Ectopic pregnancy and

What is the most appropriate dose of and mifepristone to provide for managing miscarriage?

Study details Participants Interventions Methods Outcomes and Results Comments

Full citation Sample size Interventions Details Results Limitations

Bagratee,J.S., N=104 600 micrograms of All women with an Treatment success For each outcome apart from Khullar,V., Regan,L., vaginal misoprostol incomplete miscarriage or (number/total (%)) success and need for further Moodley,J., Kagoro,H., Characteristics (repeat after 24 hours if early pregnancy < 13 weeks intervention, data is not reported A randomized needed) gestation that presented to a. In women with incomplete separately for women with controlled trial (n=52) the Early Pregnancy miscarriage incomplete and early comparing medical and Age/years (mean Assessment Unit (EPAU) of pregnancy failures. expectant management (SD)) Placebo placed St Mary's Hospital, London, Misoprostol: 7/7 (100) of first trimester vaginally (repeat after during the study period Placebo: 12/14 (85.7) Other information miscarriage, Human Misoprostol: 33.2 (6.9) 24 hours if needed) were assessed for eligibility. Reproduction, 19, 266- Placebo: 30.9 (6.3) (n=52) Of 131 eligible women, 12 b. In women with early 271, 2004 (p=0.079) elected to have surgery, 8 pregnancy failure 600 VAGINAL MISOPROSTOL VS. elected to have expectant PLACEBO

Ref Id /days management and 7 elected Misoprostol: 39/45 (86.7) (mean (SD)) to have medical Placebo: 11/38 (28.9) EARLY PREGNANCY FAILURE + 65131 management. Therefore, INCOMPLETE MISCARRIAGE Misoprostol: 73.8 (9.9) 104 women were c. Overall Country/ies where the Placebo: 73.0 (11.6) randomised. Blinding was done. There was no study was carried out (NS) Misoprostol: 46/52 (88.5) loss to follow-up. Incomplete miscarriage was Placebo: 23/52 (44.2) United Kingdom Previous miscarriage diagnosed when there was (%) a history of passage of Study type Need for further intervention Treatment doses (number/total (%)) tissue and/or blood, and Misoprostol: 23.1 (number/total (%)) was confirmed by a Misoprostol Randomised controlled Placebo: 26.9 transvaginal ultrasound - 1 dose: 17/52 (32.7) trial (NS) a. In women with incomplete scan identifying miscarriage - 2 doses: 35/52 (67.3) heterogeneous material in Previous (%) Aim of the study the uterine cavity with an Placebo Misoprostol: 0/7 (0) endometrial thickness of Placebo: 2/14 (14.3) - 1 dose: 3/52 (57.7) Misoprostol: 19.2 >15 mm. - 2 doses: 49/52 (94.2) To determine whether Placebo: 30.8 medical management b. In women with early (NS) Early pregnancy failure was using vaginal pregnancy failure Day of success (number/total (%)) diagnosed when clinical misoprostol is superior Vaginal bleeding (%) examination showed a to expectant Misoprostol: 6/45 (13.3) Misoprostol closed cervical os, and management in Misoprostol: 67.3 Placebo: 27/38 (71.1) - Day 1: 17/52 (32.7) ultrasound confirmed either

400 and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments reducing the need for Placebo: 75.0 an intact gestational sac of c. Overall - Day 2: 21/35 (60) surgical evacuation of (NS) > 20 mm in diameter with - Day 7: 8/14 (57.1) retained products of no visible embryonic pole Misoprostol: 6/52 (11.5) conception. Type of miscarriage (n (anembryonic), or an (Note: 5 incomplete, 1 with no Placebo (%)) intrauterine gestation with products passed) - Day 1: 3/52 (5.8) Study dates an of crown-rump Placebo: 29/52 (55.8) - Day 2: 4/49 (8.2) Misoprostol: length > 5 mm without heart (Note: 6 incomplete, 23 with no - Day 7: 16/45 (35.6) - Early pregnancy pulsations. products passed) August 2001 to March failure: 45 (86.5) 2002 - Incomplete Symptomatic and Duration of bleeding/days (mean miscarriage: 7 (13.5) asymptomatic miscarriages (SD)) Source of funding were differentiated by the Placebo: presence or absence of Misoprostol: 11.65 (4.4) Not reported - Early pregnancy vaginal bleeding. Placebo: 10.88 (4.78) failure: 38 (73.1) - Incomplete Sample size calculation Mean difference (95% CI): miscarriage: 14 (26.9) 0.77 (-1.02, 2.56) The required sample size Inclusion criteria was based on improving the Adverse effects (number/total success rate of 70% with (%)) Spontaneous expectant management to incomplete 95% with misoprostol. A a. Nausea miscarriage or early trial with 90% power and an pregnancy failure alpha of 0.05 required a Misoprostol: 18/52 (34.6) sample of 96 women. Placebo: 16/52 (30.8) Up to 13 weeks gestation b. Vomiting Randomisation

Exclusion criteria Misoprostol: 8/52 (15.4) Randomisation of 104 Placebo: 7/52 (13.5) women was carried out by Complete miscarriage allocation of women to c. Diarrhoea (as assessed by either misoprostol or endometrial thickness placebo. Three misoprostol Misoprostol: 11/52 (21.1) of ≤ 15 mm on or placebo tablets were Placebo: 11/52 (21.1) transvaginal placed in each of two small ultrasound) envelopes and sealed. The d. Pelvic inflammatory disease small envelopes were then Fever (> 37.5ºC) placed in consecutively Misoprostol: 1/52 (1.9) numbered large envelopes

401 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

according to randomisation Placebo: 0/52 (0) Haemoglobin < 10 schedule, and sealed by g/dl staff not involved with the Pain severity: VAS score/10 study. (mean (SD)) Contraindication to prostaglandin therapy Treatment protocol Misoprostol: 6.0 (2.7) (asthma, Placebo: 5.4 (2.7) hypertension, Followed informed consent, glaucoma, mitral women received their Mean difference (95% CI): 0.57 stenosis) allocated treatment of either (-0.49, 1.63) 3 x 200 micrograms of Excessive bleeding misoprostol or 3 placebo Satisfaction requiring emergency tablets, placed in the surgery posterior fornix of the a. VAS score/10 (mean (SD)) vagina by a doctor or nurse in the EPAU. Both the Misoprostol: 8.9 (1.3) women and the Placebo: 8.7 (1.5) investigators were blinded to treatment allocation. b. Would choose again (number/total (%)) Baseline haemoglobin and white cell count were Misoprostol: 48/52 (92.3) obtained, and Rhesus Placebo: 38/52 (73.1) negative women received anti-D immunoprophylaxis. Mean difference (95% CI): 0.25 Paracetamol with codeine (-0.30, 0.80) was prescribed for pain and they were provided with telephone numbers to contact a doctor if necessary.

All women attended for speculum and bimanual examinations, and ultrasound, the next day (day 1). Women diagnosed with a complete miscarriage were discharged with follow-up booked for 14

402 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

days time. The remaining women had a second dose of their allocated treatment, and were seen the next day (day 2). Women for whom treatment was not successful by day 2 were asked to return on day 7, and if miscarriage was not complete, were scheduled for a surgical evacuation in theatre. all women scheduled for evacuation had their surgery performed as day cases.

Follow-up

All women in the study were seen 14 days after the diagnosis of complete miscarriage or the performance of a surgical evacuation. They were assessed for signs of bleeding, pain and infection, and had repeat full blood counts and serum hCG measurements. If hCG was > 20 IU, patients were seen weekly until a negative results of < 20 IU. A questionnaire, including visual analogue scales, was used to assess the severity of pain and the satisfaction of the treatment.

Outcomes reported

403 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

1. Success rate: reported as complete miscarriage without surgical evacuation by day 7

2. Need for further intervention: the need and reason for a surgical evacuation

3. Duration of bleeding: assessed at 14 day follow- up

4. Adverse effects: incidence of pelvic inflammatory disease, nausea, diarrhoea and vomiting

5. Severity of pain: assessed using visual analogue scales at follow- up appointment

6. Satisfaction: assessed using questionnaire Full citation Sample size Interventions Details Results Limitations

Creinin,M.D., Moyer,R., N=20 400 micrograms of oral Eligible women were Treatment success Ineligible participants Guido,R., Misoprostol misoprostol identified, and a history, (number/total (%)) for medical evacuation Characteristics physical examination, On review, it was discovered that 2 of early pregnancy baseline haemoglobin and Oral: 3/12 (25) patients in the oral arm did not meet failure, Obstetrics and 800 micrograms of vaginal misoprostol blood type were taken. Vaginal: 7/8 (87.5) the ultrasound criteria for early Gynecology, 89, 768- Age/years Women meeting the (p=0.01) pregnancy failure. One passed the 772, 1997 inclusion criteria were pregnancy with a single dose, and Oral: 26.3 (7.0) recruited and suitably the other was a treatment failure. Need for further intervention Ref Id Vaginal: 29.8 (8.0) randomised. Neither the However, even if they are excluded, clinician or patient were the difference in the success rate is

404 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

65195 Gravidity (mean blinded to treatment The authors state that "no still significant (p=0.015). (SD)) allocation. woman required a suction Country/ies where the curettage because of incomplete Lack of blinding study was carried out Oral: 3.8 (2.9) Treatment protocol passage of the uterine tissue." Vaginal: 3.3 (2.1) However, considering their trial Blinding was not done. This would USA protocol and success rates, it is Women received one of two not have been possible for the Parity (mean (SD)) unclear whether women may participants, or those administering Study type treatment regimens: have had curettage for other the misoprostol, but could have been - 400 micrograms of oral reasons (i.e. no passage of Oral: 1.4 (1.7) misoprostol (repeat dose achieved for those assessing Randomised controlled tissue). Therefore, this outcome Vaginal: 0.8 (0.9) after 24 hours if needed) outcomes. trial (pilot) has not been included in the - 800 micrograms of vaginal GRADE table. Prior elective misoprostol (repeat dose Small sample size Aim of the study abortion after 24 hours if needed) Duration of vaginal bleeding (number/total (%)) N=20, and for some outcomes there Subjects in the oral arm (mean (SD)) To determine whether is missing data which reduces misoprostol 400 Oral: 6/12 (50) swallowed misoprostol in sample size further. the presence of a member (Note: the following only micrograms orally or Vaginal: 3/8 (37.5) includes successfully treated 800 micrograms of the research staff. Those patients) Other information vaginally will cause in the vaginal arm had four Prior miscarriage complete uterine 200 micrograms tablets of (number/total (%)) misoprostol administered a. Vaginal bleeding EARLY EMBRYONIC/FETAL evacuation in women with early pregnancy vaginally. DEMISE Oral: 6/12 (50) Oral: NR failure. Vaginal: 2.3 (1.4) Vaginal: 4/8 (50) Participants were asked to ORAL vs. VAGINAL keep a symptom log, Study dates b. Spotting There were no describing side effects and Point of expulsion significant differences pain medication use. All Not reported in age, race or patients received Oral: NR obstetric history. - a packet of eight 600-mg Vaginal:7.8 (3.8) Oral arm: One subject expelled Source of funding ibuprofen tablets with tissue after one dose, one after the instructions to take as c. Any bleeding repeat dose, and one passed some Inclusion criteria tissue after the first dose but had Magee Women's needed for abdominal pain tissue in the os that was withdrawn Health Foundation - a prescription for 20 Oral: NR Healthy tablets of acetaminophen Vaginal: 10.0 (2.8) using ring forceps on day 2 with codeine (300mg/30mg) English speaking - an instruction sheet with Vaginal arm: Five subjects expelled contact details for a Adverse effects of treatment uterine contents after one dose, and Diagnosis of early two subjects after the second dose.

405 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

pregnancy failure, physician (number of women/total (%)) based on ultrasound demonstration of one Participants returned the a. Any side effect of the following: next day (approximately 24 - Embryonic pole 5-14 hours later), when a history Oral: 8/12 (66.7) mm with no of events was obtained and Vaginal: 7/8 (87.5) embryonic cardiac an ultrasound was (Note: the one in the vaginal arm activity performed. If the gestational with no side effects was the - Irregular intrauterine sac was absent, the woman treatment failure) gestational sac with was scheduled to return in 2 mean sac diameter of weeks for a follow-up 16 mm or greater and b. Nausea evaluation. If the gestational no embryonic pole sac was still present, the - Abnormal growth on Oral: 6/12 (50) misoprostol dose was Vaginal: 5/8 (62.5) ultrasound over a repeated and the subject minimum of 1 week returned the following day - Yolk sac present (study day 3). If the c. Vomiting with an abnormal gestational sac was still increase in hCG (50% present on day 3, the Oral: 3/12 (25) or less) over 48 hours, woman was offered suction Vaginal: 1/8 (12.5) and an initial value curettage. Treatment was less than 2000 IU/l considered successful if d. Diarrhoea uterine contents were At least 18 years old expelled within 24 hours of Oral: 5/12 (41.7) the initial or repeat dose. Vaginal: 3/8 (37.5) Vaginal bleeding no more than spotting Follow-up Measures of pain (not requiring more than one sanitary At the follow-up visit, a. Severity of pain/10 (mean towel a day) women were asked about (SD)) the severity of their pain Gestational age of 8 using a 10 point visual Oral: 4.0 (3.6) weeks of less by analogue scale. A Vaginal: 5.9 (2.7) ultrasound or physical haemoglobin and urine (p=0.33) examination pregnancy test were also (Note: data were not available performed. If the pregnancy for 1 woman in each arm) Closed cervical os on test was negative, the study bimanual pelvic was complete. If it was positive and bleeding was

406 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

examination no longer occurring, hCG levels were obtained and Haemoglobin of followed weekly until levels 10mg/dl or more were below 10 IU/l.

Willingness and ability All patients with ultrasound to sign informed findings demonstrating no consent yolk sac or embryonic pole on day 2 or 3 had serum hCG evaluation, due to the Willingness to abstain possibility of ectopic from intercourse for pregnancy. If hCG had not the first 3 days of the declined by 50% compared study and comply with to baseline, passage of the visit schedule pregnancy was not considered complete, and Adequate venous hCG was done at 1-2 day access for intervals. If hCG plateaued phlebotomy or the patient's condition indicated, a suction Easy access to a curettage or treatment for telephone ectopic pregnancy was done.

Exclusion criteria Outcomes reported

History of inflammatory bowel 1. Successful expulsion: disease Uterine contents expelled within 24 hours of misoprostol administration Intolerance or allergy (initial or repeat dose) to misoprostol 2. Duration of vaginal bleeding: Reported only for those who were treated successfully

3. Side effects:

407 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Participants were asked to keep a symptom log, describing side effects and pain medication use

4. Pain: The maximal amount of pain was assessed using a visual analogue scale, consisting of a 10 mm line with "no pain" at one end and "severe pain" at the other end. Full citation Sample size Interventions Details Results Limitations

Kovavisarach,E., N=114 600 micrograms of 114 women meeting the Expulsion rate within 24 hours No obvious serious limitations Jamnansiri,C., vaginal misoprostol inclusion criteria were of misoprostol treatment Intravaginal Characteristics (n=57) recruited during the study (number/total (%)) Other information misoprostol 600 microg period. There were no and 800 microg for the 800 micrograms of withdrawals. After informed a. Complete expulsion treatment of early The authors report consent was obtained, their EARLY FETAL/EMBRYONIC pregnancy failure, that characteristics vaginal misoprostol DEMISE ONLY (those with an open (n=57) complete medical history 600: 26/57 (45.6) International Journal of such as maternal age, was taken and a physical 800: 39/57 (68.4) os are excluded) Gynaecology and gravidity, parity, examination confirmed their (p=0.03) Obstetrics, 90, 208- pregnancy duration, eligibility. A complete blood VAGINAL DOSAGE COMPARISON: 212, 2005 prior miscarriage, count was performed for b. Incomplete expulsion 600 vs. 800 prior elective abortion each woman and a Ref Id and body mass index coagulation profile was 600: 24/57 (42.1) Blinding was done. were similar between obtained at study entry in 800: 16/57 (28.1) 65332 the two arms. No missed miscarriage cases. further details are If the blood test results were c. No expulsion Time to expulsion/hours (mean Country/ies where the given. normal, women were (SD)) study was carried out suitably randomised to one 600: 7/57 (12.3) of two treatment regimens. 800: 2/57 (3.5) Thailand Inclusion criteria 600: 15.00 (5.7) The allocations had been 800: 12.95 (6.18) placed in opaque envelopes (Note: the authors report that the Study type Pregnancy duration (NS, p-value not reported) up to 12 weeks by a nurse not involved in rate of any expulsion any other part of the study (complete/incomplete) was Randomised controlled process. All other staff and 96.5% in the 800μg arm, and

408 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments trial Ultrasound diagnosis patients were blinded to the 87.7% in the 600μg arm) of early pregnancy regimen allocation. Aim of the study failure, defined as one Adverse effects within 24 of: Treatment protocol hours of treatment (number of - An intrauterine To determine the women/total (%) gestational sac with a effectiveness and side mean diameter of at Group 1 (600 micrograms) effects of 600 and 800 received three 200 a. Nausea least 25 mm and no micrograms of visible embryonic pole microgram tablets of intravaginal misoprostol misoprostol and 1 tablet of 600: 2/57 (3.5) - An embryonic pole 800: 7/57 (12.3) in obtaining complete of 5-14 mm with no placebo. Group 2 (800 miscarriage in cases of micrograms) received four (p=0.08) cardiac activity early pregnancy failure - Abnormal growth or 200 microgram tablets of misoprostol. All tablets were b. Diarrhoea persistent absence of Study dates fetal cardiac activity placed in the posterior vaginal fornix. The women 600: 0/57 (0) on a second scan 7- 800: 2/57 (3.5) 10 days later then remained in a semi- November 25th 2002 to prone position for 30 (p=0.15) July 31st 2003 minutes, and remained in the observation room for 24 c. Vomiting Source of funding hours. Exclusion criteria 600: 0/57 (0) 800: 0/57 (0) Not reported Vital signs, presence of Open endocervical os uterine bleeding and d. Fever conception products, and Medical and obstetric side effects such as fever, 600: 10/57 (17.5) complications lower abdominal pain, 800: 16/57 (28.1) nausea, vomiting and (p=0.18) diarrhoea were recorded by Known allergy to the nurses and physician on prostaglandins call. Pager and telephone Pain: Incidence of lower numbers were given to the abdominal pain (number of nurse in the observation women/total (%)) room for immediate consultation with the 600: 30/57 (52.6) physician if needed. 800: 42/57 (73.7) Emergency dilatation and (p=0.20) curettage (D&C) was arranged when excessive vaginal bleeding,

409 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

incomplete miscarriage or severe abdominal pain occurred.

