSTONE AS CERVICAL RIPENING AGENTS. Rajani Shakya, Joshna Shrestha, Panna Thapa Department of Pharmacy Kathmandu University, Dhulikhel, Nepal.

2. Introduction

3. Labor Induction • Induction of labor refers to the process whereby uterine contractions are initiated by medical or surgical means before the onset of spontaneous labor. • Labor is induced in around 20% of deliveries in US and UK [1,2]. • Commonest indication for induction of labor: post dates, pre-labor rupture of membranes, hypertension and intrauterine fetal growth retardation[3].

4. Cervical Ripening • The softening, effacement and dilatation that occurs before active labor and is necessary for the passage of the fetus. • When induction of labor is attempted against an unfavorable cervix, the likelihood of a successful outcome is reduced [4]. • Ripening of the cervix greatly facilitates labor and increases the likelihood of vaginal delivery [5,6].

5. Cervical Ripening (Contd…) • Bishop's score (BS): Systems for quantifying and scoring cervical factors to assist in predicting whether an induction may be successful. • When BS < 6, it is recommended that a cervical ripening agent be used before labor induction[7,8]. • Pharmacologic agents available for cervical ripening and labor induction include misoprostol, dinopropstone, mifepristone, oxytocin and relaxin.

6. Prostaglandins for cervical ripening • A Meta analysis suggests prostaglandins [9] • decrease the likelihood of failed induction • decrease the incidence of prolonged labor • increase the chances of a spontaneous vaginal delivery • Commonly used prostaglandin analogs : • dinoprostone • misoprostol

7. Dinoprostone • PGE2 analogue • It is available in following forms: • Intracervical gel • Vaginal gel • Controlled-release vaginal insert • Its use increases the likelihood that a vaginal delivery would occur within 24 hours [9,10]. • The only drawback appears to be an increased rate of uterine hyperstimulation and accompanying fetal heart rate changes [10], [11].

8. Misoprostol • PGE1 analogue • Available in 100 or 200µg tablets • Safe and inexpensive agent for cervical ripening and labor induction [14-20].

9. Misoprostol (Contd…) • A meta-analysis [21] by Sanchez-Ramos L & colleagues comparing the use of intravaginal misoprostol with that of dinoprostone, oxytocin or placebo concluded; • Misoprostol is associated with • significantly lower rate of cesarean section • higher incidence of vaginal delivery within 24 hours of application • reduced need for oxytocin augmentation • spontaneous labor in nearly 85 percent of the women

10. Misoprostol (Contd…) • A meta-analysis from the Cochrane Database have concluded that it may cause an increase in uterine hyperstimulation, and tachysystole, and therefore that further research is needed [4]. • Other uncommon complications include uterine rupture and fetal demise. • The occurrence of complications with misoprostol use appears to be dose-dependent [15, 25,26]. • Maternal side effects such as nausea, vomiting or diarrhea are uncommon [7,24].

11. Objective • To compare safety and effectiveness of intravaginal misoprostol with intracervical dinoprostone in women with unfavorable cervices and intact membranes.

12. Methodology

13. Methodology • Study site Dhulikhel Hospital, Kathmandu University Teaching Hospital (DH, KUTH) • Study design Randomized, open labeled, prospective study • Study duration Five months study startingfrom March 2006 to July 2006

14. Inclusion Criteria • ≥ 37 wks of gestation • Indication for labor induction • Bishop score ≤ 4 • Intact membrane • Cephalic presentation

15. Exclusion criteria • Previous cesarean delivery • Grand multiparity (>5) • Breech • Bishops score of > 4 • Contractions more than 3 per 10 minutes before drug administration • Premature rupture of membranes (PROM)

16. Methodology (Contd..) *Maximum up to 2 doses** Maximum up to 6 doses Misoprostol 200-mcg tablets (Misoprost, Cipla) was used to make the 50 mcg pessary. Dinoprostone gel: (Cerviprime, AstraZeneca). .

17. .

18. Methodology (Contd…) • BS was assessed just before insertion of the drug and every six hrs after drug administration. • FHR and uterine contractility was taken prior to drug administration. • All patients underwent continuous FHR and uterine contraction monitoring every 15 minutes for first two hours then every 4 hours of each dosing. • The uterine contractions were assessed by palpation and FHR by auscultation.

19. Outcomes: • Interval from start of induction to vaginal delivery • Vaginal delivery achieved within 24 hrs after randomization • Abnormalities of uterine contractility with and without FHR changes • Mode of delivery • Need of oxytocin augmentation • Maternal morbidity and side effects (e.g. fever, chills, gastrointestinal symptoms etc.) • Short-term neonatal outcome (e.g. Apgar score, meconium passage, neonatal intensive care unit admission etc.)

20. Definitions [19,20] • Tachysystole: contraction frequency of more than five within 10 minutes for two consecutive 10 minutes period. • Uterine hyperstimulation: exaggerated uterine response with late FHR decelerations or fetal tachycardia greater than 160 beats per minutes or other worrisome FHR changes. • Abnormal FHR pattern: presence of either fetal tachycardia, bradycardia, late decelerations, or a moderate to severe deceleration of FHR.

21. Statistical analysis • Statistical Package for Social Sciences (SPSS) program version 11.5 using. Means were compared with Z test and percentage by χ2 test. • A P value ≤ 0.05 was considered significant. • The results were presented as mean and standard deviation (SD). • Quantitative variables are expressed as number and percentage.

