Maeve Eogan Feb 2010
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Misoprostol for 2nd and 3rd
Trimester Loss
Misoprostol for 2nd and 3rd
Trimester Loss
Maeve Eogan
Rotunda HospitalDublin 1
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Miracle of Reproduction!Miracle of Reproduction!
25 to 30 percent chance ofbeginning a pregnancy inany given menstrual cycle
Wilcox AJ, Weinberg CR, O'Connor JF, et al. N Engl J Med1988; 319:189
Only 70 to 75 percent ofblastocysts created are ableto implant
Only 58 percent of theimplanted blastocystssurvive past the secondweek of gestation
Hertig AT. American Journal of Clinical Pathology 1967;47:249-68.
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2nd and 3rd Trimester Loss2nd and 3rd Trimester Loss
Various causes
Historically observation was best approach
Mifepristone & PG analogues revolutionary
Parental advantages
Limits autolysis: advantages in terms of
yield at perinatal autopsy
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Intrauterine DeathIntrauterine Death
90% of women will labour and deliverwithin 3 weeks
Expectant management may not beappropriate or psychologically acceptable
First case report of misoprostol use for IUDwas in 1987, use grown widely since then
Lack of uniformity in schedules for 2nd and3rd T loss: 25-400mcg, 3-12 hourly, variousroutes.
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Issues with IOL forIUDsIssues with IOL forIUDs
No longer concerns re fetal wellbeing
Ongoing concern re DIC
Systemic side effects
Uterine overactivity
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But..But..
Limited evidence base for IOL with IUD
Many descriptive series and non-
randomised comparative studies Suggest that lower overall doses required
and that duration of IOL shorter with IUD
versus live fetus Extrapolation from 2nd T TOP data and 3rd
T IOL data possible
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Misoprostol HistoryMisoprostol History
Approved in more than 85 countries since
1985.
Abundant literature supporting safety andeffectiveness for multiple reproductive
health indications.
Used off label in most countries.
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For treatment of gastric ulcer (used
off-label for OBGYN indications)
Dedicated products for OBGYN use
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AdvantagesAdvantages
Low cost
Long shelf life
Lack of need for refrigeration
Worldwide availability
No known drug interactionsTang et al. Contraception 2006;74:26-30
Goldberg et al. NEJM 2001;344:38-47
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2nd Trimester Loss2nd Trimester Loss
Misoprostol effective and commonly used
multiple schedules in use, many derived
from TOP studies and experience.
Optimal dose, schedule and route remain
undetermined
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Several StudiesSeveral Studies
Difficult to find conclusive evidence that
one schedule or route is superior to another
Qui i r r
r t t i i tur .
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Dickinson & Evans AJOG
2002;186:470-474
Dickinson & Evans AJOG
2002;186:470-474
3 dosing schedules for vaginal
administration
200mcg 6 hourly 400mcg 6 hourly
600mcg loading dose & 200mcg 6 hourly
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Dickinson & Evans AJOG
2002;186:470-474
Dickinson & Evans AJOG
2002;186:470-474
3 dosing schedules for vaginaladministration
200mcg 6 hourly
400mcg 6 hourly
600mcg loading dose & 200mcg 6 hourly
Median time to delivery shorter with
400mcg and 600mcg/200mcg schedule
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Dickinson & Evans AJOG
2002;186:470-474
Dickinson & Evans AJOG
2002;186:470-474
3 dosing schedules for vaginaladministration
200mcg 6 hourly
400mcg 6 hourly
600mcg loading dose & 200mcg 6 hourly
Median time to delivery shorter with
400mcg and 600mcg/200mcg schedule More side effects (fever, chills, GI etc) with600/200 schedule
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Lowest effective dose recommended
400mcg vaginally 6 hourly x 48 hours
recommended for 2nd T TOP
Lower doses appear equally effective in IUD
setting , with broad recommendation of
200mcg 6 hourly 13-17 weeks
100mcg 6 hourly 18-26 weeksGomez Ponce de Leon R,Wing D,Fiala C. IJOG 2007;99:S190-193.
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Based on TOP data, addition of 200mgmifepristone orally prior to misoprostol beneficial
Reduces induction time, MROP, analgesia use andlength of stay
Kapp et al. Obstet Gynecol 2007;110:1304-1310
Higher total misoprostol doses needed with longertreatment times in absence of mifepristoneGemzell-Danielsson K,LalitkumarS. Reprod Health Matters 2008;16:162-72
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What about Previous LSCS?What about Previous LSCS?
Absolute risks unclear
Many studies excluded such patients
3 RCTs included prev CS patients: no adverse
effects noted
Large retrospective study incl 108 women 17-24weeks gestation (and 216 controls).
400mcg PO & 400mcg PV followed by 400mcg 6hourly to max 5 doses
No evidence that prev. CS affected incidence ofcomplications (haemorrage, infxn, retainedplacenta, uterine rupture)
Daskalakis GJ, Mesogitis SA, Papantoniou NE et al. BJOG 2005;112:97-99
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Route ofAdministrationRoute ofAdministration
Bioavailability better with vaginal
compared with oral misoprostol - increased
efficacy at lower doses
Sublingual misoprostol may be equivalent
for first trimester loss
Wagaarachchi PT,Ashok PW,Smith NC, Templeton A. BJOG 2002;109:462-465
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Sublingual Route for 2nd and
3rd Trimester Loss
Sublingual Route for 2nd and
3rd Trimester Loss
No published research
Some studies for IOL (livebirth)
Sublingual seems an effective
route.more clinical trials to establish
effectiveness and safetyBartusevicius A,Barcaite E,Nadisauskiene R.Int J Gynaecol Obstet.