The decision to perform an emergency D&C was made by the physician on call based on clinical judgement. These physicians were blinded to the patient's treatment dose. A single investigator performed a vaginal ultrasound evaluation on all women who had not received a curettage in the last 24 hours. If the gestation sac or products of conception (defined as an hyperechoic or a mixed hyper/hypoechoic region of any thickness in the uterine cavity) were still present after 24 hours, a D&C was performed. If complete miscarriage had occurred, the women were discharged from hospital. All women were scheduled to return for a follow-up evaluation 1 week later.

Treatment was considered successful if the uterine contents were completely expelled within 24 hours of the initial drug administration, with no need

410 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

for uterine curettage.

Outcomes reported

1. Expulsion rate: The authors report the rates of complete, incomplete and no miscarriage within 24 hours of misoprostol administration.

2. Adverse effects: The incidence of fever, nausea, diarrhoea and vomiting within 24 hours of treatment are reported. This was recorded by the nurses and physicians.

3. Pain: The incidence of lower abdominal pain within 24 hours of treatment are reported, as recorded by nurses and physicians.

Analysis

The results of a small pilot study of 20 women in each arm and a power calculation resulted in a target sample size of 50 in each arm. 10% was added to compensate for withdrawals or loss to follow-up and resulted in 57 participants in each arm. The data were analysed using chi-squared

411 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

test, Fisher's exact test and t-tests as appropriate. p<0.05 was considered statistically significant. Full citation Sample size Interventions Details Results Limitations

Kushwah,B., Singh,A., N=100 200mg of oral This trial was conducted at Successful uterine evacuation Point of assessment of outcomes Sublingual versus oral mifepristone + 600 the prenatal clinic of the (number of women/total (%)) misoprostol for uterine Characteristics micrograms sublingual Department of Obstetrics The point at which adverse effects, evacuation following misoprostol and Gynaecology of Sublingual: 46/50 (92) pain and satisfaction were assessed early pregnancy failure, (n=50) Sucheta Kriplani Hospital, Oral: 42/50 (84) is not reported. International Journal of Age/years (mean Delhi, India. All participants Gynaecology and (SD)) 200mg of oral had early pregnancy failure Adverse effects of treatment Lack of blinding Obstetrics, 106, 43-45, confirmed by ultrasound 2009 Sublingual: 26.6 (4.4) mifepristone + (number of women/total (%)) 600 micrograms of oral between the 7th and 14th Blinding is not reported. Oral: 24.6 (3.8) week of gestation. Eligible Ref Id misoprostol a. Nausea (n=50) participants gave consent Other information Parity (mean (SD)) and were randomised using 65336 Sublingual: 17/50 (34) computer generated Oral: 26/50 (52) MISSED Sublingual: 2.1 (0.9) random numbers. Country/ies where the (Note: 1 woman from each arm MISCARRIAGE/ANEMBRYONIC Oral: 2.1 (0.9) study was carried out required medication) PREGNANCIES ONLY Treatment protocol India Gestation/days b. Vomiting ORAL VS. SUBLINGUAL (BOTH (mean (SD)) After assessment of blood WITH MIFEPRISTONE) Study type haemoglobin, serum Sublingual: 11/50 (22) Sublingual: 57.7 (7.8) Oral: 22/50 (44) bilirubin and urea, and urine Induction to evacuation Oral: 59.9 (9.0) (Note: 3 women from the oral Randomised controlled albumin and sugar interval/hours (mean (SD)) (Note: only 1 woman, arm required medication) trial concentrations, women from the oral arm, had received one of the Sublingual: 46 (4.5) gestation of over 80 c. Diarrhoea following: Oral: 9.4 (5.6) Aim of the study days) (Note: this only includes women for Sublingual: 24/50 (48) - 200mg of mifepristone whom evacuation was successful) Oral: 28/50 (56) To compare the Type of pregnancy given orally, following by (Note: 5 women in each arm had efficacy of misoprostol (number/total (%)) 600 micrograms of It is not reported how many women more than 4 episodes and administered misoprostol sublingually required the supplemental doses of required medication) sublingually or orally for Sublingual: - 200mg of mifepristone misoprostol. uterine evacuation after - Anembryonic: 23/50 given orally, following by (46) 600 micrograms of d. Fever: any

412 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments early pregnancy failure. - Missed miscarriage: misoprostol orally Sublingual: 10/50 (20) 27/50 (54) Oral: 26/50 (52) Study dates Oral: The women in the - Anembryonic: 34/50 sublingual group were e. Fever: ≥37.8ºC (68) instructed to place the three April 2003 to March - Missed miscarriage: 200 microgram tablets Sublingual: 0 2004 16/50 (32) under their tongue, and Oral: 4/50 (8) were not allowed to eat or Source of funding Inclusion criteria drink for 20 minutes to allow Measures of pain the tablets to dissolve (number/total (%)) Not reported completely. Women in the Gestational sac of 25 oral group were instructed mm or larger with no a. Incidence of pain requiring to swallow the three tablets no analgesia embryo present with water. Blood pressure, (anembryonic pulse rate and body Sublingual: 14/50 (28) gestation) temperature were recorded Oral: 26/50 (52) hourly. Presence of a fetal pole without cardiac b. Incidence of pain requiring Whenever women expelled analgesia pulsations (missed products of conception or miscarriage) bled vaginally, they were Sublingual: 9/50 (18) given a vaginal examination Oral: 18/50 (36) Exclusion criteria to assess the degree of expulsion, which was then c. Incidence of pain: total Vaginal bleeding determined to be complete on ultrasound. Evacuation Sublingual: 23/50 (46) Any evidence of was considered complete Oral: 44/50 (88) infection when the woman had no active bleeding, had a Reported satisfaction History of allergy to closed cervical os, and had an empty uterine cavity on (number/total (%)) misoprostol ultrasound examination. Evacuation was considered Sublingual: 46/50 (92) Major medical Oral: 36/50 (72) problems incomplete when active vaginal bleeding continued, the cervical os remained open, and products of conception were visible on ultrasound. In this case, women underwent surgical

413 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

evacuation under paracervical block.

Women who did not expel products of conception within 12 hours of the first dose of misoprostol were given up to 3 supplemental doses of 400 micrograms at three hour intervals (sublingually or orally depending on their allocation). Those who received the maximum misoprostol allocation and did not expel products of conception within 4 hours of taking the last 400 microgram dose underwent surgical evacuation under intravenous sedation and paracervical block.

After complete uterine evacuation, whether medical or surgical, the women were kept under observation for 6 hours and then discharged. They returned 7 days later for an assessment of haemoglobin level, and had a routine check-up 2 weeks after discharge.

Outcomes reported

1. Successful uterine evacuation: not directly defined, but see criteria for

414 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

complete evacuation above.

2. Adverse effects of treatment: The incidence of nausea, vomiting, diarrhoea (≤4 episodes and >4 episodes), and fever (both above and below 37.8°C) are reported. It is unclear at what point these outcomes were assessed.

3. Measures of pain: The incidence of abdominal pain requiring no analgesia and requiring analgesia are reported (along with the % of women who had no abdominal pain). It is unclear at what point this outcome was assessed.

4. Satisfaction: The proportion of women reporting being satisfied (phrased as a yes or no question) is reported.

Analysis

The chi-squared test, Fishers exact test and t-test were used where appropriate. p<0.05 was considered significant. The mean difference in induction-evacuation time was used to calculate that a sample size of 100 women

415 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

would have 80% power.

Full citation Sample size Interventions Details Results Limitations

Lelaidier,C., Baton- N=46 600 mg of Mifepristone Over a period of 6 months, Natural expulsion of products Small sample size (N=46) Saint-Mleux,C., (n=23) 64 women were referred to (number/total (%)) Fernandez,H., Characteristics the study hospital with the Baseline characteristics not reported Bourget,P., Placebo diagnosis of missed Mifepristone: 19/23 (82.6) separately for each arm of the trial Frydman,R., (n=23) miscarriage or blighted Placebo: 2/23 (8.7) Mifepristone (RU 486) Age/years (mean ovum. 50 were eligible (see 2/23 women in the placebo arm were induces embryo (SD)): 31.3 (4) inclusion criteria), of which Need for further intervention not included in the analysis because expulsion in first 4 refused to participate, they received advice from clinicians trimester non- Gestational (number/total (%)) leaving a study population resulting in regular dilatation and developing age/weeks (mean of N=46. aspiration. The technical team have pregnancies: a (range)): 11 (6.6 - 14) Mifepristone: 6/23 (26.1) (Note: 4 for treatment failure and included them in the denominator for prospective This was a randomised natural expulsion, in order that randomized trial, 2 for frank haemorrhage on days Inclusion criteria double blind trial. Tablets 2 and 3 respectively) estimates are conservative. Human Reproduction, were supplied by the 8, 492-495, 1993 Placebo: 19/21 (90.5) Evidence of a non- pharmacological unit Other information following randomisation by Ref Id developing Adverse effects: incidence of intrauterine pregnancy the method of permutation blocks (blocks of four). clinical MIFEPRISTONE VS. PLACEBO 65346 at two successive (number/total (%)) ultrasound Treatment was started in the morning under the MISSED MISCARRIAGE/BLIGHTED Country/ies where the examinations at least supervision of the clinician, Mifepristone: 1/23 (4.3) OVUM POPULATION study was carried out 7 days apart, of which Placebo: 1/21 (4.8) at least one was with women receiving either: (NS) France performed at the Day of expulsion (number expelling study centre - 600 mg of mifepristone (in on each day/total that ever had three tablets) Study type Pain: incidence (number/total expulsion (%)) Absence of bleeding - placebo (three tablets) (%)) - Day 2 Randomised controlled The external appearance of Mifepristone: 12/23 (52.2) trial No sign of any uterine Mifepristone: 2/19 (10.5) contraction the placebo was similar to Placebo: 5/21 (23.8) placebo: 0/2 (0) that of the mifepristone, and (p=0.08) Aim of the study the authors report that both Exclusion criteria - Day 3 the patients and clinicians Mifepristone: 7/19 (36.8) were blinded to the To investigate whether Placebo: 0/2 (0) Not reported treatment. Patients were

416 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments mifepristone without then discharged and associated instructed to seek medical - Day 4 prostaglandin advice in the case of severe Mifepristone: 5/19 (26.3) treatment could hasten pain or heavy bleeding. Placebo: 1/2 (50) embryo expulsion in They were also asked to non-developing first maintain a diary - Day 5 trimester pregnancies documenting vaginal Mifepristone: 5/19 (26.3) with no clinical sign of bleeding, uterine Placebo: 1/2 (50) miscarriage contraction, passage of tissue, and any side effects. Study dates Follow-up

Not reported, but it was On day 5, a repeat a 6 month period ultrasound was performed to assess the uterine cavity. Source of funding If this revealed failed expulsion, aspiration under Not reported local or general anaesthesia was performed on the same day.

hCG measurements and progesterone measurements were taken on day 1 and day 5, regardless of expulsion.

Outcomes reported

1. Natural expulsion:

2. Need for further intervention: need for a D&C is reported

3. Adverse effects: incidence of endometritis, defined as fever of at least 38ºC, is reported

417 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

4. Pain: incidence of pain is reported, as documented in women's diaries

Analysis

Student's t-test and chi- squared tests were used for analysis. A p-value of <0.05 was considered statistically significant. Full citation Sample size Interventions Details Results Limitations

Stockheim,D., N=115 Mf + Ms: 600mg of oral 115 women with a Treatment success No obvious serious limitations Machtinger,R., mifepristone, and then diagnosis of blighted ovum (number/total (%)) Wiser,A., Dulitzky,M., after 48 hours, two 400 or missed miscarriage (and Soriano,D., Characteristics Note: Participants were not blinded microgram doses of oral meeting the inclusion Mf + Ms: 38/58 (65.5) to their treatment allocation; however Goldenberg,M., misoprostol, three hours criteria) were suitably Ms only: 42/57 (73.7) Schiff,E., Age/years (mean the staff responsible for assessing apart randomised. Neither the (Note: 2 patients from Mf+Ms the results of transvaginal scan (and Seidman,D.S., A (SD), range) (n=58) patient or the treating and 9 patients from Ms only had randomized hence need for curettage) were physicians were blinded to success after the first blinded and therefore this study has prospective study of Mf + Ms: 32 (6), 20-43 the treatment allocation. medication round) misoprostol or Ms only: 32 (6), 20-44 Ms only: Two 400 not been downgraded. mifepristone followed microgram doses of oral by misoprostol when misoprostol, three hours Treatment protocol Need for further intervention CRL/mm (mean Other information needed for the apart, and then after 48 and reasons (number/total (SD)) treatment of women hours, the same dosage (%)) The regimens were as EARLY FETAL/EMBRYONIC with early pregnancy again follows: Mf + Ms: 49 (7) (n=57) DEMISE failure, Fertility and Ms only: 48 (8) Mf + Ms: 20/58 (34.5) Sterility, 86, 956-960, Mf + Ms: Patients received - Persistent gestational sac: 6/20 2006 - Emergency due to bleeding MIFEPRISTONE + MISOPROSTOL Nulliparous (%) 600mg of oral mifepristone vs. MISOPROSTOL ONLY and were discharged after 2 from incomplete miscarriage: Ref Id hours of observation 3/20 Mf + Ms: 24.6 - Other complications: 65505 Ms only: 25.8 emergency due to fever and Ms only: Patients received bleeding: 1/20 Country/ies where the Parity (mean (SD), two 400 microgram doses - Suspected RPOC after range) of oral misoprostol, three menstruation: 10/20 (of which 8

418 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments study was carried out hours apart, for a total of were hysteroscopies and 2 were Mf + Ms: 1.7 (1.8), 0- 800 micrograms. They were curettage) Israel 10 observed for 6 hours after Ms only: 1.4 (1.8), 0- the first dose. Ms only: 15/57 (26.3) Study type 10 - Persistent gestational sac: Both arms: Patients from 10/15 Randomised controlled Previous both arms were requested - Emergency due to bleeding trial miscarriage (%) to return after 48 hours, from incomplete miscarriage: when they all received 800 1/15 - Other complications: Aim of the study Mf + Ms: 31 micrograms of oral Ms only: 30.6 misoprostol, divided into emergency due to pain: 1/15 two equal doses three - Suspected RPOC after To compare the menstruation: 3/15 (of which 2 Previous induced hours apart. Any women outcome of medical who had significant vaginal were hysteroscopies and 1 was treatment of early abortion (%) curettage) bleeding underwent a pregnancy failure with transvaginal ultrasound, misoprostol (Ms) alone Mf + Ms: 13 Ms only: 12.9 and misoprostol was not Adverse effects of treatment or following given to anyone with an (number of women/total (%)) mifepristone (Mf) pre- empty uterine cavity (n=2 in treatment. Type of miscarriage Mf + Ms arm, n=9 in Ms In their discussion, the authors (%) only arm). also state that women did not Study dates experience side effects; Missed miscarriage Women were discharged however no details of how this Mf + Ms: 85.2 was assessed are reported. July 2001 to December Ms only: 79 within 6 hours of the first 2002 misoprostol dose, Blighted ovum depending on the severity Source of funding Mf + Ms: 14.8 of bleeding and pain. Ms only: 21 Patients were advised to return to the hospital if they Not reported experienced significant Inclusion criteria bleeding, severe pain or fever. All Rh- women were Blighted ovum or given anti-D. missed miscarriage diagnosed using Follow-up transvaginal ultrasound: - No fetal heart beat in If women did not bleed a fetus with CRL > 5 within 48 hours of

419 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

mm completion of the treatment, - A smaller fetus with they were requested to no appearance of a return for a transvaginal heartbeat after a 1 scan. If a gestational sac week follow-up was still present, surgical - Empty gestational evacuation was performed. sac with a proven 10-14 days after treatment, gestational age of at women were invited for a least 6 weeks clinical interview and a transvaginal scan. A well- Crown-rump length defined endometrial line, compatible with < 9 with a maximum thickness weeks gestation of < 15mm, combined with the absence of vaginal bleeding, was defined as a Agreeing to sign complete miscarriage. In informed consent the absence of any other clinical complaint, these Aged 20-45 patients were discharged.

