Early Medical Abortion: an overview Patricia A. Lohr, FACOG FRCOG FFSRH (Hons) Medical Director, British Pregnancy Advisory Service Southern Taskgroup on Abortion and Reproductive Topics EMA Conference 6 October 2018 * Cork, Ireland

Diclosures I am Medial Director of British Pregnancy Advisory Service, a non-profit provider of abortion services in the UK I have no commercial disclosures

What is medical abortion? Pregnancy termination without primary surgical intervention and resulting from the use of abortion-inducing medication Recommended medications: mifepristone and misoprostol “Early medical abortion” ≤70 days of gestation on day of mifepristone Typically outpatient Same medications may be used for termination throughout pregnancy; different regimes and location of care

Mifepristone: an antiprogestogen Rhythmic Uterine Contractions Progesterone Blockade Decidual Necrosis Cervical Softening Detachment Expulsion Abortion Binds to progesterone receptor binding affinity > progesterone does not activate the receptor Effectiveness of mifepristone alone ≈ 60-80% at ≤49 days of gestation

Mifepristone also enhances uterine response to prostaglandins Mifepristone sensitises the uterus to prostaglandin resulting in greater effectiveness of medical abortion regimen and faster expulsion than mife alone or prostaglandin alone Bygdeman & Swahn Contraception 1985 Medical abortion - clinical aspects, C. Fiala

Misoprostol: prostaglandin analogue Most commonly recommended for use with mifepristone Cheap Stable at room temperature Multiple routes of administration: vaginal, buccal, sublingual, (oral) Effective and efficient Generally well-tolerated In the very distant past, IM prostaglandins (E2 - associated with cardiovascular events) and temperature sensitive vaginal pessaries (E1 - gemeprost) used requiring hospitalisation

Early medical abortion: the past Mifepristone: 600mg oral (office) Interval: 36-48 hours Misoprostol: 400mcg oral (with observation period) Gestation: ≤49 days of gestation Follow-up: In-person ultrasound in 2 weeks Higher dose mife, long interval between medications (based on timing to max effect of mife on uterus), lower dose of miso – often with in clinic observation period of variable lengths, limited gestation, if expulsion not observed return for scan

Early medical abortion: the present Mifepristone: 200mg oral (home or office) Interval: 24-48 hours Misoprostol: 800mcg vaginal, buccal or sublingual (home) Gestation: ≤70 days of gestation Follow-up: No need for routine (i.e., in person) check Lower dose mife as effective and less expensive, data to support home or office administration, shorter interval – may reduce further or extend to 72 hours but sacrifice some effectiveness, higher dose miso by non oral routes allowed for extension of gestational age and more flexible intervals, regimen now seen as so effective that routine in person follow-up not needed and many alternatives for “remote” or self-assessment of outcome studied to reduce the burden on women and providers

Early medical abortion: efficacy Showing outcomes with buccal regimen but all non-oral regimens very similar results Highly effective through 63 and up to 70 days Effectiveness does decline as gestation advances but it is gradual – this gradual decline continues in same way post 70 days Chen & Creinin Obstet Gynecol 2015

Early medical abortion: efficiency in % 20 15 10 5 Most women complete abortion in 4 hours and almost all by 24 hours 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Before miso (hours after misoprostol) unknown uncertain More than 24 h later Time to expulsion of the sac in 1720 women with successful termination of pregnancy. The women took mifepristone on day 1 and misoprostol 48 hours later. Uncertain means expulsion at some point during 24 hours following misoprostol. Unknown means expulsion at some point later than 24 after misoprostol. Source: The New England Journal of Medicine, 1998; 338 (18): 1244 Medical abortion - clinical aspects, C. Fiala

