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
  retardation3.

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 lt 6, it is recommended that a cervical
  ripening agent be used before labor
  induction7,8.
• 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 starting from 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 (gt5)
• Breech
• Bishops score of gt 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 ?2 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
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
Bishop score Dinoprostone (n 31) Misoprostol (n 35) P value
Preinduction Bishop score 3.35 0.91 3.00 0.90 .11
After 6 hours 5.48 2.0 4.90 1.5 .22
After 12 hours 6.23 2.2 6.38 1.9 .81
Change in 6 hours 2.17 2.0 2.001.6 .72
Change in 12 hours 2.90 2.1 3.651.9 .23
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
Mode of delivery Dinoprostone (n31) Misoprostol (n35)
Vaginal 21(67.7) 25(71.5)
Spontaneous Vaginal delivery 21(67.7) 24 (68.6)
Assisted vaginal delivery 0(0) 1(2.9)
Cesarean section 10(32.3) 10(28.6)
28
Mode of delivery

• There was no significant difference in mode of
  delivery between the two groups (?2 .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
Cesarean section Dinoprostone Misoprostol
Failed induction 4(40) 5(50)
Fetal distress 5(50) 5(50)
Oligohydramnios 1(10) 0(0)
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
Outcome Dinoprostone Misoprostol P value
Induction-delivery interval (hrs) 17.1910.7 17.99 14.0 .83
Delivery within 12 hours 9 (29) 10 (28.6) .96
Delivery within 24 hours 19(61.3) 18(51.4) .42
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 gt 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 analog29.
  
  
  
  
• Likely explanation for this deviation in results
  may be the different dosage regimen of
  misoprostol.

34
Patients requiring oxytocin augmentation
Outcome Dinoprostone (n31) Misoprostol (n35) P value
Required oxytocin augmentation 21 (67.7) 13 (37.1) .013
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
Adverse effects Dinoprostone (n31) Misoprostol (n35) P value
Hyperstimulation 0(0) 0(0) ---
Abnormal fetal heart rate 2(6.5) 3(8.6) .74
Meconium passage 7(22.6) 8(22.9) .97
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
  hyperstimulation16.
• 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
Side effects No. of patients Percentage ()
Dinoprostone Dinoprostone Dinoprostone
Vomiting 2 6.5
Misoprostol Misoprostol Misoprostol
Nausea 3 8.6
Vomiting 3 8.6
Diarrhea 1 2.9
42
Maternal side effects

• Commonest adverse effects of misoprostol and
  dinoprostone are nausea, vomiting, diarrhea,
  abdominal pain, chills, headache and fever, all
  of 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
Outcome Dinoprostone (n31) Misoprostol (n35) P value
Birth weight (kg) 2.76 0.41 2.90 0.47 .23
Apgar Score lt7 at 1 min 6(19.4) 11(31.4) .26
Apgar Score lt7 at 5 min 1(3.2) 0(0) .28
Supplemental oxygen 10(32.3) 11(32.4) .99
Neonatal Intensive Care Unit 0(0) 0(0) ---
Neonatal mortality 0(0) 0(0) ---
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.

48
References

1. Normitz ER, Robinson JN, Repke TJ. Induction of
   labour. InGabbe Steven G, Niebyl RJ, Leigh Joe,
   editors. Obstetrics normal and problem
   pregnancies 2002. US Churchill Livingstone
   2002.p.373.
2. Chamberlain Geoffrey, Steer PJ. Turnbulls
   Obstetrics.3rd ed. UK Harcovet2002
3. Crane Joan. Induction of labor at term. J Obstet
   Gynaecol Can. 200123(8)717-28
4. Oxford Database of Perinatal Trials. Cochrane
   Pregnancy and Child Birth Data Base Oxford
5. Bishop EH. Pelvic scoring for elective induction.
   Obstetrics and Gynecology 1964 24 266-268.
6. Sanchez-Ramos L, Hsieh E. Pharmacologic Methods
   for Cervical Ripening and Labour Induction.
   Current Womens Health Reports 2003 3 55-60.
7. Alberta Reproductive Health Pregnancies and
   Births Table Update. AHW and Alberta Perinatal
   Health Program.2005
8. Marguilies M, Perez MC, Vato L. Misoprostol for
   induction of labor. Lancet 92339364.