Haemoglobin level at Women with suspected least 8.0 g/dL RPOC (anteroposterior diameter > 15mm or No significant vaginal presence of blood vessels bleeding in the suspicious tissue) were invited for a follow-up clinical and ultrasound Exclusion criteria exam after their first period. Women with suspected Incomplete RPOC after menstruation miscarriage underwent diagnostic and, if necessary, operative hysteroscopy. RPOC were Inevitable miscarriage suspected based on (products of gestation ultrasound images or bulging from the complaints of prolonged cervix) bleeding from patients.

Suspicion of The physicians performing extrauterine

420 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

pregnancy the vaginal scan to determine the need for CRL compatible with surgery were blinded to > 9 weeks gestation treatment allocation.

Drug or alcohol Outcomes reported abuse, as reported by the patient 1. Treatment success: Defined as no need for Abnormal complete surgical intervention blood counts routinely obtained 2. Need for further intervention: Need for either emergency curettage, or surgery for failure of medical protocol.

Analysis

Fisher's exact test, t-tests and Mann-Whitney tests were used as appropriate. Full citation Sample size Interventions Details Results Limitations

Tang,O.S., Lau,W.N., N=80 600 micrograms of A total of 80 women with a Clinical outcome Blinding Ng,E.H., Lee,S.W., sublingual misoprostol, diagnosis of first trimester (number/total (%)) Ho,P.C., A prospective Characteristics every 3 hours up to a silent miscarriage (see Blinding is not reported - this would randomized study to maximum of three inclusion criteria) were a. Complete miscarriage be impossible for the participants, compare the use of doses recruited. An ultrasound however could have been achieved repeated doses of Age/years (mean (n=40) was performed to confirm Sublingual: 35/40 (87.5) for those assessing outcomes. vaginal with sublingual (SD)) the diagnosis. Women were Vaginal: 35/40 (87.5) misoprostol in the randomised using management of first 600 micrograms of Missing data Sublingual: 32.3 (7.3) computer-generated b. Incomplete miscarriage trimester silent vaginal misoprostol, Vaginal: 33.6 (6.0) random numbers. miscarriages, Human every 3 hours up to a Unclear why not all the participants maximum of three Sublingual: 4/40 (10) responded to some of the Reproduction, 18, 176- Vaginal: 3/40 (7.5) 181, 2003 Weight/kg (mean doses Treatment protocol acceptability questions. (n=40)

421 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Ref Id (SD)) Women were randomised to c. Silent miscarriage Other information one of two treatment 65516 Sublingual: 54.1 (9.7) regimens: Sublingual: 0/40 (0) EARLY FETAL/EMBRYONIC Vaginal: 53.0 (7.1) - 600 Vaginal: 1/40 (2.5) DEMISE ONLY Country/ies where the micrograms misoprostol study was carried out sublingually, every 3 hours d. Undetermined VAGINAL vs. SUBLINGUAL Height/cm (mean up to a maximum of three Hong Kong (SD)) doses Sublingual: 1/40 (2.5) - 600 Vaginal: 1/40 (2.5) Interval between misoprostol Study type Sublingual: 158.8 micrograms misoprostol (Note: these women did not administration and start of (6.8) vaginally, every 3 hours up return on day 43 so their bleeding/hours (median)

Randomised controlled Vaginal: 158.2 (5.2) to a maximum of three outcome could not be assessed) Sublingual: 2.5 trial doses Vaginal: 3.0 Gestational Need for further intervention Aim of the study age/days (mean The sublingual group were (number of women/total (%)) (SD)) instructed to put the tablets Interval between misoprostol under their tongues Sublingual: 4/39 (10.3) administration and To compare repeated expulsion/hours (median) Sublingual: 74.6 themselves. They were not Vaginal: 4/39 (10.3) doses of sublingual allowed any food or drink (Note: 1 woman, from the with vaginal (13.1) Sublingual: 9.5 Vaginal: 75.9 (15.6) for 20 minutes to allow vaginal arm, had surgery on day misoprostol in the complete dissolution of the 7 for silent miscarriage. The Vaginal: 13.5 medical management tablets. In the vaginal other seven women had surgery (NS) of first trimester Previous live birth group, the research nurses in other facilities because of miscarriages. (number/total (%)) was responsible for putting persistent vaginal bleeding) the three misoprostol

Study dates Sublingual: 18/40 (45) tablets into the vaginal Duration of vaginal Vaginal: 22/40 (55) fornix. Blood pressure, bleeding/days (median Not reported pulse rate and side effects (range)) (including pain) were Previous recorded every hour, and miscarriages Source of funding body temperature was Sublingual: 12.5 (4 - 36) (number/total (%)) recorded every 3 hours. Vaginal: 12.0 (5 - 79) Not reported Oral or parenteral analgesic (NS) Sublingual: 13/40 was given if the women (32.5) complained of severe pain. Adverse effects of treatment Vaginal: 6/40 (15) (number of women/total (%)) Women were discharged Previous induced after the completion of the a. Nausea abortion course of misoprostol if

422 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

(number/total (%)) there was no heavy Sublingual: 24/40 (60) bleeding and they were not Vaginal: 20/40 (50) Sublingual: 9/40 in pain. The women were (22.5) asked to inform the nurse b. Vomiting Vaginal: 10/40 (25) when they passed any products at the hospital, Sublingual: 7/40 (17.5) and were given a bottle of Vaginal: 9/40 (22.5) There were no formalin to collect any significant differences products passed at home. c. Diarrhoea between the two The products were sent for groups. histological confirmation. Sublingual: 28/40 (70) Emergency surgical Vaginal: 11/40 (27.5) Inclusion criteria evacuation was performed if (p<0.005) the blood loss or abdominal First trimester silent pain was uncontrolled. d. Fever miscarriage, defined as: Follow-up Sublingual: 23/40 (57.5) - intrauterine Vaginal: 19/40 (47.5)

gestational sac with The outcome of the mean sac diameter of e. Chills treatment was assessed on ≥ 2 cm without a fetal day 7 after misoprostol. A pole Sublingual: 6/40 (15) transvaginal ultrasound was Vaginal: 3/40 (7.5) - presence of fetal done. Surgical evacuation pole with no cardiac was performed if a f. Dizziness pulsation gestational sac was still - gestational sac < 2 present, or if there was a Sublingual: 16/40 (40) cm with no interval significant amount of growth or persistent Vaginal: 10/40 (25) products of conception in absence of fetal the combined with cardiac activity on g. Fatigue heavy vaginal bleeding. If rescanning 7 - 10 the ultrasound showed days later Sublingual: 26/40 (65) complete or incomplete Vaginal: 16/40 (40) miscarriage without heavy (p=0.043) < 13 weeks gestation vaginal bleeding, no action was taken. The amount of h. Headache Exclusion criteria bleeding was monitored, and women were asked to return on day 43 to Sublingual: 18/40 (45) ascertain bleeding patterns

423 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Complete miscarriage and return of menstruation. Vaginal: 12/40 (30)

Incomplete Outcomes reported Measures of pain (number of miscarriage women/total (%)) 1. Complete miscarriage: The outcome of treatment a. Incidence of lower was classified as complete abdominal pain miscarriage if surgical evacuation was not required Sublingual: 40/40 (100) up to the time of return to Vaginal: 40/40 (100) normal menstruation. b. Degree of pain

2. Need for further - Severe, not tolerable intervention Sublingual: 6/40 (15) Vaginal: 8/40 (20) 3. Duration of bleeding: Assessed on day 43 - Tolerable Sublingual: 24/40 (60) Vaginal: 22/40 (55) 4. Adverse effects: Recorded during treatment. Fever was defined as a - Expected highest temperature of at Sublingual: 5/40 (12.5) least 38ºC. Vaginal: 4/40 (10)

- Little pain 5. Pain: Recorded during Sublingual: 3/40 (7.5) treatment. Degree of pain Vaginal: 6/40 (15) was assessed using a questionnaire. - No pain at all Sublingual: 2/40 (5) 6. Satisfaction: Assessed Vaginal: 0/40 (0) by questionnaires on days 7 and 43. Unclear which Measures of satisfaction results are reported, or (number of women/total (%)) whether they were combined. a. Would recommend treatment to others

424 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Analysis Sublingual: 36/38 (94.7) Vaginal: 33/39 (84.6) Data were analysed using Student's t-test, Mann- b. Treatment preferred if given Whitney, chi-squared and the opportunity to choose Fisher's exact test as again appropriate. - Surgery: Sublingual: 7/38 (18.4) Vaginal:10/39 (25.6)

- Vaginal misoprostol: Sublingual: 2/38 (5.3) Vaginal: 27/39 (69.2)

- Sublingual misoprostol: Sublingual: 29/38 (76.3) Vaginal: 1/39 (2.6)

- Vaginal or sublingual misoprostol: Sublingual: 0/38 (0) Vaginal: 1/39 (2.6)

c. Overall comments about treatment

- Excellent Sublingual: 4/38 (10.5) Vaginal: 3/39 (7.7)

- Satisfactory Sublingual: 26/38 (68.4) Vaginal: 28/39 (71.8)

- Fair Sublingual: 6/38 (15.8) Vaginal: 5/39 (12.8)

- Not satisfactory

425 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Sublingual: 2/38 (5.3) Vaginal: 3/39 (7.7)

(Note: Not all participants gave answers to these questions - the denominators stated above refer to those who answered, not total participants as calculated in the paper) Full citation Sample size Interventions Details Results Limitations

Tang,O.S., Ong,C.Y., N=180 600 group: 600 Women with a diagnosis of Clinical outcome Lack of blinding Tse,K.Y., Ng,E.H., micrograms of first trimester miscarriage (number/total (%)) Lee,S.W., Ho,P.C., A sublingual misoprostol were recruited. An randomized trial to Characteristics Neither participants or physicians every 3 hours up to a ultrasound examination was a. Complete miscarriage were blinded compare the use of maximum of 3 doses performed to confirm the sublingual misoprostol There were no (n=90) diagnosis of silent with or without an significant differences miscarriage (see inclusion 600: 83/90 (92.2) Missing data additional 1 week between the two criteria). 206 women with a Extended course: 84/90 (93.3) course for the Extended course arms. silent miscarriage were The denominators for the days 2 - 9 management of first group: 600 micrograms screened, however 12 b. Incomplete miscarriage adverse effects are not stated, trimester silent of sublingual Age/years (mean refused trial entry because however in order to get the % that miscarriage, Human misoprostol every 3 (SD)) they preferred the surgical the authors have reported, the Reproduction, 21, 189- hours up to a maximum 600: 0/90 (0) of 3 doses, plus an method, 8 passed products Extended course: 4/90 (4.4) denominators have to be 86 in each 192, 2006 of conception before the 600 micrograms: extended course of 400 arm. Loss to follow-up at day 9 is treatment was started, and reported as n=1 in the text, therefore Ref Id 31.7 (6.7) micrograms of c. Silent miscarriage Extended course: sublingual misoprostol 6 had other medical this missing data is unexplained. problems and did not meet 65517 32.1 (6.3) daily for a further week the inclusion criteria. (n=90) 600: 5/90 (5.6) Other information Therefore, 180 eligible 1/90 (1.1) Country/ies where the Extended course: Weight/kg (mean women were randomised to study was carried out (SD)) one of two regimens, using EARLY EMBRYONIC/FETAL d. Undetermined computer generated DEMISE Hong Kong 600 micrograms: random numbers. Blinding was not done - participants 600: 2/90 (2.2) Study type 53.2 (7.4) SUBLINGUAL DOSAGE Extended course: and investigators were (Note: One patient passed COMPARISON: 600μg vs. 600μg + 54.3 (7.8) aware of treatment tissue on day 1, but an extended course Randomised controlled allocation. ultrasound on day 9 showed incomplete miscarriage, and she Height/cm (mean Interval between misoprostol and

426 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments trial (SD)) Treatment protocols did not return on day 43. The passage of products of other did not pass any tissue on conception / hours (median Aim of the study 600 micrograms: Participants received one of day 1, and did not return on day (range)) 159.0 (3.8) two regimens: 9.) 600: 10.1 (2.8-139.5) To investigate whether Extended course: 158.5 (5.6) Extended course: 1/90 (1.1) Extended course: 9.2 (2-128) the addition of an - 600 micrograms of (NS) extended one week sublingual misoprostol (Note: This patient did not pass course of sublingual Gestational every 3 hours up to a any tissue on day 1, then an misoprostol can age/days (mean maximum of 3 doses (day ultrasound on day 9 showed improve the success (SD)) 1) incomplete miscarriage and she rate of medical - 600 micrograms of did not return on day 43.) management and 600 micrograms: sublingual misoprostol shorten the duration of 50.1 (9.6) every 3 hours up to a Duration of vaginal vaginal bleeding after Extended course: maximum of 3 doses, plus bleeding/days (median miscarriage. 50.6 (10.0) an extended course of 400 (range)) micrograms of sublingual Study dates misoprostol daily for a 600: 11.5 (5-35) Previous live birth further week (days 2-8) Extended course: 11.0 (6-42) (number/total (%)) (NS) July 2002 to January 2004 Women were instructed by 600 micrograms: the study investigator to put Adverse effects of treatment 53/90 (58.9) the three tablets of (number of women/total (%)) Source of funding Extended course: misoprostol under their 64/90 (71.1) tongue themselves. They a. Nausea: day 1 The Committee on were not allowed any food Research and Previous or drink for the next 20 Conference Grants of miscarriage minutes to allow complete 600: 38/90 (42.2) the University of Hong (number/total (%)) dissolution of the tablets. Extended course: 45/90 Kong (p=0.26) 600 micrograms: The blood pressure, pulse 20/90 (22.2) rate and side-effects were b. Nausea: days 2-9 Extended course: recorded every hour and 21/90 (23.3) the body temperature was 600: 13/86 (15.1) recorded every 3 hours. Extended course: 18/86 (20.9) Oral or parenteral analgesic Previous induced (p=0.32) was given if the women abortion (number/total (%)) complained of severe pain. c. Vomiting: day 1 The women were asked to

427 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

600 micrograms: inform the nurse when they 600: 13/90 (14.4) 23/90 (25.6) passed any tissue at the Extended course: 14/90 (15.6) Extended course: hospital and they were (p=0.81) 24/90 (26.7) given a bottle with formalin to collect any tissue passed d. Vomiting: days 2-9 Inclusion criteria at home. The tissue was sent for histological confirmation. 600: 1/86 (1.2) < 13 weeks gestation Extended course: 5/86 (5.8) (p=0.10) The women were Diagnosis of silent discharged after completion miscarriage, based of the course of misoprostol e. Diarrhoea: day 1 on: if they were not - Intrauterine experiencing heavy vaginal 600: 61/90 (67.8) gestational sac with a bleeding or pain. Women in Extended course: 63/90 (70) mean sac diameter of group 2 were given tablets (p=0.66) ≥ 2 cm without a fetal of 400 micrograms of pole misoprostol to be taken f. Diarrhoea: days 2-9 - Presence of a fetal daily at home starting from pole with no cardiac day 2 of the study. pulsation Emergency surgical 600: 19/86 (22.1) - Gestational sac evacuation was carried out Extended course: 38/86 (44.2) diameter < 2 cm with if the blood loss or (p=0.002) no interval growth or abdominal pain was persistent absence of uncontrolled. All the women g. Fever: day 1 fetal cardiac pulsation were asked to use barrier on rescanning 7-10 method for contraception if 600: 52/90 (57.8) days later necessary. Extended course: 55/90 (61.1) (p=0.65) Exclusion criteria Follow up h. Fever: days 2-9 Incomplete The outcome of the study miscarriage was assessed on day 9. A 600: 0/86 (0) transvaginal ultrasound Extended course: 0/86 (0) examination of the pelvis (p=1.0) was performed. Surgical evacuation was done if a gestational sac was still i. Chills and rigor: day 1 present or if there was

428 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

significant amount of 600: 10/90 (11.1) products of conception in Extended course: 13/90 (14.4) the uterus together with (p=0.49) clinical evidence of heavy vaginal bleeding. j. Chills and rigor: days 2-9 Otherwise, the amount of bleeding was monitored and the woman was asked to 600: 0/86 (0) come back on day 43 for Extended course: 0/86 (0) the assessment of bleeding (p=1.0) pattern and return of menstruation. The outcome k. Headache: day 1 of treatment was classified as complete miscarriage if 600: 19/90 (21.1) surgical evacuation was not Extended course: 25/90 (27.8) required. (p=0.28)

Outcomes reported l. Headache: days 2-9

1. Clinical outcome: 600: 30/86 (34.9) Complete miscarriage rate Extended course: 30/86 (34.9) is reported as the number of (p=1.0) women for whom surgical evacuation was not required. Incomplete m. Breast tenderness: day 1 miscarriage, silent miscarriage and 600: 14/90 (15.6) undetermined rates are also Extended course: 10/90 (11.1) reported. (p=0.40)

2. Duration of vaginal n. Breast tenderness: days 2-9 bleeding: Appears to have been assessed on day 43 600: 20/86 (23.3) after treatment. Extended course: 10/86 (11.6) (p=0.044) 3. Adverse effects of treatment: Incidences on (Note: the authors also report day 1, and days 2-9 are that no serious complications

429 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

reported. Diarrhoea is occurred) defined as more than three episodes. Fever is defined Measures of pain as a highest temperature of at lest 38ºC. a. Incidence of lower abdominal pain: day 1 4. Measures of pain: The incidence of lower abdominal pain on day 1, 600: 88/90 (97.8) and days 2-9 is reported. Extended course: 88/90 (97.8) (p=1.0) Analysis b. Incidence of lower abdominal pain: days 2-9 Student’s t-test, Mann– Whitney U-test , χ2-test and the Fisher exact test were 600: 66/86 (76.7) used for analysis, as Extended course: 74/86 (86.0) appropriate.The difference (p=0.12) in complete miscarriage rate was used to calculate the sample size required. According to the previous studies, the use of this regimen of sublingual misoprostol without an extended course would achieve a complete miscarriage rate of 87.5%. The use of an extended course of misoprostol would be considered superior if it could achieve a complete miscarriage rate of 97.5%. A sample size of 90 in each group gave 80% power in detecting a difference of 10% in complete miscarriage rate with an alpha of 0.05.

