Misoprostol for 2 nd and 3 rd Trimester Loss Maeve Eogan Rotunda Hospital Dublin 1

Miracle of Reproduction! 25 to 30 percent chance of beginning a pregnancy in any given menstrual cycle Wilcox 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:

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 2 nd and 3 rd T loss: mcg, 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 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;74:26-30 Goldberg et al. NEJM 2001;344:38-47

2 nd 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

Dickinson & Evans AJOG 2002;186: dosing schedules for vaginal administration 200mcg 6 hourly 400mcg 6 hourly 600mcg loading dose & 200mcg 6 hourly

Dickinson & Evans AJOG 2002;186: 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: 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 weeks 100mcg 6 hourly weeks Gomez Ponce de Leon R, Wing D, Fiala C. IJOG 2007;99:S

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: Higher total misoprostol doses needed with longer treatment times in absence of mifepristone Gemzell-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 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:

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 ;(4):CD

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):CD Alfirevic Z, Weeks A. Oral misoprostil for induction of labour. Cochrane Database Syst Rev 2006(2):CD 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 RouteDoseFrequency PV25mcg4 hourly (max 6 doses) PO50mcg4 hourly (max 6 doses) PO soln20-25mcg2 hourly (double dose after 2 doses) Weeks A, Alfirevic Z, Faundes A, Hofmeyr GJ, Safar P, Wing D. IJOG 2007;99:S

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 mcg 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:S

What about higher misoprostol doses? Mifepristone priming GestMiso DoseRegimen wks200mgPV followed by PO q 3 hrs >34 wks100mcgPV 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: 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:

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: 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 misoprostol Dodd JM, Crowther CA. Eur J Obstet Gynecol Reprod Biol 2006;125:3-8