Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Comparison 1. Oral vs. Vaginal

Creinin, 1997

Type of study:

RCT

Setting and country:

USA

Funding and conflicts of interest:

Magee Women's Health Foundation

Inclusion criteria:

-Healthy

-English speaking

-Diagnosis of early pregnancy failure, based on ultrasound demonstration of one of the following:

* Embryonic pole 5-14 mm with no embryonic cardiac activity

* Irregular intrauterine gestational sac with mean sac diameter of 16 mm or greater and no embryonic pole

 * Abnormal growth on ultrasound over a minimum of 1 week

* Yolk sac present with an abnormal increase in hCG (50% or less) over 48 hours, and an initial value less than 2000 IU/l

- At least 18 years old

- Vaginal bleeding no more than spotting (not requiring more than one sanitary towel a day)

- Gestational age of 8 weeks of less by ultrasound or physical examination

- Closed cervical os on bimanual pelvic examination

- Haemoglobin of 10mg/dl or more

Willingness and ability to sign informed consent

- Willingness to abstain from intercourse for the first 3 days of the study and comply with visit schedule

- Adequate venous access for phlebotomy

- Easy access to a telephone

Exclusion criteria:

- History of inflammatory bowel disease

- Intolerance or allergy to misoprostol

N total at baseline:

Intervention (Oral): 12

Control (Vaginal): 8

Important prognostic factors²:

age ± SD:

I:26.3 ± (7.0)

C: 29.8 ± (8.0)

Prior miscarriage (number/total (%))

I: 6/12 (50%)

C: 4/8 (50%)

Groups comparable at baseline.

Describe intervention:

400 micrograms of oral misoprostol (repeat dose after 24 hours if needed)

Subjects in the oral arm swallowed misoprostol in the presence of a member of the research staff.

Describe control:

800 micrograms of vaginal misoprostol (repeat dose after 24 hours if needed)

Those in the vaginal arm had four 200 micrograms tablets of misoprostol administered

Length of follow-up:

1 day

Loss-to-follow-up:

Not mentioned

Incomplete outcome data:

Not mentioned

Outcome measures and effect size (include 95%CI and p-value if available):

Treatment success

I: 3/12 (25%)

C: 7/8 (87.5%)

P=0,01

Side effects

a. any side effects

I: 8/12 (67%)

C:7/8 (87%)

b. Nausea

I: 6/12 (50%)

C: 5/8 (62.5%)

c. Vomiting

I: 3/12 (25%)

C: 1/8 (12%)

d. Diarrhoea

I: 5/12 (42%)

C: 3/8 (38%)

Pain

Defined as: 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.

Severity of pain/10 (mean (SD))

I: 4.0 (3.6)

C: 5.9 (2.7)

Aim of the study:

To determine whether misoprostol 400 micrograms orally or 800 micrograms vaginally will cause complete uterine evacuation in women with early pregnancy failure.

Ngoc, 2004

Type of study:

RCT

Setting and country:

Vietnam

Funding and conflicts of interest:

David and Lucille Packard Foundation

Inclusion criteria:

First trimester, missed miscarriage, defined as:

- ultrasound evidence of an intact gestational sac

 - no evidence of fetal cardiac activity (6 weeks after last menstrual period) - closed cervical os

- history of no or minimal bleeding

No known contraindications to misoprostol

General good health

Willingness to attend a follow-up visit

Exclusion criteria:

See above

N total at baseline:

Intervention (Oral): 101

Control (Vaginal): 99

Important prognostic factors²:

For example

age range:

19-45

The authors give no further details, but report that there were no significant differences between the two groups, confirming that randomisation was effective.

Groups comparable at baseline

Describe intervention:

800 micrograms of oral misoprostol (four tablets of 200microgram)

Every woman self-administered their misoprostol in the presence of a study investigator.

Describe control):

800 micrograms of vaginal misoprostol (four tablets of 200 microgram)

Every woman self-administered their misoprostol in the presence of a study investigator.