430 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Full citation Sample size Interventions Details Results Limitations

Ngoc,N.T., Blum,J., N=200 800 micrograms of Recruitment for this study Treatment success Lack of blinding Westheimer,E., oral misoprostol occurred at Hung Vuong (number/total (%)) Quan,T.T., Winikoff,B., Characteristics (n = 101) Hospital, a premier Blinding the patient would have been Medical treatment of research and referral facility Oral: 89/101 (88.1) missed abortion using difficult (although not impossible), 800 micrograms of in Ho Chi Minh City, Vaginal: 91/99 (91.9) however those assessing outcomes misoprostol, Age/years (range): 19 Vietnam. During the study International Journal of - 45 vaginal misoprostol such as treatment success and need (n = 99) period, 200 women with Need for further intervention for further intervention could have Gynaecology and confirmed first trimester (number/total (%)) Obstetrics, 87, 138- been blinded to treatment allocation. Education/years missed miscarriage 142, 2004 (mean): 8 consented to participate a. Total and were randomised to Misdiagnoses Ref Id Nulliparous (%): 30 one of two treatment Oral: 11/100 (11) regimens. All women would Vaginal: 7/98 (7.1) Two women with an invasive 69531 have been advised to have (NS) choriocarcinoma and a cervical No prior elective a surgical evacuation under pregnancy were included after being Country/ies where the (%): 65 general anaesthesia as part b. Medically indicated before incorrectly diagnosed with a missed study was carried out of the normal standard of study end miscarriage. This particularly affects care. the outcome of hospitalisation. Vietnam The authors give no further details, but Oral: 5/100 (5) (Note: 3 were for haemostatic Study type report that there were Treatment protocol Other information no significant control, 1 for incomplete differences between Women were randomised to miscarriage, and 1 for an EARLY EMBRYONIC/FETAL Randomised controlled the two groups, unspecified reason) trial receive either: DEMISE ONLY confirming that - Four 200 Vaginal: 2/98 (2.0) randomisation was (Note: reasons not stated) micrograms tablets of ORAL vs. VAGINAL Aim of the study effective. misoprostol orally (NS) - Four 200 c. Intervention at patient To compare the Inclusion criteria micrograms tablets of Time to expulsion/hours (mean) request efficacy of two routes of misoprostol vaginally Oral: 21.0 misoprostol First trimester, missed Every woman self- Oral: 6/100 (6) Vaginal: 13.5 administration (oral and miscarriage, defined administered their Vaginal: 5/98 (5.1) (p=0.04) vaginal) for the as: misoprostol in the presence (NS) treatment of missed - ultrasound evidence of a study investigator. miscarriage. of an intact Neither the investigator or gestational sac the patient was blinded to Study dates - no evidence of fetal cardiac activity (6

431 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

January to August weeks after last treatment allocation. 2003 menstrual period) - closed cervical os Follow-up Admission to hospital - history of no or Source of funding (number/total (%)) minimal bleeding All women were given a follow-up appointment two Oral: 0/100 (0) David and Lucille No known days later, at which time Vaginal: 2/98 (2.0) Packard Foundation contraindications to miscarriage status was misoprostol evaluated using ultrasound. (Note: 1 was due to a suspected If substantial debris molar pregnancy following General good health remained in the uterus, failure of the initial treatment. women were given the She was subsequently Willingness to attend option to return 5 days later discovered to have an invasive a follow-up visit (one week after misoprostol choriocarcinoma, requiring a administration) to allow hysterectomy. The other woman Exclusion criteria additional time for complete required a blood transfusion expulsion. If women did not after uncontrolled bleeding due See above wish to wait, they were to a cervical pregnancy. given a surgical evacuation. Therefore, these women were If, at the second follow-up incorrectly diagnosed with a visit, miscarriage was not missed miscarriage. The complete, a surgical analysis was performed both evacuation was performed. with and without these women All women were advised without a significant change in that they could return to the results.) hospital at any time if complications or questions arose, and that they could Duration of bleeding/days request a surgical (mean) completion at any point. (Note: n=95 in each arm for this Data was collected to outcome) record clinical outcome, any additional interventions, a. All bleeding acceptability and side effects. Women were asked Oral: 2.87 to keep a diary of side Vaginal: 2.69 effects, including pain. (NS)

432 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Outcomes reported b. Heavy bleeding

1. Treatment success: Oral: 0.89 Complete uterine Vaginal: 0.90 evacuation without the need (NS) for surgical evacuation c. Normal bleeding

2. Need for further Oral: 1.29 intervention: Medically Vaginal: 1.09 indicated surgical (NS) evacuation and evacuations at the patient's request are d. Light bleeding reported. Oral: 0.73 3. Hospitalisation Vaginal: 0.73 (NS) 4. Duration of bleeding: The duration of heavy bleeding (more than a Adverse effects of treatment period), normal bleeding (number of women/total (%)) (like a period), and light bleeding (less than a a. Vomiting period) are reported. Oral: 4/95 (4.2) 5. Adverse effects of Vaginal: 14/95 (14.7) treatment: The incidence of (p=0.023) diarrhoea, fever/chills, and vomiting is reported. This b. Diarrhoea was self reported by the women, using a diary. Oral: 24/95 (25.3) Vaginal: 23/95 (24.2) (NS) 6. Measures of pain: The incidence of pain/cramps is c. Fever/chills self reported, as with adverse effects. Oral: 7/95 (7.4) Vaginal: 7/95 (7.4) 7. Measures of

433 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

satisfaction: The number (NS) of women reporting being satisfied or very satisfied Measures of pain: Incidence with their allocated method of pain/cramps (number of was assessed at follow-up, women/total (%)) and women were also asked to describe the best Oral: 84/95 (88.4) and worst features of their Vaginal: 85/95 (89.5) allocated method. (NS)

Analysis Measures of satisfaction

Data was analysed using a. Satisfied or very satisfied frequencies, cross- with the method (number of tabulations, chi-squared women/total (%)) tests and t-tests where appropriate. Differences Oral: 86/100 (86.0) were considered to be Vaginal: 88/98 (89.8) statistically significant if p<0.05. b. Would choose the method again (%) Two women in the vaginal group and one in the oral Oral: 85.0 group were lost to follow-up; Vaginal: 92.9 however one woman in the (NS) vaginal group was later reached by telephone. c. Would recommend the Analysis is based on the method to a friend (%) 198 women for whom follow-up information was Oral: 83.0 available. Vaginal: 90.8

434 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Full citation Sample size Interventions Details Results Limitations

Blanchard,K., N=169 Single dose of 600 Women meeting the Complete miscarriage Lack of blinding Taneepanichskul,S., microgram, oral inclusion criteria that (number/total (%)) Kiriwat,O., Sirimai,K., misoprostol presented at 2 teaching Svirirojana,N., Characteristics Neither participants or providers (n=86) hospitals in Bangkok Single dose: 57/86 (66.3) were blinded to treatment allocation. Mavimbela,N., (Chulalongkorn Hospital Double dose: 58/83 (69.9) Winikoff,B., Two Study site and Siriraj Hospital) were regimens of (number/total (%)) Double dose (4 hours Point of assessment of outcomes apart) of 600 enrolled. A total of 169 Need for further intervention misoprostol for women were enrolled, treatment of incomplete microgram, oral (number/total (%)) Study site A: 68/169 however 1 woman at site A Not reported how and when abortion, Obstetrics misoprostol (total dose (40.2) and 2 women at site B were satisfaction was assessed and Gynecology, 103, of 1200μg) a. Medically necessary Study site B: (n=83) lost to follow-up. 860-865, 2004 101/169 (59.8) Single dose: 22/85 (25.9) Other information Ref Id After signing an informed Double dose: 18/81 (22.2) Note: The following consent form, women were INCOMPLETE MISCARRIAGE 77948 characteristics are randomised using a b. Intervention at patient ONLY reported split by study pseudo-random number request Country/ies where the site, and by the arm generator and opaque study was carried out that participants were envelopes that contained ORAL DOSAGE COMPARISON - randomised details of the allocated Single dose: 4/85 (4.7) 600 micrograms vs. 2 x 600 0/81 (0) Thailand regimen. Neither the Double dose: micrograms (4 hours apart)

Age/years (mean) provider nor the woman Study type was blinded to the c. Intervention because of Misoprostol taken as scheduled

treatment regimen. provider preference (number/total (%)) Study site A: 28.9 Randomised controlled Study site B: 27.7 0/85 (0) trial Treatment protocol Single dose: Study site A: 64/68 (94.1) p=0.26 1/81 (1.2) Double dose: Study site B: 101/101 (100) (p=0.02) Aim of the study Single dose: 28.6 Women were randomised to d. Intervention for other Double dose: 27.7 receive either: reasons - A single, oral dose of 600 To evaluate two p=0.41 Single dose: 84/86 (97.7) microgram misoprostol misoprostol regimens Double dose: 81/83 (97.6) - Two oral doses of 600 Single dose: 2/85 (2.4) and estimate whether (p=1.00) Education microgram misoprostol, with Double dose: 4/81 (4.9) they were effective in level/years (mean) 4 hours between doses treating incomplete (Note: 1 woman from the single Decision to take second dose at miscarriage dose arm and 2 from the double home Study site A: 7.3 The decision of whether or dose arm had unknown Study site B: 9.3 not to admit the woman to outcomes, and therefore have 68/83 (81.9%) women randomised to

435 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Study dates p<0.01 hospital was made at the not been included in the the double-dose regimen chose to discretion of the local denominator for need for further take the second dose of misoprostol September 2000 to Single dose: 8.5 investigator. However, intervention) at home. This was 19/32 (59.4%) at April 2002 Double dose: 8.5 investigators were site A and 49/51 (96.1) at site B p=0.98 encouraged to admit the Duration of bleeding/days (p<0.01). initial cases if they were (mean) Source of funding concerned about the Nulliparous Differences between study sites tolerability of the regimen. a. Heavy bleeding Not reported (number/total (%)) At site A, hospital admission was the standard of care for Rates of complete miscarriage were Study site A: 22/68 the treatment of incomplete Single dose: 1.31 higher at site B (85.1%) than site A (32.4) miscarriage, therefore a Double dose: 1.63 (42.6%). Site A had higher rates of Study site B: 52/101 larger proportion of women (p=0.21) medically necessary interventions (51.5) were admitted. Each and slightly higher rates of p=0.02 woman received 500-mg b. Normal bleeding intervention at patient request. The tablets of paracetamol and regimens were better accepted was instructed to take 2 overall at site B. More women at site Single dose: 34/86 Single dose: 2.86 tablets every 6 hours to A reported heavy bleeding, normal (39.5) Double dose: 2.76 manage pain. bleeding, nausea and pain. Double dose: 40/83 (p=0.79) (48.2)

p=0.33 Follow-up c. Spotting

Women were asked to Time since last Single dose: 2.94 menstrual return to the clinic 2 days Double dose: 2.88 period/days (mean) after misoprostol (p=0.89) administration for their initial follow-up visit. The outcome Study site A: 88.9 was assessed by Adverse effects of treatment Study site B: 92.8 p=0.52 ultrasound examination. If the miscarriage was not a. Nausea: incidence (number complete, women were of women/total (%)) Single dose: 89.5 given the option of waiting Double dose: 93.5 an additional 5 days (1 Single dose: 15/86 (17.4) p=0.50 week from initial treatment) Double dose: 18/83 (21.7) to see if the miscarriage (p=0.62) (Note: 9 women at would become complete site A, 3 women at without further intervention. b. Nausea: duration/days site B, 2 women in If miscarriage was not (mean) single-dose group, complete after 1 week, or

436 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

and 10 women in the woman refused an Single dose: 1.40 double-dose group extension, a surgical Double dose: 1.72 had missing LMP evacuation was performed (p=0.51) data. Where women according to the standard knew the month but practise at the hospital. c. Vomiting: incidence not date, the 15th was (Note: 59% of women (number of women/total (%)) assigned) chose to wait for the further 5 days) Single dose: 6/86 (7.0) Previous induced Double dose: 7/83 (8.4) abortion Outcomes reported (p=0.95) (number/total (%)) d. Vomiting: duration/days 1. Complete miscarriage: (mean) Study site A: 13/68 assessed by ultrasound (19.1) examination as described Single dose: 1.17 Study site B: 13/101 above Double dose: 1.00 (12.9) (p=0.36) p=0.37 2. Need for further intervention: criteria, or e. Fever/chills: incidence Single dose: 13/86 reasons, for further (number of women/total (%)) (15.1) intervention are reported. Double dose: 13/83 Single dose: 12/86 (14.0) 10/83 (12.1) (15.7) 3. Duration of bleeding: Double dose: p=0.91 Heavy bleeding is defined (p=0.89) as heavier than that of a Previous normal period. f. Fever/chills: duration/days miscarriage (mean) (number/total (%)) 4. Adverse effects: Self- Single dose: 1.00 reported nausea, vomiting Double dose: 2.30 Study site A: 15/68 and fever/chills using diary (p=0.10) (22.1) of side effects Study site B: 76/101 Measures of pain: (75.2) 5. Pain: Measured using a p<0.01 visual analogue scale of 7 a. Pain/cramps: incidence circles, with the smallest (number of women/total (%)) Single dose: 49/86 indicating no pain and the (57.0) largest indicating the worst Single dose: 57/86 (66.3) Double dose: 42/83 pain women had ever Double dose: 63/83 (75.9) (50.6)

437 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

p=0.50 experienced. (p=0.23)

6. Satisfaction: Not b. Pain level/7 (mean) reported how and when this Inclusion criteria was assessed Single dose: 3.65 (n=85) Double dose: 4.09 (n=81) (p=0.20) Women with signs of Analysis incomplete miscarriage, with A sample size calculation (Note: The assessment of pain ultrasound findings was performed, and the level does not include the 3 consistent with first authors aimed to enrol 100 women lost to follow-up) trimester miscarriage, women in each arm to give who would have been 80% power to detect a Measures of satisfaction advised to have a difference of 20% between (number of women/total (%)) surgical evacuation the two groups. Chi- squared test, Fisher's exact a. Satisfied or very satisfied In good general health test, sample t-tests and with treatment Mann-Whitney tests were used to compare variables Single dose: 68/85 (80.0) Agree to return for where appropriate. A p- Double dose: 63/81 (77.8) follow-up and value of <0.05 was (p=0.87) complete a diary of considered statistically side effects significant. b. Would choose this method again Good access to emergency care Single dose: 74/85 (87.1) facilities Double dose: 71/81 (87.7) (p=0.91)

c. Would recommend this method to a friend

79/85 (92.9) Exclusion criteria Single dose: Double dose: 71/81 (87.7) (p=0.37) Known allergy to misoprostol (Note: the 3 women lost to follow-up are not included in the

438 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

satisfaction outcomes) Full citation Sample size Interventions Details Results Limitations