22. Results and Discussion

23. Postdate PROM 5% 11% Bad obstetric history 6% 6% IUGR 52% HTN 11% 9% Oligohydramnios Decreased fetal movement Indications for preinduction

24. Indications for preinduction • Most common indication for preinduction was found to be post dated pregnancy in many studies done worldwide [21,27]. • Other common causes reported are: diabetes mellitus, preeclampsia, macrosomnia, polyhydramnious, isoimmunization, renal disease, and sickle cell anemia [28,29].

25. Change in Bishop Score * no of patients ** mean ± S.D

26. Change in Bishop Score • Improvements in BS by both of these agents are comparable [28]. • A comparative study done by Yuthika Sharma et al showed significant improvement in the BS of both groups but no significant difference between two groups in mean change of BS [23]. • Another study done in Portugal have also shown insignificant difference between the 2 groups in terms of mean change in BS, 6 hours after the initial dose [26].

27. Mode of delivery

28. Mode of delivery • There was no significant difference in mode of delivery between the two groups (χ2 = .618). • Result is consistent with previous studies done by Ramsey et al [27] and L Sanchez-Ramos et al [29]. • Similar trend has been found in the study done by Wing DA et al. 14.7% misoprostol-treated patients and 19.4% of the dinoprostone-treated patients had cesarean deliveries [16].

29. Indications for cesarean section

30. Indications for cesarean section • Carlan et al found indication for CS being mainly fetal distress, followed by failed induction [20]. • Other indications: [26,30,29] Arrest of cervical dilatation or arrest of descent , non-assuring FHR, abnormal labor patterns, hyperactivity, worsening conditions.

31. Preinduction to delivery time

32. Preinduction to delivery time • M. Elhassan et al. have also found insignificant difference in preinduction to delivery interval (17.5 ± 7.6 hr with misoprostol and 19.15 ± 6.9 hr with dinoprostone, P > 0.05) [31]. • Various studies have shown considerable variation as far as preinduction to delivery time is concerned ranging from 9 hours [32] to 17.9 hours [33]. • Ramsey et al. also showed no significant difference in deliveries within 24 hours between two groups [27].

33. Preinduction to delivery time • Luis Sanchez-Ramos and colleagues have found significantly shorter time interval from induction to delivery with misoprostol when compared with PGE2 analog[29]. • Likely explanation for this deviation in results may be the different dosage regimen of misoprostol.

34. Patients requiring oxytocin augmentation

35. Patients requiring oxytocin augmentation • Wing DA et al also reported more no. patients in dinoprostone group requiring oxytocin augmentation (33.8% with misoprostol vs 65.7% in dinoprostone) [16]. • Study done by Jose et al. found better result with oral misoprostol with less need for oxytocin augmentation and lesser cesarean section operations for failed induction [30].

36. Adverse effects

37. Adverse effects • L Sanchez-Ramos & colleagues confirms the safety of intravaginal misoprostol with similar incidences of uterine hyperstimulation in misoprostol, dinoprostone and control group [21,29]. • Wing et al have also reported no difference between two groups regarding incidences of hyperstimulation[16]. • The Cochrane Pregnancy and Childbirth Group have reported hyperstimulation and tachysystol with misoprostol [34].

38. Adverse effects • Absence of hyperstimulation or tachysystol in the present study may be due to following reasons: • lower dose used • Longer time interval between drug administration • Smaller sample size • There is less risk of hyperstimulation with lower dose of misoprostol but also decreases the effectiveness for labor induction [35].

39. Adverse effects • The route of administration also affects incidence of hyperstimulation. • Adair et al, in a randomized, double masked trial found similar efficacy between oral and vaginal administration, but the oral route was associated with more frequent uterine contractility, including an unexpected high rate of hyperstimulation syndrome (41 % vs 18%) [36].

40. Adverse effects • Ramsey et al. had also reported no difference in meconium passage in two groups [27]. • Meconium passage may be result of effect of prostaglandins on gastrointestinal tract rather than a sign of fetal distress.

41. Maternal side effects

42. Maternal side effects • Commonest adverse effects of misoprostol and dinoprostone are nausea, vomiting, diarrhea, abdominal pain, chills, headache and fever, allof which are dose dependent. • Less incidences of side effects may be due to low dose of study drugs. • Study by Gemund et al also reported nausea, vomiting and diarrhea to be the common side effects observed in the patients [14].

43. Neonatal outcomes

44. Apgar Score of 0-3 shows severe depression score of 4-6 shows mild depression and score of 7-10 indicates no depression [37]. • Studies have reported similar perinatal outcome (Apgar score, birth weight, and admission to intensive care unit etc.) between the treatment groups [27, 12, 38].

45. Cost comparison • There is significant price difference between misoprostol and dinoprostone. • Dinoprostone is 7 times more expensive. Oxytocin augmentation will further increase the cost. • Patrik S. Ramsey et al have also found that misoprostol is more cost effective than dinoprostone as an adjuvant to labor induction in women with unfavorable cervix [27].

46. Conclusion • We found no differences in terms of effectiveness and safety between vaginal misoprostol and intracervical dinoprostone. • Misoprostol in lower dose of 50 mcg 6 hrly appears to be equally effective and safer than higher dose given for inducing labor in a woman with an unfavorable cervix. • Selection of misoprostol as a choice for cervical ripening would be of great aid in underdeveloped country like ours.

47. Recommendations • Potential areas of interest for misoprostol use for labor induction include oral administration and a crushed or gel form, in addition to lowering the dose and increasing the interval between administrations. • Researchers can design further trials to develop the safest dose, form and route of misoprostol administration.

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