Length of follow-up:

1 week

Loss-to-follow-up:

I: N=1 (1%)

C: N=1 (1 %)

Incomplete outcome data:

Not mentioned

Outcome measures and effect size (include 95%CI and p-value if available):

Treatment success

I: 89/101 (88%)

C: 91/99 (92%)

Need for further intervention (number/total (%))

a. Total

I: 11/100 (11%)

C: 7/98 (7%)

(NS) 60

503b. Medically indicated before study end

I: 5/100 (5%)

C: 2/98 (2%)

(NS)

c. Intervention at patient request

I: 6/100 (6%)

C: 5/98 (5%)

(NS)

Adverse effects of treatment (number of women/total (%))

a. Vomiting

I: 4/95 (4%)

C: 14/95 (15%)

(p=0.023)

b. Diarrhoea

I: 24/95 (25.3)

C: 23/95 (24.2)

(NS)

c. Fever/chills

I: 7/95 (7%)

C: 7/95 (7%)

(NS)

Measures of pain:

Incidence of pain/cramps (number of women/total (%))

I: 84/95 (88%)

C: 85/95 (89%)

(NS)

Measures of satisfaction

a. Satisfied or very satisfied with the method (number of women/total (%))

I: 86/100 (86.0)

C: 88/98 (89.8)

b. Would choose the method again (%)

I:85.0 %

C: 92.9 %

(NS)

c. Would recommend the method to a friend (%)

I: 83.0%

C: 90.8%

Aim of the study

To compare the efficacy of two routes of misoprostol administration (oral and vaginal) for the treatment of missed miscarriage.

Rita, 2006

Type of study:

RCT

Setting and country:

India

Funding and conflicts of interest:

Not reported

Inclusion criteria:

-Gestation less than 13 weeks

-Haemodynamically stable

-Haemoglobin more than 10gm%

-Closed cervical os

-Axillary temperature of < 37.5ºC

Exclusion criteria:

-History of inflammatory bowel disease

-Allergy to misoprostol

N total at baseline:

Intervention: 50

Control:50

Groups comparable at baseline.

Describe intervention:

400 micrograms given orally, and repeated every 4 hours up to a maximum of three doses

Over the next 10-12 hours, complete, incomplete, or no expulsion was documented by transvaginal ultrasound. The absence of an echogenic structure measuring less 15 mm in diameter suggested complete miscarriage. Nothing was given by mouth except medication for pain relief until complete expulsion or surgical evacuation. Information was obtained regarding side effects. Rh- women were given anti D immunoglobulin.

Describe control):

600 micrograms inserted into the posterior vaginal fornix, with a second dose repeated after 4 hours

Over the next 10-12 hours, complete, incomplete, or no expulsion was documented by transvaginal ultrasound. The absence of an echogenic structure measuring less 15 mm in diameter suggested complete miscarriage. Nothing was given by mouth except medication for pain relief until complete expulsion or surgical evacuation. Information was obtained regarding side effects. Rh- women were given anti D immunoglobulin.

Length of follow-up:

1 day

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size:

Treatment success (number/total (%))

I: 18/50 (36%)

C: 40/50 (80%)

Need for further intervention (number/total (%))

I: 32/50 (64%)

C: 10/50 (20%)

Adverse effects of treatment (number/total (%))

a. Nausea

I: 25/50 (50%)

C: 20/50 (40%)

b. Vomiting

I: 6/50 (12%)

C: 3/50 (6%)

c. Diarrhoea

I: 5/50 (10%)

C: 5/50 (10%)

d. Hyperpyrexia

I: 2/50 (4%)

C: 2/50 (4%)

Measures of pain: incidence of severe pain (number/total (%))

I: 8/50 (16%)

C: 5/50 (10%)

Aim of the study

To compare the safety and efficacy of oral versus vaginal misoprostol for medical management of missed miscarriage.

Outcomes reported

1. Treatment success: Defined as complete, drug induced expulsion of the products of conception

2. Need for further intervention: The number of women requiring surgical evacuation

3. Adverse effects of treatment: Incidence of nausea, vomiting, diarrhoea and hyperpyrexia are reported.

4. Pain: Incidence of severe pain is reported; however it is unclear what criteria was used to judge severity.

Marwah, 2016

Type of study:

RCT

Setting and country:

Single center, India

Funding and conflicts of interest:

None

Funding not mentioned

Inclusion criteria:

- Females of age group 18-45 years;

- Gestational age ≤ 12 weeks by last menstrual period (LMP);

- Diagnosis of missed abortion on USG;

-Mild vaginal bleeding or spotting per vaginum;

-Closed cervix on bimanual pelvic examination;

-Haemoglobin ≥9gm/dl;

-Axillary temperature <37.5 degree C; -No history of inflammatory bowel disease, asthma, liver disease or contraindication to use of misoprostol;

-Place of residence within 100 km from of the hospital;

-Willingness and ability to give informed consent;

-Willingness to abstain from intercourse for first 14 days of study; -Willingness to comply with follow-up schedule

Exclusion criteria:

-Women <18 years or >45 years of age;

- Fetal gestational age >12 weeks;

- Any degree of cervical dilatation;

-Excessive uterine bleeding;

-Haemoglobin concentration <9gm/dl);

-Haemodynamic instability;

-Blood pressure ≥160/90 mmHg;

-Poor general health of any cause;

-Deranged coagulation profile (defined as PTI≤85%)

-Signs or symptoms of infection;

-Maternal history of asthma or cardiac disease or cerebral disease;

- Use of anticoagulants or H/O any bleeding disorder;

-Known allergy to or C/I to misoprostol use;

-Active lactation;

-Any prior medical or surgical treatment to interrupt current pregnancy;

-Twin gestation sac;

- Molar pregnancy;

-Inability or refusal of patient to adhere to follow-up.