Ngoc,N.T.N., Blum,J., N=300 Single dose of 600 During the study period, Success rate (number/total Lack of blinding Durocher,J., Quan,T.T., microgram oral 300 women presenting with (%)) Winikoff,B., A misoprostol diagnosed incomplete randomized controlled (Note: 5 were lost to Blinding is not reported in this study. follow-up, and their (n=150) miscarriage (see inclusion Single dose: 142/150 (94.7) study comparing 600 criteria) were recruited at a versus 1,200 microg data has been Double dose: 137/150 (91.3) Missing data excluded from all Double dose (4 hours large tertiary facility in Ho oral misoprostol for Chi Minh City. Ultrasound medical management analyses, therefore apart) of 600 microgram was only used for diagnosis Loss to follow-up was 1/150 of incomplete abortion, reported population is oral misoprostol (total when there was a suspicion Need for further (0.7%) in the single dose arm and Contraception, 72, 438- N=295) dose of 1200 that the uterus had been intervention (number/total 4/150 (2.7%) in the double dose arm 442, 2005 micrograms) (%)) (n=150) emptied (i.e. when the (NS). Apart from the loss to follow-up Characteristics choriodecidual reaction in they reported, there is missing data Ref Id the uterine cavity measured a. Due to incomplete for 1 participant in the double dose Age/years (mean <11 mm). If products of miscarriage at study end group for the outcomes of adverse 78319 (range)) conception were seen or felt effects, pain and satisfaction at the external os, (n=145). This omission is not Country/ies where the Single dose: 4/149 (2.7) ultrasound was not explained. study was carried out Single dose: 28.5 Double dose: 4/146 (2.7) (18-48) performed. All these women (NS) would have received Vietnam Double dose: 28.6 Other information (18-46) surgical evacuation using aspiration, with or without b. Medically indicated surgical Study type anaesthesia, if misoprostol intervention before study end INCOMPLETE MISCARRIAGE Education/years had not been available. ONLY Randomised controlled (mean) Eligible women who gave Single dose: 3/149 (2.0) trial informed consent were Double dose: 4/146 (2.7) ORAL DOSAGE COMPARISON: Single dose: 8.0 randomised using a (NS) 600 micrograms vs. 2 x 600 Aim of the study Double dose: 7.7 computer generated micrograms (4 hours apart) random sequence in (Note: 6 were medically envelopes (not reported if To document the Gestational indicated for haemostatic Time to expulsion they were opaque). effectiveness of 600 age/weeks (mean) control and 1 was given on day micrograms vs. 1200 3 when the woman presented 60% of the women had completed Treatment protocol micrograms of oral Single dose: 8.0 with signs of infection) their miscarriages by study day 3. misoprostol as a non- Double dose: 8.3 The remaining women with surgical treatment for Women were randomised to c. Surgical completion for successful treatment had completed one of two treatment provider preference before it by study day 7. At the follow-up

439 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments incomplete miscarriage Parity (mean) protocols: study end visit, women were asked if they had - A single dose of 600 observed the expulsion. 85.2% in the Study dates Single dose: 1.4 microgram oral misoprostol Single dose: 0/149 (0) single dose group and 80.0% in the Double dose: 1.3 - Two 600 microgram doses Double dose: 1/146 (0.7) double dose group had observed the of oral misoprostol 4 hours (NS) expulsion (note: women who May 2002 to January apart, for a total of 1200 reported having observed the 2003 Primigravida micrograms expulsion were more likely to indicate (number/total (%)) (Note: this woman was given that they were satisfied with the Source of funding All women swallowed their surgical completion after the method, p<0.001). Single dose: 57/149 misoprostol in the presence provider suspected an (38.3) of study staff at the hospital. intracervical polyp on follow-up David and Lucille examination) The mean time (in hours) to Packard Foundation Double dose: 51/146 Women in the repeated expulsion was: (34.9) dose group were asked to Single dose: 13.6 remain in the hospital for Duration of bleeding/days Double dose: 14.0 Number of previous their second dose. All (mean (SD)) (NS) elective abortions women were released (mean (range)) shortly after misoprostol a. Any bleeding administration. Women were given eight 500mg Single dose: 0.52 (0- paracetamol tablets to Single dose: 4.1 (2.3) 5) manage any pain, Double dose: 3.7 (2.3) Double dose: 0.44 counselled about the side (NS) (0-6) effects of misoprostol, and scheduled to return for b. Heavy bleeding Number of previous follow-up care 2 days later. Women were also asked to miscarriages (mean Single dose: 0.8 (0.8) complete a diary card to (range)) Double dose: 0.8 (0.7) record any side effects and (NS) use of pain medication. Single dose: 0.16 (0- They were told that they 3) could return to the hospital c. Normal bleeding Double dose: 0.12 or contact the study (0-2) providers at any time if they Single dose: 1.2 (0.9) had additional questions or Double dose: 1.2 (1.2) The authors report concerns. (NS) that there were no significant differences Follow-up in the characteristics d. Light bleeding of the two study At the follow-up visit, each Single dose: 2.1 (2.1)

440 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

groups. woman's miscarriage status Double dose: 1.8 (2.1) was assessed. Women with (NS) Inclusion criteria retained products in the cervix (i.e. intrauterine Adverse effects of treatment echoic mass > 12 mm, (number of women/total (%)) Women with dilated cervix and/or heavy incomplete bleeding on study day 3) miscarriage, were offered the option of a. Nausea diagnosed using the waiting an additional week following criteria: to see if these products Single dose: 33/149 (22.1) - Transvaginal would evacuate on their Double dose: 19/145 (13.1) ultrasound evidence own. If they agreed, they (p=0.04) of substantial debris in were given a second follow- the uterus (echogenic up appointment on study b. Vomiting mass >12 mm) day 7 after initial treatment. - Past or present Women who did not want to history of vaginal wait were given an Single dose: 19/149 (12.8) bleeding during immediate surgical Double dose: 17/145 (11.7) pregnancy completion. All women with (NS) - Open cervical os, retained products on study with or without day 7 were given surgery. c. Diarrhoea products of Upon completion of conception present in treatment, women were Single dose: 51/149 (34.2) the cervical or vaginal interviewed to gauge the Double dose: 68/145 (46.7) canal acceptability of the (p=0.03) treatment. Aged 18 years or d. Fever/chills older Outcomes assessed

Single dose: 15/149 (10.1) Living or working 1. Success rate: The Double dose: 12/145 (8.3) within 1 hour of the primary outcome for this (NS) study hospital study was complete uterine evacuation without recourse No known to surgical intervention at (Note: they report that there contraindication to any point for any reason were no serious complications misoprostol during the study period. or adverse effects reported by any of the participants in the study) 2. Surgical intervention before study end: They

441 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

General good health report the incidence of Measures of pain medically indicated surgery, Exclusion criteria and surgery due to provider a. Incidence of pain/cramps preference (number of women/total (%)) Not reported (but those lost to follow-up 3. Duration of bleeding: Single dose: 125/149 (83.9) were excluded from They report duration of Double dose: 120/145 (82.8) all analyses) heavy bleeding (more than (NS) a period), normal bleeding (like a period) and light bleeding (less than a b. Pain level/7 (mean) period). Single dose: 3.7 4. Adverse effects: Double dose: 3.6 Incidence of nausea, (NS) vomiting, diarrhoea and fever/chills. Information was Measures of satisfaction collected using the diary (number of women/total (%)) card which was reviewed at the exit interview. a. Satisfied or very satisfied with treatment 5. Measures of pain: Incidence of pain/cramps Single dose: 143/149 (96.0) was collected using the Double dose: 136/145 (93.8) diary card which was reviewed at the exit interview. Pain level was (Note: 4/149 (2.7%) in the single measured on a seven point dose group and 3/145 (2.1%) in scale. the double dose group were unsatisfied. The remainder were neutral) 6. Measures of satisfaction: Overall satisfaction (very satisfied, b. Would choose method satisfied, neutral, again unsatisfied), whether the woman would choose the Single dose: 139/149 (93.3) method again, and whether Double dose: 129/145 (89.0) she would recommend it to

442 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

a friend were assessed in c. Would recommend method an exit interview. The best to a friend and worst features of the methods were also Single dose: 144/149 (96.6) assessed. Double dose: 135/145 (93.1)

Analysis Best features of the methods (number/total (%)) 5 women (1 from single dose group and 4 from the a. Successful, feels good after double dose group) were lost to follow-up. Every effort was made to contact Single dose: 84/149 (57.1) them by home visits and Double dose: 70/145 (48.6) phone calls; however this was unsuccessful and their b. Does not affect health outcomes are unknown. They have been excluded Single dose: 57/149 (38.8) from all analyses. Double dose: 49/145 (34.0)

Data entry and analysis c. Perceived better method were conducted using SPSS. Chi-squared and t- tests were used as Single dose: 18/149 (12.2) appropriate, and p<0.05 Double dose: 24/145 (16.7) was considered statistically significant. d. Avoid curettage

Single dose: 5/149 (3.4) Double dose: 7/145 (4.9)

e. Fewer side effects

Single dose: 7/149 (4.8) Double dose: 5/145 (3.5)

443 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

f. Others

Single dose: 1/49 (1.0) Double dose: 4/145 (2.8)

g. Don't know

Single dose: 9/149 (6.1) Double dose: 11/145 (7.6)

Worst features of the methods (number/total (%))

a. None

Single dose: 122/149 (82.4) Double dose: 118/145 (82.0)

b. Pain, body aches

Single dose: 12/149 (8.1) Double dose: 14/145 (9.7)

c. Diarrhoea, vomiting

Single dose: 6/149 (4.1) Double dose: 4/145 (2.8)

d. Too time consuming

Single dose: 6/149 (4.1) Double dose: 5/145 (3.5)

e. Bleeding

444 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Single dose: 4/149 (2.7) Double dose: 6/145 (4.2)

f. Weakness, fatigue

Single dose: 5/149 (3.4) Double dose: 5/145 (3.5)

g. Anxious, worried

Single dose: 1/149 (1.0) Double dose: 1/145 (1.0)

h. Other reason

Single dose: 2/149 (1.4) Double dose: 0/145 (0) Full citation Sample size Interventions Details Results Limitations

Rita, Gupta,S., N=100 400 micrograms of oral This study was conducted Treatment success Definition of outcomes Kumar,S., A misoprostol, repeated in the Department of (number/total (%)) randomised every three hours up to Obstetrics and comparison of oral and Characteristics Unclear how and when "severe pain" a maximum of 3 doses Gynaecology of SMGS Oral: 18/50 (36) and adverse effects were judged. vaginal misoprostol for (n=50) Hospital, Government Vaginal: 40/50 (80) medical management Age/years (number Medical College, Jammu. of first trimester missed of women/total (%)) Blinding 600 micrograms of All women satisfying the Need for further intervention abortion, JK Science, inclusion criteria underwent 8, 35-38, 2006 15-20 vaginal misoprostol, with (number/total (%)) a second dose after 4 transvaginal ultrasound to There is no reported blinding. It Oral: 9/50 (18) confirm the diagnosis, after would have been difficult to blind the Ref Id Vaginal: 8/50 (16) hours Oral: 32/50 (64) (n=50) a thorough physical and Vaginal: 10/50 (20) participants, however the physicians systemic examination. 100 assessing the treatment success and 78403 21-25 women consented to need for further intervention could Oral: 25/50 (50) participate and were Adverse effects of treatment have been blinded to treatment Country/ies where the Vaginal: 21/50 (42) randomised (using (number/total (%)) allocation. study was carried out permuted block method). 26-30 a. Nausea Oral: 14/50 (28) Other information

445 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

India Vaginal: 17/50 (34) Treatment protocol Oral: 25/50 (50) EARLY EMBRYONIC/FETAL Vaginal: 20/50 (40) DEMISE ONLY Study type 31-35 Women received one of two Oral: 2/50 (4) b. Vomiting regimens: ORAL vs. VAGINAL Randomised controlled Vaginal: 4/50 (8) - 400 micrograms given trial orally, and repeated every 4 Oral: 6/50 (12) (p=0.87) hours up to a maximum of Vaginal: 3/50 (6) Number of doses required in successfully treated patients Aim of the study three doses Gravidity (number of - 600 micrograms inserted c. Diarrhoea (number/total (%)) women/total (%)) into the posterior vaginal To compare the safety fornix, with a second dose Oral: 5/50 (10) Oral (n=18) and efficacy of oral 1 repeated after 4 hours Vaginal: 5/50 (10) 1: 3/18 (16.7) versus vaginal Oral: 21/50 (42) 2: 6/18 (33.3) misoprostol for medical d. Hyperpyrexia 3: 9/18 (50) Vaginal: 19/50 (38) Over the next 10-12 hours, management of missed miscarriage. complete, incomplete, or no Oral: 2/50 (4) Vaginal (n=40) 2 expulsion was documented Oral: 8/50 (16) Vaginal: 2/50 (4) 1: 9/40 (22.5) by transvaginal ultrasound. 2: 31/40 (77.5) Study dates Vaginal: 15/50 (30) The absence of an echogenic structure Measures of pain: incidence 2002 to 2003 3 measuring less 15 mm in of severe pain (number/total Time interval between first dose Oral: 12/50 (24) diameter suggested (%)) and expulsion/hours (mean (SD)) Vaginal: 8/50 (16) Source of funding complete miscarriage. Nothing was given by Oral: 8/50 (16) Oral: 9.83 (2.09) 4 mouth except medication Vaginal: 5/50 (10) Vaginal: 8.15 (2.85) Not reported Oral: 9/50 (18) for pain relief until complete (p=0.01) Vaginal: 8/50 (16) expulsion or surgical

evacuation. Information was (p=0.37) obtained regarding side effects. Rh- women were Residence (number given anti D of women/total (%)) immunoglobulin.

Urban Surgical evacuation was Oral: 32/50 (64) performed in the case of Vaginal: 29/50 (58) heavy vaginal bleeding, or when transvaginal Rural ultrasound did not Oral: 18/50 (36) document complete Vaginal: 21/50 (42)

446 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

expulsion after 10-12 hours. (p=0.53) Outcomes reported Period of gestation/weeks 1. Treatment success: (number Defined as complete, drug of women/total (%)) induced expulsion of the products of conception 6-8 Oral: 9/50 (18) Vaginal: 7/50 (14) 2. Need for further intervention: The number 8-10 of women requiring surgical Oral: 10/50 (20) evacuation Vaginal: 10/50 (20) 3. Adverse effects of 10-12 treatment: Incidence of Oral: 18/50 (36) nausea, vomiting, diarrhoea Vaginal: 15/50 (30) and hyperpyrexia are reported. 12-13 Oral: 13/50 (26) 4. Pain: Incidence of severe Vaginal: 18/50 (36) pain is reported; however it is unclear what criteria was (p=0.89) used to judge severity.

Inclusion criteria

Gestation less than 13 weeks

Haemodynamically stable

Haemoglobin more than 10gm%

447 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Closed cervical os

Axillary temperature of < 37.5ºC

Exclusion criteria

History of inflammatory bowel disease

Allergy to misoprostol Full citation Sample size Interventions Details Results Limitations

Shah,N., Azam,S.I., N=50 400 micrograms of This is a prospective open- Complete miscarriage rate Blinding Khan,N.H., Sublingual sublingual misoprostol, labelled trial conducted in (number/total (%)) versus vaginal Characteristics every three hours up to the Department of Blinding was not done. Blinding the misoprostol in the a maximum of 5 doses Obstetrics and management of missed a. In those ≤ 12 weeks participants would have been difficult (n=25) Gynaecology at Civil (although not impossible), however miscarriage, Journal of Age/years (mean Hospital, Karachi. A total of the Pakistan Medical (SD)) Sublingual: 11/22 (50) they could have blinded the 400 micrograms of 50 women diagnosed with a Vaginal: 10/19 (52.6) physicians judging treatment success Association, 60, 113- missed miscarriage were 116, 2010 Sublingual: 26.2 (4.2) vaginal misoprostol, (p=0.557) and need for further intervention. every three hours up to admitted from the out- Vaginal: 26.4 (4.4) patient clinic after doing a Ref Id (p=0.870) a maximum of 5 doses b. In those > 12 weeks Indirectness of population (n=25) pelvic examination and gaining informed consent. 78450 Sublingual: 2/3 (66.7) Parity (median Women were randomised Vaginal: 2/6 (33.3) For need for further intervention, (range)) (Note: those with a using consecutive sealed adverse effects, and satisfaction, the Country/ies where the (p=0.404) gestational age and envelopes. population includes women with study was carried out uterine size of more Sublingual: 2 (0-5) c. All women gestational ages that are outside the than 12 weeks were scope of the guideline. Pakistan Vaginal: 2 (0-5) Treatment protocol (p=0.845) given 200 micrograms of Sublingual: 13/25 (52.0) Study type misoprostol instead, in Women received one of two Vaginal: 12/25 (48.0) Small sample size Gestational both arms) regimens: (p=0.571) Randomised controlled age/weeks (mean - 400 micrograms of N=50 (SD)) sublingual misoprostol, every three hours up to a Need for further intervention

448 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments trial Sublingual: 10.1 maximum of 5 doses (number/total (%)) Other information (2.62) - 400 micrograms of vaginal Aim of the study Vaginal: 10.6 (2.92) misoprostol, every three Sublingual: 11/25 (44.0) EARLY EMBRYONIC/FETAL (p=0.480) hours up to a maximum of 5 Vaginal: 13/25 (52.0) DEMISE (Note: 22/25 in the doses (Note: 1 further woman in the To compare the sublingual arm and sublingual group had an efficacy of sublingual SUBLINGUAL vs. VAGINAL 19/25 in the vaginal However, patients with a incomplete miscarriage - it is not and vaginal arm had a gestational reported whether she had a misoprostol in the gestational age of more age of less than or than 12 weeks, whose surgical evacuation) Interval between misoprostol and medical management equal to 12 weeks, expulsion/hours (mean (SD)) of missed miscarriage. uterine size was also more and hence constitute than 12 weeks, were given the main population of 200 micrograms instead of Adverse effects of treatment Sublingual: 13.07 (5.63) Study dates interest for this review 400 micrograms in both (number/total (%)) Vaginal: 13.29 (5.63) question) sublingual and vaginal (NS) Not reported groups. a. Any side effects Uterine size/weeks Source of funding (range) Patients were monitored by Sublingual: 18/25 (72.0) the duty doctor for blood Vaginal: 5/25 (20.0) Sublingual: 8-16 (p<0.001) Not reported pressure, pulse, Vaginal: 8-18 temperature, lower (p=0.952) abdominal pain or bleeding, b. Nausea and the development of any Inclusion criteria side effects. Women were Sublingual: 5/25 (20.0) told to inform the duty Vaginal: 1/25 (4.0) (p=0.094) Ultrasound diagnosis doctor if they experienced pain, bleeding, passed the of missed miscarriage c. Unpleasant taste < 20 weeks gestation gestational sac, or developed any side effects like fever or shivering. Two Sublingual: 15/25 (60.0) Exclusion criteria tablets of oral paracetamol Vaginal: 1/25 (4.0) were given if women (p<0.001) Incomplete complained of severe lower miscarriage abdominal pain. d. Shivering

Sublingual: 6/25 (24.0) Retained products of Information regarding age, Vaginal: 4/25 (16.0)} conception parity, gestational age, (p=0.362) uterine size, ultrasound Previous caesarean diagnosis, number of doses, induction interval, side

449 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

section scars effects and treatment Satisfaction (%) success were recorded on structured proformas. Sublingual: 52 Women who expelled the Vaginal: 48 sac were sent for (NS) ultrasound to exclude the (Note: the authors report that possibility of RPOC. Those this closely followed the success who failed to miscarry after rate of the regimen) 5 doses of misoprostol, and those who had incomplete miscarriage were sent for surgical evacuation under general anaesthesia on the next day. They were discharged 6 hours after the evacuation. Patients were not called for any follow-up visit.

