maeve eogan feb 2010

8/6/2019 Maeve Eogan Feb 2010

1/31

Misoprostol for 2nd and 3rd

Trimester Loss

Misoprostol for 2nd and 3rd

Trimester Loss

Maeve Eogan

Rotunda HospitalDublin 1


2/31

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.


3/31

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


4/31

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.


5/31

Issues with IOL forIUDsIssues with IOL forIUDs

No longer concerns re fetal wellbeing

Ongoing concern re DIC

Systemic side effects

Uterine overactivity


6/31

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


7/31

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.


8/31

For treatment of gastric ulcer (used

off-label for OBGYN indications)

Dedicated products for OBGYN use


9/31

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


10/31

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


11/31

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 .


12/31

Dickinson & Evans AJOG

2002;186:470-474


2002;186:470-474

3 dosing schedules for vaginal

administration

200mcg 6 hourly 400mcg 6 hourly

600mcg loading dose & 200mcg 6 hourly


13/31


2002;186:470-474


2002;186:470-474

3 dosing schedules for vaginaladministration

200mcg 6 hourly

400mcg 6 hourly


Median time to delivery shorter with

400mcg and 600mcg/200mcg schedule


14/31


2002;186:470-474


2002;186:470-474

3 dosing schedules for vaginaladministration

200mcg 6 hourly

400mcg 6 hourly


Median time to delivery shorter with

400mcg and 600mcg/200mcg schedule More side effects (fever, chills, GI etc) with600/200 schedule


15/31

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.


16/31

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


17/31

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


18/31

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


19/31

Sublingual Route for 2nd and

3rd Trimester Loss


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.


20/31


3rd Trimester Loss


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.


21/31

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


22/31

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


23/31

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


24/31

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.


25/31

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.


26/31

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


27/31

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


28/31


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


29/31


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


30/31

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


31/31

maeve eogan feb 2010

Documents