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Misoprostol for 2 nd and 3 rd Trimester Loss

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

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Misoprostol for 2 nd and 3 rd Trimester Loss

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

  2. 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; 47:249-68.

  3. 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

  4. 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.

  5. Issues with IOL for IUDs • No longer concerns re fetal wellbeing • Ongoing concern re DIC • Systemic side effects • Uterine overactivity

  6. 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. 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.

  8. For treatment of gastric ulcer (used ‘off-label’ for OBGYN indications) Dedicated products for OBGYN use

  9. 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

  10. 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

  11. Several Studies • Difficult to find conclusive evidence that one schedule or route is superior to another

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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 mifepristone Gemzell-Danielsson K, Lalitkumar S. Reprod Health Matters 2008;16:162-72

  17. 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

  18. 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

  19. 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.

  20. 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.

  21. 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

  22. 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’

  23. 3 commonly used Regimens • No great evidence that one superior to other Weeks A, Alfirevic Z, Faundes A, Hofmeyr GJ, Safar P, Wing D. IJOG 2007;99:S194-197

  24. 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.

  25. What about higher misoprostol doses? • Mifepristone priming 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.

  26. 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

  27. 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

  28. 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

  29. 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’

  30. 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

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