Misoprostol for 2nd and 3rd Trimester Loss

Maeve EoganRotunda Hospital

Dublin 1

Miracle of Reproduction!

• 25 to 30 percent chance of beginning a pregnancy in any given menstrual cycleWilcox AJ, Weinberg CR, O'Connor JF, et al. N Engl J

Med 1988; 319:189

• Only 70 to 75 percent of blastocysts created are able to implant

• Only 58 percent of the implanted blastocysts survive past the second week of gestation

Hertig AT. American Journal of Clinical Pathology 1967; 47:249-68.

2nd 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

Intrauterine Death

• 90% of women will labour and deliver within 3 weeks

• Expectant management may not be appropriate or psychologically acceptable

• First case report of misoprostol use for IUD was in 1987, use grown widely since then

• Lack of uniformity in schedules for 2nd and 3rd T loss: 25-400mcg, 3-12 hourly, various routes.

Issues with IOL for IUDs

• No longer concerns re fetal wellbeing• Ongoing concern re DIC• Systemic side effects• Uterine overactivity

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

Misoprostol History

• Approved in more than 85 countries since 1985.

• Abundant literature supporting safety and effectiveness for multiple reproductive health indications.

• Used off label in most countries.

For treatment of gastric ulcer (used ‘off-label’ for OBGYN indications)

Dedicated products for OBGYN use

Advantages

• Low cost• Long shelf life• Lack of need for refrigeration• Worldwide availability• No known drug interactions

Tang et al. Contraception 2006;74:26-30Goldberg et al. NEJM 2001;344:38-47

2nd 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

Several Studies

• Difficult to find conclusive evidence that one schedule or route is superior to another

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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

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

• Median time to delivery shorter with 400mcg and 600mcg/200mcg schedule

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

• Median time to delivery shorter with 400mcg and 600mcg/200mcg schedule

• More side effects (fever, chills, GI etc) with 600/200 schedule

• 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 weeks

Gomez Ponce de Leon R, Wing D, Fiala C. IJOG 2007;99:S190-193.

• Based on TOP data, addition of 200mg mifepristone orally prior to misoprostol beneficial

• Reduces induction time, MROP, analgesia use and length of stay

Kapp et al. Obstet Gynecol 2007;110:1304-1310

• Higher total misoprostol doses needed with longer treatment times in absence of mifepristoneGemzell-Danielsson K, Lalitkumar S. Reprod Health Matters 2008;16:162-72

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 17-24

weeks gestation (and 216 controls). • 400mcg PO & 400mcg PV followed by 400mcg 6

hourly to max 5 doses• No evidence that prev. CS affected incidence of

complications (haemorrage, infxn, retained placenta, uterine rupture)

Daskalakis GJ, Mesogitis SA, Papantoniou NE et al. BJOG 2005;112:97-99

Route of Administration

• 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

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 safety’

Bartusevicius A, Barcaite E, Nadisauskiene R.Int J Gynaecol Obstet. 2005;91(1):2-9.

Sublingual Route for 2nd and 3rd Trimester Loss

• Cochrane review: 3 studies: 502 pts• Trends towards advantages of SL route• ‘Inadequate data looking at complications and

side-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.

3rd Trimester Loss

• Extrapolate from evidence base of >100 RCTs for IOL 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 induction of labour. Cochrane Database Syst Rev 2003(1):CD000941

• Alfirevic Z, Weeks A. Oral misoprostil for induction of labour. Cochrane Database Syst Rev 2006(2):CD001338

• Muzonzini G, Hofmeyr GJ. Buccal or sublingual misoprostol for cervical ripening or induction of labour. Cochrane Database Syst Rev 2004(4):CD004221

3rd Trimester Loss

• Main points:• Good induction agent!• 25mcg and 50mcg seem to be equally effective

vaginally• Hyperstimulation (with and without CTG

changes) more common with 50mcg• Meconium staining of liquor more common in

some study groups• Main problem lies with difficulty in accurately

administering 25-50mcg of misoprostol• Recent interest in ‘titrated oral solution’

3 commonly used Regimens

• No great evidence that one superior to other

Route Dose FrequencyPV 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

IUD vs Viable Fetus

• Hyperstimulation / Meconium may be less of an issue

• 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.

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, Narvekar NN, Smith NC, Templeton A.

Medical management of late intrauterine death using a combination of mifepristone andmisoprostol. BJOG. 2002;109(4):443-7.

Results

• 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

Previous CS and 3rd T IOL

• Uterine Rupture• One trial d/c prematurely due to ‘disruption

of uterine incision’ in 2/17 women (25mcg PV 6 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 dinoprostone

Plaut MM, Schwartz ML, Lubarsky SL. AJOG 1999;180:1532-42

Previous CS and 3rd T IOL

• Uterine Rupture• Retrospective review - No uterine rupture in

48 women induced with 50mcg vaginally 4 hourly

Choy-Hee L, Raynor BD. AJOG 2001;184:1115-7

• 2 ruptures in 142 (1.4%) women induced with varying vaginal misoprostol regimens (included women with >1CS and those with classical CS): similar to oxytocin alone

Lin C, Raynor BD. AJOG 2004;190:1476-8

Previous 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 over 60,000 women would be required to

evaluate an increase in the background scar rupture rate of ~0.5% in women undergoing VBAC

• ‘General’ recommendation is to use lowest possible vaginal dose, and to avoid ‘doubling’

Cervagem

• Most common PG used prior to misoprostol• Was ‘standard of care’• Meta-analysis of 6 studies of two treatments

(601 pts)• Comparable for outcomes but potentially

insufficiently powered for major adverse events

• Operational advantages of misoprostolDodd JM, Crowther CA. Eur J Obstet Gynecol Reprod Biol 2006;125:3-8