2005;91(1):2-9.
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Sublingual Route for 2nd and
3rd Trimester Loss
Sublingual Route for 2nd and
3rd Trimester Loss
Cochrane review: 3 studies: 502 pts
Trends towards advantages ofSL route
Inadequate data looking at complications andside-effects
Safety and optimal doses need to be established
by larger clinical trials
Muzonzini G, Hofmeyr GJ. Cochrane Database Syst Rev. 2004 18;(4):CD004221.
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3rd Trimester Loss3rd Trimester Loss
Extrapolate from evidence base of >100 RCTs forIOL with viable fetus
3 significant Cochrane Reviews with aim of
finding safe and effective induction dose Oxytocin still gold standard if favourable cervix
Priming with mifepristone recommended
Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening and inductionof labour. Cochrane Database Syst Rev 2003(1):CD000941
Alfirevic Z,Weeks A. Oral misoprostil for induction of labour. Cochrane Database SystRev 2006(2):CD001338
Muzonzini G, Hofmeyr GJ. Buccal or sublingual misoprostol for cervical ripening orinduction of labour. Cochrane Database Syst Rev 2004(4):CD004221
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3rd Trimester Loss3rd Trimester Loss
Main points:
Good induction agent!
25mcg and 50mcg seem to be equally effective
vaginally
Hyperstimulation (with and without CTGchanges) more common with 50mcg
Meconium staining of liquor more common insome study groups
Main problem lies with difficulty in accuratelyadministering 25-50mcg of misoprostol
Recent interest in titrated oral solution
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3 commonly used Regimens3 commonly used Regimens
No great evidence that one superior to other
Route Dose Frequency
PV 25mcg 4 hourly (max 6
doses)
PO 50mcg 4 hourly (max 6
doses)
PO soln 20-25mcg 2 hourly (double
dose after 2
doses)
Weeks A, Alfirevic Z, Faundes A, Hofmeyr GJ, Safar P,
Wing D. IJOG 2007;99:S194-197
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IUD vs Viable FetusIUD vs Viable Fetus
Hyperstimulation / Meconiummaybe less of anissue
Need to minimise side effects, so use minimum
effective dose Recommend starting with 25mcg, increase to 50-
100mcg if ineffective contractions
Maximum dose should not exceed 600mcg/24
hours Success affected by Bishops score, parity and
gestation: 67-83% deliver within 24 hours.Gomez Ponce de Leon R,Wing D,Fiala C. IJOG 2007;99:S190-193.
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What about higher misoprostol
doses?
What about higher misoprostol
doses?
Mifepristone priming
Gest Miso Dose Regimen
24-34 wks 200mg PV followed by
PO q 3 hrs
>34 wks 100mcg PV followed by
PO q 3 hrs
Wagaarachchi PT,Ashok PW,NarvekarNN,Smith NC, Templeton A.
Medical management of late intrauterine death using a combination of
mifepristone andmisoprostol. BJOG. 2002;109(4):443-7.
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ResultsResults
98.9% delivered within 72 hours
Avg induction-delivery interval 8.5 hours
No recorded cases of Uterine tachysystole
Hypertonicity
Haemorrage Coagulopathy
?reduced sensitivity to PG
following IUD
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Previous CS and 3rd T IOLPrevious CS and 3rd T IOL
Uterine Rupture
One trial d/c prematurely due to disruption
of uterine incision in 2/17 women (25mcgPV6 hourly to max of 4 doses)
Wing DA,Lovett K, Paul RH. AJOG 1998;91:828-30
Retrospective review - uterine rupture in
5/89 (5.6%) with PV misoprostol versus
1/423 (0.2%) with dinoprostonePlaut MM,Schwartz ML,Lubarsky SL. AJOG 1999;180:1532-42
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Previous CS and 3rd T IOLPrevious CS and 3rd T IOL
Uterine Rupture
Retrospective review - No uterine rupture in48 women induced with 50mcg vaginally 4hourly
Choy-Hee L, RaynorBD. AJOG 2001;184:1115-7
2 ruptures in 142 (1.4%) women induced
with varying vaginal misoprostol regimens(included women with >1CS and those withclassical CS): similar to oxytocin alone
Lin C, RaynorBD. AJOG 2004;190:1476-8
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Previous CS and 3rd T IOLPrevious CS and 3rd T IOL
Data less clear for PO Misoprostol
One study (abstract) indicated rupture rate of 10%(4/41)
Gherman RB, Heath T. Obstet Gynecol 2001;97:S68
Encouraging data from Cochrane reviews
Trial of over60,000 women would be required toevaluate an increase in the background scar
rupture rate of ~0.5% in women undergoingVBAC
General recommendation is to use lowestpossible vaginal dose, and to avoid doubling
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CervagemCervagem
Most common PG used prior to misoprostol
Was standard of care
Meta-analysis of6 studies of two treatments(601 pts)
Comparable for outcomes but potentiallyinsufficiently powered for major adverse
events Operational advantages of misoprostol
Dodd JM, Crowther CA. Eur J Obstet Gynecol Reprod Biol 2006;125:3-8
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