Outcomes reported

1. Complete miscarriage rate: This is split by those with a pregnancy of less than or equal to 12 weeks, and those with a pregnancy of more than 12 weeks.

2. Need for further intervention

3. Adverse effects of treatment: The incidence of any side effects, nausea, unpleasant taste and shivering are reported.

4. Satisfaction: Assessed

450 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

by verbally asking patients whether they were satisfied, dissatisfied or neutral with regards to their treatment regimen. Full citation Sample size Interventions Details Results Limitations

Tanha,F.D., Feizi,M., N=220 400 micrograms of Recruitment for this trial Complete evacuation Dosage Shariat,M., Sublingual vaginal misoprostol took place at Mirza Kochak (number/total (%)) versus vaginal Characteristics every 6 hours Khan Hospital, a premier The trial protocol does not state misoprostol for the (n=110) research and referral facility Vaginal: 51/110 (46.4) whether there was a maximum management of missed in Tehran. An ultrasound Sublingual: 93/110 (84.5) number of tablets that a woman abortion, Journal of Age/years 400 micrograms of examination was performed could receive. The mean number of Obstetrics and on all women to confirm the RR (95% CI): 0.54 (0.442-0.681) tablets was 4.45 in the vaginal group Gynaecology Vaginal: 29.1 sublingual misoprostol every 6 hours diagnosis of first trimester (p<0.0001) and 4.85 in the sublingual group Research, 36, 525-532, Sublingual: 28.5 silent miscarriage (see (p=0.211). 2010 (p=0.516) (n=110) inclusion criteria). All Need for further intervention eligible women were Ref Id (number/total (%)) Lack of blinding Gestational suitably randomised to one age/weeks of two treatment regimens. 78505 Vaginal: 59/110 (53.6) Those assessing treatment outcome Neither the clinician or the (Note: 15 due to persistent were not blinded to Vaginal: 10.8 patient were blinded to Country/ies where the gestational sac after 2 days; 44 treatment allocation. Sublingual: 10.6 treatment allocation. study was carried out due to incomplete miscarriage. (p=0.655) Histology from 3 of the patients Misdiagnosis Iran Treatment protocols showed a partial mole) Gravidity 5 of the participants were later Study type Women received one of two Sublingual: 17/110 diagnosed as having a partial or Vaginal: 2.87 treatment regimens: (Note: 5 due to persistent complete mole (however, this gestational sac after 2 days; 12 Randomised controlled Sublingual: 2.85 - 400 micrograms of vaginal represents only 2.3% of the study trial (p=0.926) misoprostol every 6 hours due to incomplete miscarriage. population) - 400 micrograms of Histology from 2 of the patients sublingual misoprostol showed a partial mole and Aim of the study Parity Other information every 6 hours complete hydatiditiform mole) Vaginal: 0.44 To evaluate the RR (95% CI): 3.471 (2.168- EARLY FETAL/EMBRYONIC Sublingual: 0.23 The research resident was efficacy of two routes of 5.555) DEMISE (p=0.013) responsible for misoprostol (p<0.0001) administration of the vaginal administration misoprostol, placing the VAGINAL vs. SUBLINGUAL (sublingual and Previous

451 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments vaginal) for the miscarriage tablet into the posterior Adverse effects of treatment COMPARISON treatment of missed fornix. Women in the (number of women/total (%)) miscarriage. Vaginal: 0.60 sublingual group were Time to expulsion/hours (mean) Sublingual: 0.71 instructed to place the a. Vomiting Study dates (p=0.528) misoprostol tablet under Vaginal: 19.86 their tongues themselves. Vaginal: 13/110 (11.8) Sublingual: 9.53 Live children They were not allowed any Sublingual: 22/110 (20) (p=0.000) January 2005 to food or drink for the next 20 February 2007 Vaginal: 0.84 minutes to allow complete RR (95% CI): 0.591 (0.255- Sublingual: 0.96 dissolution of the tablet. 1.128) Source of funding (p=0.535) (p=0.140) All women were admitted to b. Diarrhoea Not reported (Note: it is not the hospital, and a follow-up appointment was conducted reported what Vaginal: 40/110 (36.4) these statistics at the hospital for 1-2 days later. Miscarriage status Sublingual: 76/110 (69.1) represent, although the technical team was determined at that point using ultrasound. If RR (95% CI): 0.526 (0.399- hypothesise that they 0.694) represent means) substantial debris (anteroposterior diameter > (p<0.0001) 15 mm on transvaginal Inclusion criteria scan) remained in the c. Fever uterus, women were given a Silent miscarriage, dilatation and curettage. Vaginal: 4/110 (3.6) defined as: Sublingual: 26/110 (23.6)

- intrauterine Outcomes reported gestational sac with a RR (95% CI): 0.154 (0.056- mean sac diameter of 0.426) at least 2 cm without a 1. Success rate: Defined (p<0.0001) fetal pole as the passage of products - presence of a fetal of conception without pole with no cardiac needing Measures of pain (number of activity or dilatation and curettage. women/total (%)) - gestational sac < This was assessed at the 2 cm with no interval follow-up appointment 1-2 a. Cramp pain growth, or persistent days after treatment. absence of fetal Vaginal: 62/110 (56.4) cardiac pulsation on 2. Need for further Sublingual: 94/110 (85.5) rescanning 7-10 days intervention: The number RR (95% CI): 0.660 (0.550-

452 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

later of women requiring surgery, 0.791) and reasons for the (p<0.0001) < 13 weeks gestation intervention are reported. b. Severe pain

No known 3. Adverse effects of treatment: This is reported Vaginal: 42/110 (38.2) contraindications to Sublingual: 77/110 (70) misoprostol by the women for the period from 1 hour to 24 hours after every administration of RR (95% CI): 0.859 (0.713- General good health misoprostol, up to the first 1.036) follow-up visit. Fever is (p=0.091) No vaginal bleeding defined as an oral temperature of at least 37.8°C. Exclusion criteria Measures of satisfaction (%)

4. Measures of pain: The a. Reported being satisfied Incomplete with treatment miscarriage incidence of cramping pain and severe pain are reported by the women for Vaginal: 53.6 Inevitable miscarriage the period from 1 hour to 24 Sublingual: 93.6 (products of gestation hours after every (p=0.001) bulging from the administration of cervix) misoprostol, up to the first b. Would recommend method follow-up visit. to others

Suspicion of an extra- Vaginal: 53.6 uterine pregnancy 5. Measures of Sublingual: 84.5 satisfaction: Assessed by (p=0.004) Drug or alcohol abuse questionnaire at follow-up as reported by the (Note: satisfaction was also woman Analysis related to success of treatment)

Abnormal blood count Data were analysed using tests obtained chi squared, t-tests, and risk routinely ratios where appropriate. A p-value < 0.05 was considered significant.

453 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Full citation Sample size Interventions Details Results Limitations

Wood,S.L., Brain,P.H., N=50 800 micrograms of Eligible women (see Complete miscarriage 4/25 (16%) women did not return Medical management misoprostol vaginally inclusion criteria) gave (number/total (%)) their questionnaires for the of missed abortion: a Characteristics (repeat after 24 hours if informed consent, and then satisfaction outcomes. randomized clinical needed) were randomly allocated to Misoprostol: 20/25 (80) trial.[Erratum appears (n=25) receive either 800 Placebo: 4/25 (16) Adverse effects and satisfaction are in Obstet Gynecol 2002 Age/years (mean micrograms of misoprostol (p < 0.001) only reported for one arm of the trial Jul;100(1):175 Note: (SD)) Placebo (repeat after 24 vaginally or placebo. Dosage error in hours if needed) Randomisation was Need for a D&C (number/total Small sample size (N=50) published abstract; Misoprostol: 32 (5.0) (n=25) achieved using a computer MEDLINE/PubMed Placebo: 33 (3.9) (%)) generated random number Other information abstract corrected], list, and pharmacy staff Obstetrics and Misoprostol: 7/25 (28) Gestational placed either placebo or Gynecology, 99, 563- Placebo: 21/25 (84) age/weeks (mean misoprostol into numbered 800 MICROGRAMS VAGINAL 566, 2002 (p < 0.001) (SD)) envelopes. The MISOPROSTOL VS. PLACEBO investigators were not Ref Id Misoprostol: 11.4 (2.2) aware of the randomisation Adverse effects: gastrointestinal EARLY FETAL/EMBRYONIC Placebo: 11.7 (2.7) schedule. Because the side effects (number/total (%)) DEMISE ONLY 78565 tablets were not identical, additional precautions were Misoprostol: 1/25 (4) Blinding was done. Country/ies where the Diameter of taken to maintain allocation Placebo: NR study was carried out gestational sac/mm (mean (SD)) concealment. After the clinical assessment, the Canada Satisfaction (number/total (%)) Misoprostol: 3.8 (1.6) study nurse placed the pills in an opaque vaginal Study type Placebo: 3.6 (1.5) a. Agree/strongly agree that they introducer, which the would choose again physician then used to Randomised controlled Inclusion criteria insert the tablets. Misoprostol: 19/21 (90.5) trial Placebo: NR Ultrasound diagnosis The women were provided Aim of the study of a non-viable with acetaminophen and b. Agree/strongly agree that they pregnancy, defined as combined would recommend to a friend acetaminophen/codeine To estimate the one of the following: tablets for analgesia. They Misoprostol: 18/21 (85.7) efficacy of vaginal - embryo greater than were instructed to use one Placebo: NR misoprostol for medical 7 mm with no or two of these tablets every management of missed embryonic cardiac 4 hours as needed. miscarriage activity - irregular gestational Subjects were also asked to complete a patient

454 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Study dates sac with mean sac satisfaction questionnaire diameter greater then and a symptom log. An February 1999 to April 16 mm information sheet was 2000 - gestational sac provided with instructions to greater than 15 mm return to the hospital if with no visible fetal heavy bleeding occurred. Source of funding pole Heavy bleeding was defined as saturating more than one Office of the Associate Closed internal os heavy pad every hour for Dean of Research, more than two hours, or Faculty of Medicine, more than one heavy pad University of Calgary Exclusion criteria per 30 minutes for more than an hour. Active vaginal bleeding (note: those A container was provided with light spotting, for any products of without cramping, conception that the subjects were eligible) were able to retrieve. Baseline haemoglobin and Cramping hCG levels were obtained. The serum hCG was Dilatation of the repeated at 48 hours and internal os the haemoglobin at 1 week.

Non-viable embryo Follow-up that measured greater than a 12 week size Follow-up was arranged at 24 hours, 48 hours, and at 1 week. Speculum and bimanual examinations were performed at each visit, and any tissue passed by subjects was examined. If complete miscarriage was not suspected after 24 hours, the medication was repeated. At 48 hours if there had been no response to the medication or an incomplete miscarriage was

455 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

suspected, the subjects were offered a D&C.

Transvaginal ultrasound was used in cases of suspected incomplete miscarriage, as appropriate. An ultrasound finding of a focal hyperechoic intrauterine mass was considered sufficient for diagnosis of incomplete miscarriage. All subjects with a clinically suspected complete miscarriage were instructed to have a urine hCG test after 4 weeks. Pathology reports for all tissue submitted for examinations were reviewed.

The subjects were also asked to complete a post- treatment questionnaire.

Outcomes reported

1. Complete miscarriage: defined as either the expulsion of the products of conception without D&C with a negative follow-up urine hCG test at 4 weeks, OR the absence of products of conception in the surgical specimen from D&C in subjects who had suspected incomplete miscarriage

456 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

2. Need for further intervention: the rates of are reported

3. Adverse effects: gastrointestinal side effects are reported in the misoprostol arm only

4. Satisfaction: Patient satisfaction was assessed by asking the women to rate their degree of agree with the following statements: - I would recommend the treatment with the vaginal tablets to a friend or family member who had a missed miscarriage - I would try treatment with the vaginal tablets again if I had another missed miscarriage. The subjects indicated their agreement on a five-point scale: strongly disagree, disagree, neutral, agree or strongly agree Full citation Sample size Interventions Details Results Limitations

Ayudhaya,O.P.N., N=138 400 micrograms of 138 women with a Clinical outcome of treatment Blinding Herabutya,Y., misoprostol orally every diagnosis of early (number/total (%)) Chanrachakul,B., (however 2 4 hours, up to a pregnancy failure who Blinding is not reported. It would Ayuthaya,N.I.N., maximum of 6 doses presented to the Prasertsawat,P., A participants were later a. Complete miscarriage have been difficult to blind the excluded) (n=68) Department of Obstetrics participants (although not comparison of the and Gynaecology at efficacy of sublingual Oral: 17/66 (25.8) impossible); however those 400 micrograms of Ramathibodi Hospital, Sublingual: 15/70 (21.4) assessing the outcome of the

457 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments and oral misoprostol Characteristics misoprostol sublingually Bangkok, were recruited. (NS) treatment could have been blinded to 400 microgram in the every 4 hours, up to a An ultrasound examination allocation. management of early Age/years (mean maximum of 6 doses was performed in all cases b.Incomplete miscarriage pregnancy failure: A (SD)) (n=70) to confirm the diagnosis. Other information randomized controlled Women were randomised Oral: 23/66 (34.8) trial, Journal of the Oral: 32.0 (5.8) using computer generated Sublingual: 27/70 (38.6) Medical Association of random numbers. However, EARLY EMBRYONIC/FETAL Sublingual: 33.4 (6.2) (NS) DEMISE Thailand, 89, S5-S10, (NS) 2 women from the oral 2006 group were excluded for having an incomplete c. Medical failure ORAL vs. SUBLINGUAL Ref Id Gestational medical record. age/weeks (mean Oral: 26/66 (39.4) Induction to expulsion 78585 (SD)) Sublingual: 28/70 (40.0) Treatment protocol (NS) interval/hours (mean (SD))

Country/ies where the Oral: 10.7 (1.5) Oral: 10.7 (6.6) study was carried out Sublingual: 11.0 (1.4) Women received one of two (NS) treatments: Sublingual: 8.7 (5.4) Thailand - 400 micrograms of Adverse effects of treatment Nulliparous misoprostol orally every 4 Total dosage received/micrograms Study type hours, up to a maximum of (number of women/total (%)) (mean (SD)) (number/total (%)) 6 doses - 400 micrograms of a. Nausea/vomiting Randomised controlled Oral: 31/68 (45.6) Oral: 1706 (90.1) misoprostol sublingually trial Sublingual: 27/70 Sublingual: 1640 (83.0) every 4 hours, up to a Oral: 3/66 (4.5) (NS) (38.6) Sublingual: 2/70 (2.9) (NS) maximum of 6 doses Aim of the study b. Diarrhoea Inclusion criteria Women in the sublingual To compare repeated group had two tablets Oral: 7/66 (10.6) doses of sublingual placed under the tongue by Sublingual: 6/70 (8.6) with oral misoprostol in Diagnosis of early a nurse. They were not the medical pregnancy failure, allowed to eat for 20 c. Fever management of early defined as one of the minutes, to allow complete pregnancy failure. following: dissolution. A nurse was Oral: 2/66 (3.0) - Intrauterine also responsible for oral gestational sac with Sublingual: 15/70 (21.4) Study dates administration to the mean sac diameter of patients. Patients were d. Chills >2 cm without a fetal allowed 30 ml of water to November 2004 to pole (blighted ovum) drink, then misoprostol was December 2005 Oral: 0/66 (0) - Presence of a fetal given the same way every 4 pole without cardiac hours until products of

458 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Source of funding pulsations conception were detected. Sublingual: 4/70 (5.7) - Gestational sac Not reported diameter <2cm with The blood pressure, pulse (Note: these % have been no interval growth or a rate, and body temperature calculated by the technical team persistent absence of were recorded every 4 and differ slightly from those fetal cardiac pulsation hours. Adverse effects reported in the paper, because on re-scanning after including abdominal pain, the authors calculated % using 7-10 days diarrhoea, nausea, 68 women in the oral arm, vomiting, chills and despite reporting excluding Gestational age of 7- headache were recorded. If them, and excluding them for 12 weeks patients complained of other outcomes. The authors severe pain, they were also report that no serious Exclusion criteria given two oral tablets of complications occurred in either 500mg paracetamol. group.) Parenteral pethidine was Abnormal vaginal given if the pain persisted. If bleeding body temperature was > Measures of pain: abdominal 38ºC, two tablets were also pain (number of women/total Severe abdominal provided every 4 hours. (%)) pain If patients passed products Oral: 40/66 (60.6) of conception or Sublingual: 47/70 (67.1) experienced vaginal bleeding, they were told to inform the nurses who could then notify the attending doctor. The doctor determined if the miscarriage was complete by performing a vaginal examination. Complete miscarriage was defined as no active bleeding, closed cervical os and endometrial thickness < 1 cm. Incomplete miscarriage was defined as active vaginal bleeding or open cervical os and endometrial thickness >

459 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

1 cm. Those with incomplete miscarriage underwent emergency surgical evacuation under local anaesthesia. Medical failure was defined as the patients who received 6 doses and did not pass products of conception. These patients were scheduled for surgical evacuation the following morning. The products of conception were sent for histological diagnosis. All patients had a follow-up appointment two weeks after discharge.