N total at baseline:

Intervention: 50

Control:50

Important prognostic factors²:

age ± SD:

I:23.9 ± 3.7

C: 23.7 ± 3.9

Previous spontaneous abortion:

N (%)

I: 17 (34%)

C: 18 (36%)% M

Groups comparable at baseline.

Describe intervention:

Fifty women were dispensed 400μg of oral misoprostol, repeated every six hours for a maximum of three doses. Women swallowed the pills with sips of water in presence of the doctor.

Describe control:

Fifty women were administered 400μg of misoprostol intravaginally into posterior fornix (soaked in normal saline solution), repeated six hourly up to a maximum of three doses. Vaginal cleansing had been performed before insertion with 10% povidone iodine (Betadiene). Following insertion, women were asked to remain in fully recumbent position for three hours.

Length of follow-up:

6 weeks

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Outcome measures and effect size:

Treatment success (number/total (%))

I: 37/50 (74%)

C: 46/50 (92%)

Adverse events of treatment

a. Nausea/vomiting

I: 36/50 (72%)

C: 30/50 (60%)

b. Diarrhoea

I: 7/50 (14%)

C: 6/50 (12%)

c. Severe Crampy Pain

I: 24 (48%)

C: 15 (30%)

d. Fever/Hyperpyrexia

I: 4 (8%)

C: 2 (4%)

Measures of satisfaction

a. Satisfied or very satisfied with the method (number of women/total (%))

I: 35/50 (70%)

C: 38/50 (76%)

b. Would choose the method again (%)

I: 39/50 (78%)

C: 41 (82%)

c. Would recommend the method to a friend (%)

I: 37/50 (74%)

C: 39/50 (78%)

Time to expulsion/hours (mean) Vaginal: 19.86 Sublingual: 9.53 (p=0.000)

Aim of the study

Outcomes

Treatment success

Success was defined as non-surgical evacuation of POCs confirmed by absence of echogenic structure measuring≥15mm in AP diameter on USG

Comparison 2. Sublingual vs. Vaginal

Tanha, 2010

Type of study: RCT

Setting and country:

Iran,

Mirza Kochak Khan Hospital, a premier research and referral facility in Tehran.

Funding:

Not reported

 and conflicts of interest:

Inclusion criteria:

Silent miscarriage, defined as: - intrauterine gestational sac with a mean sac diameter of at least 2 cm without a fetal pole - presence of a fetal pole with no cardiac activity - gestational sac < 2 cm with no interval growth, or persistent absence of fetal cardiac pulsation on rescanning 7-10 days later

< 13 weeks gestation

No known contraindications to misoprostol

General good health

No vaginal bleeding

Exclusion criteria:

Incomplete miscarriage

Inevitable miscarriage (products of gestation bulging from the cervix)

Suspicion of an extra-uterine pregnancy

Drug or alcohol abuse as reported by the woman

Abnormal blood count tests obtained routinely

N total at baseline:

N=220

Intervention: 110

Control:110

Important prognostic factors²:

Age/years

Vaginal: 29.1 Sublingual: 28.5 (p=0.516)

Gestational age/weeks Vaginal: 10.8 Sublingual: 10.6 (p=0.655)

Gravidity Vaginal: 2.87 Sublingual: 2.85 (p=0.926)

Parity Vaginal: 0.44 Sublingual: 0.23 (p=0.013)

Previous miscarriage Vaginal: 0.60 Sublingual: 0.71 (p=0.528)

Live children Vaginal: 0.84 Sublingual: 0.96 (p=0.535)

(Note: it is not reported what these statistics represent, although the technical team hypothesise that they represent means)

Groups comparable at baseline.

Describe intervention:

400 micrograms of sublingual misoprostol every 6 hours (n=110)

Dosage The trial protocol does not state whether there was a maximum number of tablets that a woman could receive. The mean number of tablets was 4.45 in the vaginal group and 4.85 in the sublingual group (p=0.211).