Gestational age (days) 57-63 days vs. 64-70 days Gestational age (days) P-value 57-63 64-70 success ongoing Misoprostol regimen (number studies) N* Success n (%) Ongoing n (%) Success 800 mcg BUC (4) 781 730 (93.5) 18 (2.3) 480 444 (92.5) 15 (3.1) 0.25 0.19 400 mcg SL (1) 382 362 (94.8) 7 (1.8) 321 295 (91.9) 7 (2.2) 0.07 0.37 800 mcg PV (1) - 127 120 (94.5) 7 (5.5) TOTAL 1163 1092 (93.9) 25 (2.1) 928 859 (92.6) 29 (3.1) Comparing outcomes at 57-63 days and 64-70 days in prospective studies – no difference between 57-63 and 64-70 *Number followed Abbas D et. al Contraception 2015

Early medical abortion: side effects Post mife side effects mainly spotting, some mild cramping. Post misoprostol side effects do occur but are transient and should resolve within if not before 24 hours after use. Mifepristone package insert. Approved 2016 http://www.earlyoptionpill.com/wp-content/uploads/2016/03/MIFEPREX-Labeling-and-MG-FINAL_March2016.pdf Mifepristone package insert. Approved 2016 http://www.earlyoptionpill.com/wp-content/uploads/2016/03/MIFEPREX-Labeling-and-MG-FINAL_March2016.pdf

Early medical abortion: safety Retrospective review 200mg mifepristone + 800mcg buccal misoprostol ≤ 63 days 317 US sites over 2 years, N=233,805 Overall clinically significant adverse event: 1.6 per 1000 A&E treatment 1 per 1000 IV antibiotics 2 per 10,000 Transfused 5 per 10,000 Hospitalised 6 per 10,000 Undiagnosed ectopic 7 per 100,000 Mortality: 0.4/100,000 One of the most studied methods of abortion, there is now a very large body of evidence demonstrating the safety and effectiveness of early medical abortion up to 9 weeks gestation Cleland K et al Obstet Gynecol 2013

57-63 days vs. 64-70 days Fewer expulsions within 3h; no difference by 24h More vomiting, diarrhoea, fever, weakness No difference adverse events, e.g., hospital admissions, transfusions (0.7% vs. 0.5%, p=0.31) Work on-going to 77 days p=0.001 at 3 h p=0.43 at 24 h Winikoff B et al Obstet Gynecol 2012 Time to expulsion shorter in 57-63 day group, more frequent side effects but importantly no difference in adverse events Abbas D, et al. Contraception 2015

Ectopic pregnancy: a very rare occurrence with early abortion Ectopic pregnancy in the general population: ≈1 in 100 Ectopic pregnancy in women seeking abortion US trial of surgical abortions <6 weeks’ gestation: 5.9 per 1,000 Largest single study of medical abortion (n=16,369): 1.3 per 1,000 Review of 57 prospective medical abortion trials (n=44,789) found a rate of 2 in 10,000 diagnosed after treatment Edwards J and Carson A AJOG 1997; Ulmann A et al Acta Obstet Gynecol Scand. 1992 ; Shannon C et al Obstet Gynecol 2004

Early medical abortion care pathway Decision-making Eligibility Contraception/STI Assessment Tablets or prescription Anti-D if needed Expulsion at home Treatment Remote or in person Review as needed Aftercare

Pre-abortion assessment Understand woman’s decision about the pregnancy Determine gestational age ≤10 weeks Assess eligibility for method and location of care Decide if anti-D prophylaxis is indicated An invitation to discuss contraception and screening for STIs also form part of pre-abortion care

Do women need counselling? Most women seeking abortion Are sure of their decision before contacting a clinician Have already discussed the decision with friends/relatives (9% with a counselling service) Do not want further counselling In one study, 18% (33 of 185) wanted decision-making support from their doctor or nurse Of these, 6 chose not to have the abortion None booked with local counselling service Allen 1985; Barrett et al 2004; Lakha & Glasier 2006; Cameron & Glasier 2013, Baron et al 2015

