Medical abortion with mifepristone and misoprostol: overview Dr. Rodica Comendant, ICMA Operations Coordinator Bangkok, Thailand, March 2012

Outlines Definition of MA, what is known, the use in the world The actual trends in MA The regimens for 10-12 weeks, 2nd trimester Misoprostol alone regimen Alternative ways for follow up

What is medical abortion? A way of inducing termination of pregnancy with medicines (pills) A “non-surgical” abortion The regimen for first trimester medical abortion, consists of two drugs, included in 2005 on the WHO Essential Medicines list: mifepristone followed 1–3 days later by misoprostol “Medical abortion” is the use of drugs to terminate a pregnancy. It is sometimes also called non-surgical abortion. The regimen for first trimester medical abortion consists of two drugs, included in 2005 on the WHO Essential Medicines list: mifepristone (an anti-progestogen that blocks progesterone, the hormone necessary to sustain a pregnancy), followed 1–3 days later by misoprostol (a prostaglandin that makes the uterus contract).

Why medical abortion is important? Medical abortion can make abortion: earlier, more accessible, safer, less traumatic, less medicalised and less expensive. There is no medical reason for adolescents do not have medical abortion. It has increased access to safe abortion and reduced maternal mortality, including in legally restricted settings.

What we know today about MA? Registered in 50 countries (2011) Use by 2.5 - 3 million women outside of China Use by more than 22 million women in China Good efficacy : 92-97% Extremely good safety record, lower risk of infection and trauma than surgery Women like the method very much (it’s private, natural and similar to menstruation) Safety: No long term consequences Medical abortion doesn’t affect women’s ability to become pregnant or have a child in the future Women can become pregnant again within three weeks of having MA

What is mifepristone? How does it work? Antiprogestin compound Discovered in 1980 in Russel Uklaaf laboratory First clinical trial in 1982, Geneva Binds to progesterone receptor to block action of progesterone Increases endogenous prostaglandins Increases uterine contractility and sensitivity to prostaglandins Decidua and trophoblast separate Cervix softens and dilates, facilitating abortion GHP From DH: Progesterone during pregnancy: Inhibits contractility of myometrium Inhibits secretion of prostaglandins in endometrium Maintains closed cervix The inhibition or blocking of receptors: Detachment of the embryo, drop in BHCG, luteolysis Increase in contractility of the myometrium directly affected by mifepristone as well as increase in the synthesis of prostaglandins in the endometrium Opening and softening of the cervix (without increase of prostaglandin in the cervical tissue). Flux of water and leucocytes. Mifepristone alone: 80% abortion rate

What is misoprostol? How does misoprostol work? Prostaglandin E1 analogue, approved for prevention and treatment of gastric ulcers Drug causes contractions of smooth muscles of the uterus -> empties the uterus Drug can soften the cervix -> increases dilation for interuterine procedures, facilitates expulsions

Widely available (over 80 countries) Inexpensive (~ $0.35 per 200 mcg) Simple to administer No refrigeration needed: stable at ambient temperatures Misoprostol is increasingly used for a variety of ob/gyn indications

Mechanism of Action in MA: Mifepristone + Misoprostol Rhythmic Uterine Contractions Progesterone Blockade Decidual Necrosis Cervical Ripening Detachment Expulsion Abortion © Lisa Penalver

Misoprostol: routes of administration Oral Rapid absorption (peak 30 mins) Levels fall sharply in 1-2 hours Vaginal Peak later (80 mins) but lower Higher levels longer in plasma Buccal Later, lower peak, sustained levels (similar to vaginal) Sublingual Rapid absorption, high peak levels, sustained levels Rectal Lower peak but higher levels longer than oral

Vaginal, oral and sublingual pharmacokinetics Misoprostol: routes of administration: Oral Rapid absorption (peak 30 mins) Levels fall sharply in 1-2 hours Vaginal Peak later (80 mins) but lower Higher levels longer in plasma Buccal Later, lower peak, sustained levels (similar to vaginal) Sublingual Rapid absorption, high peak levels, sustained levels Rectal Lower peak but higher levels longer than oral Tang, et al, 2002

Contraindications to method Suspected ectopic pregnancy (rule out) IUD in place (take out) Chronic adrenal failure Current long term corticosteroids Known allergy to the medications Clotting disorder/anticoagulant therapy Inherited porphyria Mifepristone is not an effective treatment for ectopic pregnancy; suspicion of ectopic pregnancy demands further investigation and, if confirmed, immediate treatment

Gastrointestinal side effects Fever, chills Dizziness, headache Expected side effects: go away within several hours and don’t need serious medical treatment Pain, cramping Bleeding Gastrointestinal side effects Fever, chills Dizziness, headache Counselling is very important!!!