Outcomes reported

1. Clinical outcomes: Complete miscarriage, incomplete miscarriage, and medical failure within 24 hours.

2. Adverse effects: Nausea or vomiting, diarrhoea, fever and chills are reported.

3. Abdominal pain

460 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Full citation Sample size Interventions Details Results Limitations

Lister,M.S., N=36 800 micrograms of Women presenting to the Treatment success Following randomisation, 2 women Shaffer,L.E., Bell,J.G., vaginal misoprostol Riverside Methodist (number/total (%)) withdrew (1 from each arm). 1 did not Lutter,K.Q., Characteristics (repeat after 24 hours if Hospital in Columbus, Ohio, complete the protocol and 1 did not Moorma,K.H., needed) with early pregnancy failure Misoprostol: 15/19 (78.9) meet the criteria for early pregnancy Randomized, double- (n=19) were eligible if they met the Placebo: 2/17 (11.8) failure. The technical team have blind, placebo- Age/years (mean) inclusion criteria. Patients included them in the denominator for controlled trial of Placebo (repeat after 24 provided informed consent the outcome of treatment success vaginal misoprostol for Misoprostol: 33.7 hours if needed) and enrolled within 14 days Need for further intervention only, in order that the estimate is as management of early Placebo: 34.4 (n=17) after diagnosis. (number/total (%)) conservative as possible. pregnancy failures, (p=0.706) Randomisation was blocked American Journal of and stratified by physician Misoprostol: 3/18 (16.7) For the outcomes of pain severity Obstetrics and Gestational office and timing of (Note: 1 patient was re-treated 2/18 (11.1%) of women from the Gynecology, 193, age/weeks (mean) treatment in relation to with misoprostol and had misoprostol arm have missing data. 1338-1343, 2005 diagnosis. The study complete expulsion at 32 days; For the outcome of satisfaction, 1/16 Misoprostol: 8.7 epidemiologist generated 2 patients had D&Cs at 9 and 19 (6.3) women from the placebo arm Ref Id Placebo: 9.5 the allocation sequence. It days after treatment) and 3/18 (16.7%) from the (p=0.079) was anticipated that some misoprostol arm had no data 78608 patients would need time to Placebo: 13/16 (81.1) available. accept their diagnosis and (Note: 11 elected to receive Country/ies where the Ultrasound criteria (n consider participation in the misoprostol and 2 had a D&C. A Small sample size (N=36) study was carried out (%)) study. Patients who enrolled further 1 patient had expectant some time after diagnosis management, but this has not USA a. Embryonic pole/no Other information cardiac activity might have uterine been reported here) environments more Study type 800 MICROGRAMS VAGINAL favourable to medical Misoprostol: 12 (66.7) Unplanned visit to medical MISOPROSTOL VS. PLACEBO expulsion of contents. The Placebo: 6 (37.5) facility (number/total (%)) Randomised controlled diagnosis date was defined EARLY EMBRYONIC/FETAL trial as the date that the b. Irregular Misoprostol: 0/18 DEMISE intrauterine management options were Aim of the study gestational sac/no first reviewed with patient. Placebo: 3/16 (18.8) Blinding was done. embryonic pole (Note: 1 patient was seen for

Of the 36 women enrolled, vaginal bleeding after 4 days To determine whether Women who failed to pass their Misoprostol: 10 (55.6) 1 was removed by her and had products removed from misoprostol medical uterine contents after 48 hours were Placebo: 10 (62.5) physician on day 2 without the cervical os, and was given management of early offered expectant management, D&C completing the protocol, Methergine; 1 patient was seen pregnancy failures is or misoprostol treatment. 71% chose c. Abnormal growth and 1 was excluded for for pain requiring IV analgesics more effective than misoprostol treatment. This may on ultrasound failure to meet the early after expulsion of uterine pregnancy failure criteria. have impacted secondary outcomes

461 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments expectant management Therefore, the main products at home 5 days after of pain and satisfaction. Misoprostol: 4 (22.2) analysis involved 34 placebo; 1 patient elected to Study dates Placebo: 3 (18.8) patients, of which 16 receive misoprostol after The trial was stopped early because received placebo and 18 placebo failure and came to the the success rate in the placebo arm d. Yolk sac/abnormal received misoprostol. emergency department with was lower than expected. The February 15th 2002 to rise in hCG heavy bleeding, after which authors report that the study March 19th 2003 Treatment protocol products were removed and she continued as an open-label registry Misoprostol: 1 (5.6) received Methergine) of patients treated with misoprostol Source of funding Placebo: 1 (6.3) Each physician received an for early pregnancy failure. opaque randomisation Riverside Methodist Inclusion criteria packet containing Adverse effects of treatment Hospital Medical instruction sheets (number/total (%)) Research Foundation (physician and patient), Women presenting data sheets, prescriptions a. Nausea with early pregnancy for pain medication, and 2 failure, with the vials of unmarked hard Misoprostol: 4/18 (22.2) diagnosis confirmed gelatin capsules containing Placebo: 3/16 (18.8) by transvaginal either placebo, or 800 ultrasound, using one micrograms of misoprostol. b. Vomiting of the following The physician placed the parameters: contents of 1 vial into the Misoprostol: 1/18 (5.6) - embryonic pole 5-16 posterior fornix and secured Placebo: 3/16 (18.8) mm without cardiac them with a cotton ball or activity tampon. Both the physician c. Diarrhoea - irregular gestational and the patient were sac with mean sac blinded to treatment Misoprostol: 1/18 (5.6) diameter of 16-50 mm allocation. Patients then Placebo: 1/16 (6.3) with no embryonic had their blood drawn for pole progesterone, haemoglobin, d. Headache - embryo growth of hCG, type and screen. less than 0.6 mm per Misoprostol: 3/18 (16.7) day over 1 week Patients received Placebo: 2/16 (12.5) - yolk sac present with information sheets on hCG increasing less misoprostol and the e. Dyspepsia than 50% over 48 expected side effects. The hours instruction sheet contained Misoprostol: 2/18 (11.1) 24 hour contact information. Placebo: 2/16 (12.5) Closed cervical os on They also received bimanual examination prescriptions for eight 600 f. Constipation mg ibuprofen tablets and 12

462 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Haemoglobin of at Percocet tablets. A study Misoprostol: 1/18 (5.6) least 10 mg/dL nurse contacted each Placebo: 1/16 (6.3) patient within the first 24 Exclusion criteria hours of treatment to check Measures of pain on her progress.

History of a. Incidence of menstrual Follow-up cramping (number/total (%)) inflammatory bowel disease On day 2, approximately 24 Misoprostol: 11/18 (61.1) hours after initial Allergy to misoprostol Placebo: 5/16 (31.3) administration, patients returned for a repeat Vaginal bleeding b. Incidence of abdominal ultrasound and recording of cramping (number/total (%)) greater than spotting side effects within the past (defined as requiring 24 hours. If no gestational Misoprostol: 3/18 (16.7) less than one sanitary sac was seen, the patients napkin per day) Placebo: 1/16 (6.3) were instructed to abstain from intercourse and return Dilated cervical os c. Highest level of pain during in 2 weeks. If the ultrasound study (mean/10) showed persistence of the Viable first trimester gestational sac at 24 hours, Misoprostol: 5.6 (n=16) pregnancy or ectopic the patients received a pregnancy Placebo: 5.2 (n=16) second blinded dose in the (p=0.806) posterior vaginal fornix. Previous incision on These patients returned on the contractile portion day 3, approximately 48 Satisfaction (number/total (%)) of the uterus hours after initial treatment. (myomectomy or At that time, data was a. Reported satisfaction classical caesarean collected on side effects section) experienced by the patients Misoprostol: 14/15 (93.3) in the last 24 hours and Placebo: 12/15 (80) another ultrasound was performed. If the gestational b. Would choose this method sac was absent, then the again patient was asked to return in 2 weeks. If the Misoprostol: 13/16 (81.3) gestational sac was still Placebo: 13/16 (81.3) present, the patient was considered a treatment c. Would recommend to others failure. Remaining blinded,

463 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

the patients and physicians Misoprostol: 16/16 (100) together chose a course of Placebo: 12/16 (75) further treatment: expectant management, D&C or misoprostol. These patients also returned to their physicians for a final study evaluation 2 weeks after uterine evacuation.

At the final evaluation, the patient was asked to answer a questionnaire evaluating her satisfaction with the treatment, the likelihood that she would recommend it to others, type of pain medication used and the amount of pain that she experienced. if a woman was bleeding at the 2-week follow-up, a urine pregnancy test was performed. If it was positive, quantitative hCG was drawn and followed to normal.

Outcomes reported

1. Successful medical treatment: Complete evacuation of uterine contents within 24 hours of administration of misoprostol or placebo

2. Need for further intervention: Reported as the number of women who required additional

464 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

misoprostol or a D&C~~

3. Unplanned visit to a medical facility

4. Adverse effects: Reported at 24 or 48 hours after treatment

5. Pain: At the final evaluation appointment, patients were asked to view a scale of evenly spaced numbers from 0 to 10, and to circle the number that represented their maximum pain during the study. They also reported incidence of menstrual cramping and abdominal cramping.

6. Satisfaction: Patients were asked at follow-up if they were satisfied with their treatment.

Analysis

The study design established an accrual goal of 84 women to provide 90% power to detect an expected 35% difference in success rates between study groups, assuming an anticipated success rate of 50% in the placebo group and 85% in the misoprostol group. The chosen alpha error was 0.05. Statistical

465 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

analysis used Fisher's exact test, Student's t-test, and the Wilcoxon rank sum test as appropriate. All tests were 2 sided and a p-value <0.05 was considered significant. Full citation Sample size Interventions Details Results Limitations

Pang,M.W., Lee,T.S., N=201 800 micrograms vaginal All patients admitted to the Complete uterine evacuation Lack of blinding Chung,T.K.H., misoprostol, with a gynaecology unit with a (number of women/total (%)) Incomplete Characteristics repeat dose after 4 diagnosis of incomplete Blinding was not reported. It would miscarriage: A hours if needed miscarriage were invited to Vaginal: 58/96 (60.4) randomized controlled have been difficult (but not (n=96) participate. Diagnosis was Oral: 67/105 (63.8) impossible) to blind participants or trial comparing oral Age/years (mean confirmed using (Note: These % were calculated with vaginal (SD)) those administering treatment; 800 micrograms oral transvaginal ultrasound by the technical team in order however those assessing outcomes misoprostol for medical showing evidence of that the estimate of efficacy is evacuation, Human misoprostol, with a could have been blinded. Vaginal: 32.4 (6.1) retained products of conservative. The authors % Reproduction, 16, repeat dose after 4 Oral: 32.3 (5.9) conception. Patients were differ slightly because they 2283-2287, 2001 hours if needed Population (NS) (n=105) suitably randomised using excluded 1 woman from each computer generated arm who declined treatment Ref Id Less than 15% of women in each Gestation/weeks random numbers in blocks following randomisation, and 1 of five, and opaque from the oral arm who arm had an open cervical os - it is 81209 (mean (SD)) envelopes. 201 patients developed a rash and therefore unclear why this should be the case were randomised. Two treatment was discontinued) in a population of women with Country/ies where the Vaginal: 10.60 (2.3) declined treatment following incomplete miscarriage. study was carried out Oral: 10.22 (2.0) randomisation (one from Need for further intervention (NS) each arm), and one patient Hong Kong (number of women/total (%)) Loss to follow-up from the oral arm developed Admission a rash after the first Study type Vaginal: 37/95 (38.9) 12 patients were lost to follow-up at 2 haemoglobin (mean misoprostol dose and weeks. 8 could not be contacted, but (SD)) further medical treatment Oral: 36/103 (35.0) Randomised controlled (NS) the other 4 were contacted by phone was abandoned. 198 and reported being asymptomatic trial patients completed the (Note: 1 woman from the oral Vaginal: 12.6 (1.1) after discharge. 3 women were also medical treatment regime arm also required a repeat Oral: 12.4 (1.4) surgery after 2 weeks due to excluded by the authors - 2 did not Aim of the study (95 in the vaginal arm and (NS) persistent vaginal bleeding and receive allocated intervention and 1 103 in the oral arm). 12 developed a rash so treatment was were lost to follow up at 2 RPOC) To compare the Cervical os open discontinued. For the outcome of efficacy, side effects, treatment success, these women

466 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments and short term (number/total (%)) weeks (6 from each arm). Duration of bleeding/days have been included by the technical complications (median (range)) team in the denominator in order to associated with oral Vaginal: 12/96 (12.5) Treatment protocol ensure estimates of efficacy are and vaginal Oral: 13/105 (12.4) Vaginal: 8 (0-14) (n=89) conservative. administration of (NS) Patients were randomised Oral: 8 (0-14) (n=97) misoprostol as the (NS) Other information initial management of to receive either: incomplete Prior termination of - 800 micrograms oral miscarriage. pregnancy misoprostol Adverse effects of treatment INCOMPLETE MISCARRIAGES (number/total (%)) - 800μg micrograms (number of women/total (%)) (unclear why so few had open os) misoprostol Study dates - 0 a. Nausea ORAL vs. VAGINAL Vaginal: 73/96 (76.0) The dose was repeated September 1998 to Oral: 64/105 (61.0) after 4 hours if the patient Vaginal: 7/95 (7.4) March 1999 Interval between first dose and had not passed any Oral: 12/103 (11.7) passage of POC/hours (mean - 1 products of conception. A (NS) (range)) Source of funding Vaginal: 16/96 (16.7) repeat transvaginal Oral: 30/105 (28.6) ultrasound was performed b. Vomiting Vaginal: 7.7 (2.5 - 30.8) Not reported on all subjects the following - 2 day. Patients with an Vaginal: 2/95 (2.1) Oral: 7.7 (2.0 - 35.3) Vaginal: 3/96 (3.1) intrauterine dimension of Oral: 6/103 (5.8) (NS) Oral: 11/105 (10.5) <11cm2 were considered to (NS) have an empty uterus and - 3+ were discharged. The c. Diarrhoea Vaginal: 4/96 (4.2) remainder underwent Oral: 0/105 (0) surgical evacuation. Vaginal: 12/95 (12.6) (the incidence of Oral: 62/103 (60.2) subjects who had a Follow-up (p<0.01) past termination of pregnancy was higher d. Fever in the oral arm, All patients were assessed p<0.01) clinically 2 weeks after Vaginal: 11/95 (11.6) discharge to review their Oral: 6/103 (5.8) symptoms. A urinary (NS) pregnancy test was also There were also no performed. significant differences (Note: the authors also state that in parity, gravidity, there were no surgical number of previous Outcomes reported complications such as miscarriages, or prior haemorrhage, uterine

467 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

ectopic pregnancy. 1. Complete uterine perforation, transfusion or evacuation: evaluated on infection in those undergoing Inclusion criteria day 1 after treatment surgery)

Clinical diagnosis of 2. Need for further incomplete intervention: The number Measures of pain miscarriage, of women who required a supported by a urinary surgical evacuation before a. Duration of pelvic pain/days pregnancy test and discharge. (median (range)) confirmed by ultrasound evidence 3. Duration of bleeding: Vaginal: 2 (0 - 11) (n=89) of RPOC assessed at 2 week follow- Oral: 1 (0 - 14) (n=97) up appointment (p=0.02) Exclusion criteria 4. Adverse effects: Intrauterine dimension Nausea, vomiting, diarrhoea measuring <11cm2 and fever are reported as (considered to have immediate side effects. an empty uterus) Fever is defined as a temperature of at least 38ºC. Severe blood loss 5. Pain: The number of Sepsis days of pelvic pain was assessed at the 2 week Known allergy to follow-up appointment prostaglandins or their analogues Analysis