What women want: decision-making support Qualitative interviews with women seeking abortion advise that most women need/want Non-judgmental interaction with a provider An explanation of treatment options and risks Prompt treatment Decision-support tools available to assist the generalist or referral to existing counselling/crisis pregnancy centres Baron C et al J Fam Plann Reprod Health Care. 2015 ; Kumar U et al J Fam Plann Reprod Health Care. 2004

Determining gestational age Goal: determine eligibility for early medical abortion No need to be as accurate as when dating for antenatal care Regimen effectiveness decreases gradually with gestation Absence of evidence that routine ultrasound improves the safety of medical abortion Some evidence that most women seeking medical abortion know their LMP and that LMP (± bimanual) can accurately determine eligibility for most women Kulier and Kapp Contraception. 2011: Kaneshiro et al Contraception. 2011; Schonberg et al 2014; Raymond & Bracken 2015

Indications for ultrasound Unknown LMP Adnexal mass or pain Significant size/dates discrepancy Provider uncertainty with exam History of previous ectopic pregnancy Became pregnant with IUD in place

Contraindications and cautions Chronic adrenal failure (long term systemic steroid use) Severe asthma uncontrolled by therapy Inherited porphyria Suspected extra-uterine pregnancy Haemorrhagic disorders or concurrent anticoagulant therapy Allergy to mifepristone or misoprostol If IUD in situ, remove before treatment In the absence of specific studies, mifepristone not recommended those with malnutrition, hepatic or renal failure

Treatment Tailoring to women’s needs Medications (office or home use) and how to use them Advice on pain and symptom management Normal process vs. worrying signs and symptoms How to get help/advice Mel Chin "RU 486 Quilt" (1996)

Misoprostol at home: safe, effective, preferred by women Systematic review: 9 prospective cohort studies Home vs. in-clinic use (n = 4,522) Odds complete abortion: 0.8 (95% CI: 0.5–1.5) Serious complications rare and not different between groups More choosing home use would choose medical again Ngo TD et al Bull WHO 2011

Mifepristone at home also preferable, acceptable, feasible and safe Armenia, the Republic of Georgia, Azerbaijan, and Uruguay) explicitly allow this option in their clinical guidelines. Australia allows for pharmacy distribution of mifepristone Telemedicine medical abortion services such as Women on Web and the Willow Women's Clinic in Vancouver have demonstrated the feasibility of outside-office use of mifepristone or methotrexate in regular clinical services as they send the medical abortion drugs to women through the mail after consultation Success and complication rates not different between home and clinic users Gold M and Chong E Contraception 2015

Routine (in person) follow-up no longer recommended after medical abortion Treatment highly effective; very few need intervention With guidance, those needing intervention will present Out-of-hours helpline helpful Multiple visits neither feasible nor desirable for women or providers Routine post-scan may increase unnecessary interventions Options Pre/post serum hCG Urine hCG with phone call or self assessment checklist Ultrasound only as needed or if preferred “I still feel pregnant” both sensitive and specific WHO Safe abortion: technical and policy guidance for health systems. 2012. Grossman D et al Obstet Gynecol . 2004

hCG decline after misoprostol Can assess for percentage decline from baseline using serum hCG as soon as 4 days post-abortion or use a low sensitivity pregnancy tests 2 weeks post or high sensitivity urine pregnancy test 3-4 weeks post – long tail to value less than high sensitivity pregnancy test so be mindful of false positives but don’t delay assessment for ongoing pregnancy. Poicus KD et al Contraception 2017

In case of… Ongoing pregnancy: surgical evacuation, repeat regimen (no data but common), repeat misoprostol only ≈ 35% effective Incomplete abortion or retained non-viable pregnancy: repeat misoprostol, surgical evacuation, or watch and wait Urgent or emergent intervention very uncommon Reeves MF et al Contraception 2008

Early medical abortion care pathway Decision-making Eligibility Contraception/STI Assessment Tablets or prescription Anti-D if needed Expulsion at home Treatment Remote or in person Review as needed Aftercare

Thank you for your attention. patricia.lohr@bpas.org