Safety of MA Uterine blood loss in surgical or medical abortion is the same With medical bleeding lasts more days 95.000 MA, complication (heavy bleeding) - 2.2 per 1000 women (PPF, USA, 2001-2005). Mortality 1,1 per 100.000(one death) France ~1000.000 abortion, no one death Hemorrage: - Aspiration to stop bleeding(0,4-2%) - Transfusion (0,2%) (Early surgical abortion: 0,1%) Infection: medical - 0,09-0,5% (surgical - 0.2-5.4%) Incomplete :Persistence of gestational sac or retention (2,9%) (surgical : 2-

Safety of Medical Abortion Medical Abortion Early Surgical abortion Transfusion: 0,2% 0,1% Aspiration to stop bleeding (0,4-2%) Infection 0,09-0,5% 0.2-5.4% 3-5% incomplete abortion, 1-3% ongoing pregnancy,

French regimen (early 90es), for 49 days LMP Visit 1: Patient eligibility, counseling (!) Swallow 3 tabs mifepristone Visit 2: +36-48 hr Oral Misoprostol (400 µg) 3-4 hour monitoring in clinic Visit 3: +10-12 days Follow-up visit

Recommended mifepristone plus misoprostol regimens (WHO 2012) Up to 9 completed weeks (63 days) LMP 200 mg mifepristone followed after 24-48 hours by 800 µg misoprostol, administered vaginally, sublingually or buccally Or, for up to 7 completed weeks (49 days) 400 µg oral misoprostol. Regimen Innovations and actual trends in MA: de-medicalisation 200 mg vs. 600 mg mifepristone Different doses and routes of misoprostol administration Home use of misoprostol Use after 49 days LMP, use in 10-12 weeks Timing of misoprostol Alternative follow-up, etc, etc.

Home Use of Misoprostol Overwhelmingly preferred choice in U.S. 98-99% (n = 4345) Schaff, 1998, 1999, 2000 Similar preference in developing countries: Vietnam 80% (n =112) Elul, et al., 2000 Tunisia 87% (n =191) Elul, et al., 2000 Home administration recently approved in France, in many EU countries

Is misoprostol in clinic needed for safety reasons? No serious adverse events in 4 hours post-misoprostol in clinic – 1059 patients in 4 developing countries Pop Council trial in 2121 U.S. women: 4 transfusions, none during clinic waiting time Schaff study of 2295 women: no interventions required within 4 hours of misoprostol

Regimens in later first trimester: 10-12 weeks LMP Beginning to be more widely used 200mg mifepristone orally followed after 36–48 hours by 800 µg vaginal misoprostol, administered in a health facility. A maximum of 4 further doses of misoprostol 400 µg may be administered at 3-hourly intervals, vaginally or orally.(WHO, 2012) A clinic-based procedure that takes several hours to a day Many women prefer the faster surgical approach, especially when that is offered as a rapid outpatient procedure

Regimens for second trimester: 12-21 weeks 200 mg mifepristone followed after 36-48 hours by 400 µg oral or 800 µg vaginal misoprostol followed by 400 µg vaginal or sublingual misoprostol every 3 hours up to a maximum of 5 doses, administered in a health facility. After 24 weeks gestation, the dose of misoprostol should be reduced. (WHO, 2012)

Alternative follow-up: checklists Clark et al. Ob & Gyn 2010, N=>3000 : simple checklist works Simple checklist identified all ongoing pregnancies Checklist also identified all women needing any other additional care for their medical abortion 24

A semi-quantitative pregnancy test + the checklist The semi-quantitative pregnancy test is an accurate alternative method of follow-up The semi-quantitative pregnancy test correctly identified all ongoing pregnancies The acceptability and feasibility of using simple semi-quantitative pregnancy tests with a simple checklist are now under the research 25

The routine use of ultrasound – not needed! Total of 4484 women seeking MA in US Women provided their LMP + vaginal exam The estimations were compared to ultrasound data Conclusion: LMP and physical exam, without use of ultrasound are highlely efective for early MA H. Bracken, W. Clark, etc. Alternative to routine ultrasound for eligibility assessment prior to early termination of pregnancy with mifepristone-misoprostol, BJOG, 2011

MA safely provided by mead-level providers (the Lancet, 2011) A study in Nepal, 1295 women, randomly assigned to receive the care to a doctor or to a mead-level providers Similar safety and effectiveness

Misoprostol alone for abortion Induced abortion (0-12 weeks): 800g vaginally 12-hrly Missed abortion (0-12 weeks)800g vaginally 3-hrly OR 600g sublingually 3-hrly Incomplete abortion (0-12 weeks)600g orally stat. Induced abortion (13-24 weeks)400g vaginally 3-hrly x5 Weeks A & Faundes A. International Journal of Gynecology and Obstetrics 2007;99:S156-9.

Misoprostol alone versus mifepristone+misoprostol regimen A study in Vietnam, 400 women Randomized to two groups: two doses of 800 mcg buccal miso or 200 mife+800 mcg miso In miso group the efficacy 76,2%, in mife+miso – 96,5% Ongoing pregnancy in miso group -16,6% In mife+miso group – 1,5% Published in Contraception, 2010

Thank you! Questions?