History of asthma Two sample t-tests, chi- squared tests and Mann Any reason, in the Whitney tests were used to opinion of the compare the two arms. attending physician, that would make the patient unsuitable for misoprostol administration

468 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Full citation Sample size Interventions Details Results Limitations

Blohm,F., N=126 400 micrograms of Women seeking medical Treatment success Maximum score for the visual Fridé,n BE, vaginal misoprostol attention due to signs of (number/total (%)) analogue scale used to judge Milsom,I., Platz- Characteristics (n=64) miscarriage in the first nausea, vomiting, diarrhoea and pain Christensen,J.J., trimester, and who fulfilled a. At follow-up (6-7 days) is not reported Nielsen,S., A Placebo placed the inclusion criteria, were randomised double Age/years (mean vaginally invited to participate in the Misoprostol: 52/64 (81.3) Outcomes (with the exception of blind trial comparing (SD)) (n=62) study. 136 women were Placebo: 32/62 (51.6) "need for further intervention") are misoprostol or placebo eligible, of which 126 not reported separately for women in the management of Misoprostol: 32.1 (4.9) agreed to participate and b. At completion of study, in the with and without an open cervical os early miscarriage, Placebo: 32.1 (6.0) were included and absence of a D&C on inclusion. BJOG: An International randomised. All patients Journal of Obstetrics Gestational age/days underwent a gynaecological Misoprostol: 56/64 (87.5) Other information and Gynaecology, 112, (mean (SD)) examination, including Placebo: 37/62 (59.7) 1090-1095, 2005 vaginal ultrasound, which Misoprostol: 72.8 involved measurement of 400 MICROGRAMS VAGINAL Ref Id (12.2) Need for further intervention MISOPROSTOL VS. PLACEBO the anterior-posterior (number/total (%)) Placebo: 77.8 (12.9) diameter of the uterine 81264 INCLUDES BOTH WOMEN WITH cavity. a. In women with an open Previous miscarriage AN OPEN AND WOMEN WITH A Country/ies where the cervical os (%) Patients were randomised CLOSED CERVICAL OS study was carried out to either misoprostol or Misoprostol: 0/7 (0) Misoprostol: 18.8 placebo by drawing a Treatment success, split by anterio- Sweden Placebo: 21.0 Placebo: 2/11 (18.2) sealed envelope from a posterior diameter of gestational box. Each envelope Study type b. In women with a closed residue (number/total (%)) Previous legal contained either two abortion (%) cervical os placebo tablets or two 200 a. Misoprostol arm Randomised controlled microgram misoprostol trial Misoprostol: 21.9 Misoprostol: 8/57 (14.0) tablets, for self- Placebo: 23/51 (45.1) 15-21 mm: 21/26 (80.8) Placebo: 25.8 administration intra- 22-50 mm: 35/38 (92.1)

Aim of the study vaginally by the woman at Duration of bleeding c. In all women home. 400 micrograms of b. Placebo arm before misoprostol was chosen as To study if misoprostol Misoprostol: 8/64 (12.5) recruitment/days this was the standard dose 15-21 mm: 11/20 (55) 400 micrograms, Placebo: 25/62 (40.3) (mean (SD)) used in medical, legal 22-50 mm: 25/42 (59.5) administered vaginally, abortions in their increased the (Note: the other 9 women who Misoprostol: 26.6 (9.6) department, following Treatment success was achieved successful resolution of had incomplete miscarriage at Placebo: 28.8 (10.1) administration of more often in women with a uterine early miscarriage follow-up chose expectant mifepristone. The placebo

469 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments compared with placebo Open cervical os on tablets were identical in management) size of 22-50 mm, but this difference inclusion appearance to the active was not significant. Study dates (number/total (%)) misoprostol tablets, and Adverse effects were delivered to the Source of funding Misoprostol: 7/64 independent hospital a. Nausea: VAS/mm (mean (10.9) pharmacy where they were (SD)) Placebo: 11/62 (17.7) inserted into numbered University of Goteborg envelopes in blocks of 10, Misoprostol: 17.4 (24.7)

Inclusion criteria according to a random table Placebo: 14.9 (23.8) Hjalmar Svensson system. The randomisation (p=0.57) Research Foundation list was retained by the Circulatory stable pharmacy and was not b. Vomiting: VAS/mm (mean (stable blood pressure broken until after (SD)) and haemoglobin > 90 completion of the study g/L) when statistical analyses Misoprostol: 8.1 (20.2) were performed. Patients Placebo: 7.3 (21.7) Gestational residue were enrolled by clinicians (p=0.85) 15 - 50 mm who were unaware of the randomisation sequence. c. Diarrhoea: VAS/mm (mean Non-viability of the Compliance of taking (SD)) conceptus confirmed misoprostol or placebo and accepted by both tablets was checked at the Misoprostol: 7.5 (15.0) the physician and return visit, and all patients Placebo: 8.9 (20.4) patient reported that they had taken (p=0.69) the medication as Above the age of 18 instructed. d. Infection: years old incidence (number/total (%)) During the initial Exclusion criteria consultation, the patients Misoprostol: 3/64 (4.7) underwent a vaginal Placebo: 0/62 (0) Signs of ultrasound examination, (Note: the patients were treated genital infection (3 or physical examination and with antibiotics, and no further more of the following laboratory tests. The intervention was needed) criteria: purulent women were informed vaginal discharge, about expected pain and Pain: severity using VAS (mean elevated body bleeding associated with (SD)) temperature > 38º C, miscarriage. Patients were pain on palpation of provided with paracetamol Misoprostol: 60.4 (31.0) the uterus and/or alone or in combination with Placebo: 43.8 (37.1) codeine for pain. Anti-D

470 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

adnexa, serum C- immunoglobulin was (p<0.007) reactive protein > 10 administered to all Rh- mg/L) negative women. If the women had unacceptable Not able to pain or bleeding, they were understand the instructed to return to the information regarding ward and a D&C was done. the study Follow-up Possible allergy or medical All women were scheduled contraindications for for a follow-up examination analgesics or within one week (6-7 days) misoprostol after the primary visit. The women were then divided into two groups: "successful" and "failed" treatment. If the anterior- posterior diameter for the gestational residue was < 15 mm, the patient was considered to have had successful treatment, provided a urine pregnancy test performed 4 weeks after the primary visit was negative. Women who had a gestational residue > 15 mm were considered to be treatment failures, and were given the option of further expectancy or a D&C. They were then followed until the pregnancy test was negative.

All patients were asked to complete an anonymous, self-administered questionnaire, which

471 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

included forced-choice questions relating to past obstetric history, general health, need for pain treatment, sick leave and duration of vaginal bleeding.

Outcomes reported

1. Success treatment: success at 6-7 day follow- up, and success rate on completion of the study without a D&C are reported

2. Need for further intervention: the number of women requiring a D&C

3. Adverse effects: assessed using the questionnaire, collected at the last follow-up visit. Nausea, vomiting and diarrhoea were assessed using a visual analogue scale (maximum score not reported, likely to be 100). Incidence of infection is also reported. Women were judged to have an infection if three or more of the following criteria were observed within one month of the initial consultation: purulent vaginal discharge, elevated body temperature (> 38º C) for 24 hours, pain on palpation of uterus and/or adnexa, and C-

472 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

reactive protein > 10 mg/dL.

4. Pain: severity of pain was assessed using a visual analogue scale (maximum score not reported, likely to be 100) on the questionnaire, collected at the last follow-up visit

Analysis

A power calculation calculated that 60 women would be needed in each arm to achieve 80% power using an alpha value of 0.05. The results of the two groups were compared using students t test and Fishers exact test.

Full citation Sample size Interventions Details Results Limitations

Kovavisarach,E., N=54 400 micrograms of After obtaining written Outcome of medical Randomisation Sathapanachai,U., vaginal misoprostol informed consent, eligible treatment (number/total (%)) Intravaginal 400 microg Characteristics (n=27) women were randomly Method of randomisation not stated misoprostol for allocated to receive either a. Complete miscarriage pregnancy termination two 200 microgram tablets Blinding in cases of blighted Age/years (mean Placebo (n=27) of misoprostol or two tablets Misoprostol: 17/27 (63.0) ovum: a randomised (SD)) of a placebo. The Placebo: 5/27 (18.5) Blinding not reported controlled trial, administration time was (P<0.001) Australian and New Misoprostol: 26.2 (5.3) recorded, and women were Method of administration Zealand Journal of Placebo: 26.9 (5.1) given a prescription for 20 b. Incomplete miscarriage Obstetrics and (p=0.602) tablets of acetaminophen. The method of drug administration Gynaecology, 42, 161- Misoprostol: 8/27 (29.6) (i.e. physician or self administered) is 163, 2002 Gestational After treatment, women Placebo: 3/27 (11.1) not reported. It is also not stated age/weeks (mean rested for 30 minutes and (P<0.001) whether the placebo was (SD)) were then discharged from

473 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

Ref Id the hospital. The patients c. No miscarriage administered vaginally or orally. Misoprostol: 10.6 (1.4) were then reassessed 81292 Placebo: 10.9 (1.2) about 24 hours later and a Misoprostol: 2/27 (7.4) Other information (p=0.293) history of events following Placebo: 19/27 (70.4) Country/ies where the drug administration was (p<0.001) study was carried out Previous miscarriage obtained. Physical and 400 MICROGRAMS VAGINAL MISOPROSTOL VS. PLACEBO (n (%)) vaginal examinations were Adverse effects (number/total Thailand performed. 9%)) BLIGHTED OVUM ONLY Misoprostol: 5 (18.5) Study type Placebo: 2 (7.4) The patients were asked to a. Nausea and/or vomiting return to the hospital before Time interval from insertion to Randomised controlled Previous elective the appointment if they Misoprostol: 2/27 (7.4) complete miscarriage/hours (mean trial abortion (n (%)) experienced: Placebo: 1/27 (3.7) (SD)) - severe pain that did not (p=0.552) Misoprostol: 3 (11.1) improve after taking Misoprostol: 14.9 (6.9) Aim of the study Placebo: 7 (25.9) acetaminophen b. Diarrhoea Placebo: 21.8 (4.9) - a moderate amount of (p<0.001) To investigate the Inclusion criteria bleeding Misoprostol: 2/27 (7.4) effectiveness and side - passage of products of Placebo: 0/27 (0) effects of intravaginal conception through the (p=0.150) misoprostol 400 Maximum gestational introitus age of 12 weeks micrograms compared c. Fever with a placebo for Follow-up Blighted ovum facilitating complete Misoprostol: 4/27 (14.8) miscarriage in cases of Any patients who had Closed cervix Placebo: 0/27 (0) blighted ovum retained products of (p<0.05) conception per os, or Study dates Exclusion criteria exhibited heavy vaginal bleeding was sent for Pain: incidence of lower immediate curettage. All abdominal pain (number/total July 1st 1998 to Medical or obstetric (%)) complication other patients were January 31st 1999 examined by vaginal Misoprostol: 20/27 (74.1) Pelvic infection ultrasound. If the Source of funding gestational sac was absent, Placebo: 6/27 (22.2) (p<0.001) Allergy to misoprostol the patient was scheduled Not reported to return in one week for a follow-up evaluation.

If the gestational sac or products of conception were

474 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

still present, the patient was offered a uterine curettage and scheduled to return in one week for a follow-up evaluation.

Outcomes reported

1. Complete miscarriage: uterine contents completely expelled within 24 hours of initial drug administration without uterine curettage

2. Adverse effects: nausea and/or vomiting, diarrhoea and fever are reported within 24 hours after drug administration

3. Pain: incidence of lower abdominal pain within 24 hours of drug administration

Analysis

Chi-squared test, Fisher's exact test and student's t- test were used to analyse data where appropriate. p<0.05 was considered statistically significant. Full citation Sample size Interventions Details Results Limitations

Paritakul,P., N = 64 600 micrograms of oral Following informed consent Treatment success (n/total Blinding Phupong,V., misoprostol procedures, any eligible (%)) Comparative study Characteristics (n = 32) women were hospitalised There is no reported blinding. It between oral and and randomised into one of Oral: 28/32 (87.5) would have been difficult to blind the sublingual 600 microg 600 micrograms of two treatment arms. Sublingual: 27/32 (84.4) participants, however the physicians

475 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments misoprostol for the Age/years sublingual misoprostol Randomisation was assessing the treatment success and treatment of incomplete (mean±SD) (n = 32) performed using a random Need for unplanned need for further intervention could abortion, Journal of number table. The co- intervention (n/total (%)) have been blinded to treatment Obstetrics and Oral: 32.2±7.4 investigator generated the allocation. Gynaecology Sublingual: 29.0±6.7 allocation sequence. When Oral: 2/32 (6.3) Research, 36, 978-983, (p = 0.071) a woman met the study Sublingual: 5/32 (15.6) Other information 2010 inclusion criteria study staff Gestational selected a sequentially (Note: these were all from the Ref Id number opaque envelope treatment failures and were ORAL vs. SUBLINGUAL age/weeks (mean±SD) which then assigned women who chose to have a 154648 women to the allocated curettage at 48 hours) INCOMPLETE MISCARRIAGE

Oral: 10.4±1/8 treatment. Country/ies where the Sublingual: 10.5±2.7 Adverse effects (n/total (%)) study was carried out Duration of miscarriage/hours (p = 0.956) Treatment protocol a. Nausea (mean±SD) Thailand Women in both groups Inclusion criteria received a 600 microgram Oral: 7/32 (21.9) Oral: 18.6±16.1 Study type dose of misoprostol, in Sublingual: 8/32 (25.0) Sublingual: 21.1±17.1 Less than 14 weeks three tables of 200 each. Randomised controlled gestation Drug administration was b. Vomiting trial done by a nurse. Women in Incomplete the sublingual arm were Oral: 0/32 (0) miscarriage, instructed to keep the drug Sublingual: 0/32 (0) Aim of the study diagnosed clinically: under their tongue for 15 - - history of vaginal 20 minutes. In the oral c. Diarrhoea To evaluate and bleeding in the current group, they were swallowed compare the pregnnacy whole with 50 ml of water. Oral: 5/32 (15.6) effectiveness, side - pregnancy retained Sublingual: 9/32 (28.1) effects and patient in the uterus Follow-up acceptability of oral - open cervical os with d. Fever/chills and sublingual or without products Women were admitted to misoprostol for the present in the cervical the hospital for 48 hours to Oral: 9/32 (28.1) treatment of incomplete canal monitor side effects and Sublingual: 14/32 (43.8) miscarriage complications. They were Positive pregnancy counselled to report any Study dates test passing of tissue and to Measures of pain complete a diary of side Evidence of retained effects. At 48 hours after a. Incidence of pain/cramps July 2007 to August products by administration of (n/total (%)) transvaginal misoprostol, a physical

476 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

2008 ultrasound exam and transvaginal Oral: 8/32 (25.0) ultrasound were done to Sublingual: 10/32 (31.3) Source of funding Good health evaluation if the miscarriage had completed. Complete b. Pain level/100 (mean±SD) Exclusion criteria miscarriage was confirmed None reported by a history of passing Oral: 22.2±15.0 tissue vaginally, combiend Sublingual: 29.1±21.2 Intrauterine diameter 2 with the finding of an empty (p = 0.139) < 11 cm in sagittal uterus. plus transverse plane If the woman had a Incidence of heavy bleeding Haemodynamically complete miscarriage, she (n/total (%)) unstable was discharged and followed up at one week. If Oral: 0 (0) Suspected septic she still had an incomplete Sublingual: 0 (0) abortion miscarriage at 48 hours, she could choose wheher to History of allergt to have an immediate surgical Measures of satisfaction misoprostol evacuation or to go home (n/total (%)) and wait 5 days. If a woman Suspected ectopic still did not have complete a. Reported being satisfied or pregnacny miscarriage on day 7, a very satisfied surgical evacuation was indicated. Oral: 28/32 (87.5) Sublingual: 27/32 (84.4) Analysis b. Would choose this method A sample size calculation again calculated that 32 women were needed in each arm. Oral: 30/32 (93.8) Analysis was done uising Sublingual: 29/32 (90.6) chi-square, Fisher-exact test and the independent t- c. Would recommend to a test as appropriate. p<0.05 friend was considered significant. Oral: 30/32 (93.8) Outcomes reported Sublingual: 29/32 (90.6)

1. Success of medical treatment: complete

477 Ectopic pregnancy and miscarriage

Study details Participants Interventions Methods Outcomes and Results Comments

miscarriage at 48 hours after misoprostol

2. Need for unplanned intervention: curettage required

3. Adverse effects: incidence of fever/chills, diarrhoea, nausea and vomiting are reported

4. Bleeding: heavy bleeding was defined as use of more than 2 sanitary pads per hour for two consecutive hours

5. Pain: incidence of pain/cramps is reported; severity is measured using a 100 mm visual analogue scale

6. Satisfcation: assessed using questionnaire

478