49
References

1. Keirse MJ. Prostaglandins in preinduction
   cervical ripening meta-analysis of worldwide
   clinical experience. Journal of Reproductive
   Medicine 1993 38 89-100.
2. Kelly AJ, Kavanagh J, Thomas J. Vaginal
   prostaglandin (PGE2 and PGF2a) for induction of
   labor at term. Cochrane Database Syst Rev 20022
3. Evangelao G et al. comparison of misoprostol and
   dinoprostone for elective induction of labor in
   nulliparous women at full termA randomized
   prospective study. Reproductive biology and
   endocrinology 2004 270
4. Zieman M, Fong SK, Benowitz NL, Banskter D,
   Darney PD. Absorption kinetics of misoprostol
   with oral or vaginal administration. Obstet
   Gynecol 19979088-92.
5. Rehan-Uddin Khan, MRCOG, Hazem El-Refaey, MD,
   MRCOG, Sunita Sharma, MRCOG, Dev Sooranna, PhD
   and Mike Stafford, MD, MRCOG. Oral, Rectal, and
   Vaginal Pharmacokinetics of Misoprostol.
   Obstetrics Gynecology 2004103866-870
6. N Gemund Van, S Scherjon, S le Cessie, J H
   Schagen Van Leeuwen, J Van Roosmalen. A
   randomized trial comparing low dose vaginal
   misoprostol and dinoprostone for labour
   induction. BJOG. 2004 11142.

50
References

• Sanchez-Ramos L, Kaunitz AM, Del Valle GO, Delke
  I, Schroeder PA, Briones DK. Labor induction with
  the prostaglandin E1 methyl analogue misoprostol
  versus oxytocin a randomized trial. Obstet
  Gynecol 199381332-336.
• Wing DA, Jones MM, Rahall A, Goodwin TM, Paul RH.
  A comparison of misoprostol and prostaglandin E2
  gel for preinduction cervical ripening and labor
  induction. Am J Obstet Gynecol 19951721804-1810.
  
• Wing DA, Rahall A, Jones MM, Goodwin TM, Paul RH.
  Misoprostol an effective agent for cervical
  ripening and labor induction. Am J Obstet Gynecol
  19951721811-1816.
• Fletcher HM, Mitchell S, Simeon D, Frederick J,
  Brown D. Intravaginal misoprostol as a cervical
  ripening agent. Br J Obstet Gynaecol. 1993
  100641-644.
• Marjorie Meyer, MD, Jeannie Pflum, Do and Diantha
  Howard, MS. Outpatient misoprostol Compared with
  Dinoprostone Gel for preinduction Cervical
  Ripening A randomized Controlled Trial.
  Obstetrics and Gynecology. 2005105466-472
• S.J. Carlan, MD, Sheila Bouldin, MD, RPh,
  Danielle Blust, MD and Willia, F. OBrien, MD.
  Safety and Efficacy of Misoprostol Orally and
  Vaginally A randomized Trial. Obstetrics and
  Gynecology. 200198107-112.

51
References

1. Sanchez-Ramos L, Kaunitz AM, Wears RL, Delke I,
   Gaudier FL. Misoprostol for cervical ripening and
   labor induction a meta-analysis. Obstet Gynecol
   199789633-42.
2. Mitchael L. Stitely, LT, MC, USNR Josheph
   browning, Lt, MC, USNR, Mark Fowler, LT, MC,
   USNR, Richard T. Ghendron, BPharm and Robert B.
   Gherman, LCDR, MC, USNR, Outpatient Cervical
   Ripening With Intravaginal Misoprostol.
   Obstetrics and Gynecology. 200096684-688.
3. Sharma Yuthika, Kumar Sunesh, Mittal Sunita,
   Misra Renu Evaluation of glyceryl trinitrate,
   misoprostol, and prostaglandin E2gel for
   preinduction cervical ripening in term pregnancy.
   J. Obstet. Gynaecol. 2005 31(3)210-215.
4. Syeda batool Mazhar, Kinza Alam.Induced Labour
   Indications and Outcome PIMS Experience. J Surg.
   Dec 2001 2331-3.
5. K Paul A. Le Roux, Jeremiah O. Olarogun, James
   Penny, John anthony. Oral and vaginal Misoprostol
   compared for induction of labor A randomized
   controlled trial. Obstet Gynecol.200299201-205
   
6. B Filomena Nunes, MD, Rosalinda Rodrigues, MD,
   and Manuel Meirinho, MD, PhD. Randomized
   comparison between intravaginal misoprostol and
   dinoprostone for cervical ripening and induction
   of labor. Am J Obstet Gynecol. 181 626-629

52
References

1. Patrick S. Ramsey et al. Comparative efficacy and
   cost of the prostaglandin analogs dinoprostone
   and misoprostol as labor preinduction agents Am J
   Obstet Gynecol.2003 188(2)561
2. Warke HS, Saraogi RM, Sanjwalla SM. Prostaglandin
   E2 gel in ripening of cervix in induction of
   labor. J of Postgraduate Med, 199945105-9
3. Luis Sanchez-Ramos, Dirk E. Peterson, Isaac
   Delke, Francisco l. Gaudier, Andrew M. Kaunitz.
   Labor Induction with Prostaglandin E1.
   Misoprostol Compared With Dinoprostone Vaginal
   Insert A Randomized Trial. Obstetrics
   Gynecology.199891401-405
4. Jose L.Bartha, MD, Rafael Comino-Delgado, MD,
   Fatima Garcia-Benasach, MD Pilar
   Martinez-Del-Fresno, MD, Luis J, Moreno-Corral,
   MD. Oral misoprostol and intracervical
   dinoprostone for cervical ripening and labor
   induction a randomized comparison. Obstet
   Gynecol. 200096465-469
5. M. Elhassan , O.A. Mirghani , I. Adam.
   Intravaginal misoprostol vs. dinoprostone as
   cervical ripening and labor inducing agent. Intl
   J of Gynec and Onstet.200485285-286
6. Noah ML, Decoster JM, Fraser W. Preinduction
   cervical softening with endocervical PGE2 gel. A
   multicentric trial. Acta Obstet Gynecol Scand.
   1987 663-7.  

53
References

1. Thiery M, Decoster JM, Parewijck W. Endocervical
   prostaglandin E2 gel for preinduction cervical
   softening. Clin Obstet Gynaecol 1984 27429-439
2. Hofmeyr GJ, Gulmezoglu AM, Alfirevic Z.
   Misoprostol for induction of labour a systematic
   review. Br J Obstet Gynaecol. 1999 106798-803
3. Patrick Dallenbach, MD, Michel Boulvain, MDlt PhD,
   Caroline Viardot, MD, Oliver Irion, MD. Oral
   Misoprostol or vaginal dinoprostone for labor
   induction a randomized controlled trial. Obstet
   Gynaecol. 2002188162-167
4. Adair CD, Weeks JW, Barrileaux S, Edwards M,
   Burlison K, Lewis DF. Oral or vaginal misoprostol
   administration for induction of labor
   arandomized, double-blind trial. Obstet Gynaecol.
   199992810-3.
5. Dutta DC. Text book of obstetrics.6th ed. Konkar
   Hiralal, editor. Calcutta New central book
   agency2004
6. Chang Ch, Chang FM. Randomized comparison of
   misoprostol and dinoprostone for preinduction
   cervical ripening and labor induction. J Formos
   Med assoc.199796366-9.

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