Describe control:

400 micrograms of vaginal misoprostol every 6 hours (n=110)

Length of follow-up:

Loss-to-follow-up:

Not reported

Incomplete outcome not reported

Outcome measures and effect size:

Complete evacuation (number/total (%))

Sublingual: 93/110 (84.5)

Vaginal: 51/110 (46.4)

RR (95% CI): 0.54 (0.442-0.681) (p<0.0001)

Need for further intervention (number/total (%))

Vaginal: 59/110 (53.6) (Note: 15 due to persistent gestational sac after 2 days; 44 due to incomplete miscarriage. Histology from 3 of the patients showed a partial mole) Sublingual: 17/110 (Note: 5 due to persistent gestational sac after 2 days; 12 due to incomplete miscarriage. Histology from 2 of the patients showed a partial mole and complete hydatiditiform mole)

RR (95% CI): 3.471 (2.168-5.555) (p<0.0001)

Adverse effects of treatment (number of women/total (%))

a. Vomiting Vaginal: 13/110 (11.8) Sublingual: 22/110 (20) RR (95% CI): 0.591 (0.255-1.128) (p=0.140)

b. Diarrhoea Vaginal: 40/110 (36.4) Sublingual: 76/110 (69.1) RR (95% CI): 0.526 (0.399-0.694) (p<0.0001)

c. Fever Vaginal: 4/110 (3.6) Sublingual: 26/110 (23.6) RR (95% CI): 0.154 (0.056-0.426) (p<0.0001)

Measures of pain (number of women/total (%))

a. Cramp pain Vaginal: 62/110 (56.4) Sublingual: 94/110 (85.5) RR (95% CI): 0.660 (0.550-

0.791) (p<0.0001)

b. Severe pain Vaginal: 42/110 (38.2) Sublingual: 77/110 (70) RR (95% CI): 0.859 (0.713-1.036) (p=0.091)

Measures of satisfaction (%)

a. Reported being satisfied with treatment Vaginal: 59/110 (53.6%) Sublingual: 103/110 (93.6%) (p=0.001)

b. Would recommend method to others Vaginal: 53.6 Sublingual: 84.5 (p=0.004)

(Note: satisfaction was also related to success of treatment)

Aim of the study

To evaluate the efficacy of two routes of misoprostol administration (sublingual and

vaginal) for the treatment of missed miscarriage.

Outcomes reported

1. Success rate: Defined as the passage of products of conception without needing vacuum aspiration or dilatation and curettage. This was assessed at the follow-up appointment 1-2 days after treatment.

2. Need for further intervention: The number

of women requiring surgery, and reasons for the intervention are reported.

3. Adverse effects of treatment: This is reported by the women for the period from 1 hour to 24 hours after every administration of misoprostol, up to the first follow-up visit. Fever is defined as an oral temperature of at least 37.8°C.

4. Measures of pain: The incidence of cramping pain and severe pain are reported by the women for the period from 1 hour to 24 hours after every administration of misoprostol, up to the first follow-up visit.

5. Measures of satisfaction: Assessed by questionnaire at follow-up

Tang, 2003

Type of study:

RCT

Setting and country:

Hong Kong

Funding and conflicts of interest:

Not reported

Inclusion criteria:

First trimester silent miscarriage, defined as:

- intrauterine gestational sac with mean sac diameter of ≥ 2 cm without a fetal pole

 - presence of fetal pole with no cardiac pulsation - gestational sac < 2 cm with no interval growth or persistent absence of fetal cardiac activity on rescanning 7 - 10 days later

< 13 weeks gestation

Exclusion criteria:

-Complete miscarriage

- Incomplete miscarriage

N total at baseline:

Intervention: 40

Control:40

Important prognostic factors²:

age ± SD:

I:32.3 ± 7.3

C: 33.6 ± 6.0

Groups comparable at baseline.

Describe intervention:

600 micrograms of sublingual misoprostol, every 3 hours up to a maximum of three doses

The sublingual group were instructed to put the tablets under their tongues themselves. They were not allowed any food or drink for 20 minutes to allow complete dissolution of the tablets.

Describe control:

600 micrograms of vaginal misoprostol, every 3 hours up to a maximum of three doses

In the vaginal group, the research nurses was responsible for putting the three misoprostol tablets into the vaginal fornix.

Length of follow-up:

6 weeks

Loss-to-follow-up:

Not mentioned)

Incomplete outcome data:

Not mentioned

4

Outcome measures and effect size:

a. Complete miscarriage

Sublingual: 35/40 (87.5)

 Vaginal: 35/40 (87.5)

Need for further intervention (number of women/total (%))

I: 4/39 (10%)

C: 4/39 (10%)

Adverse effects of treatment (number of women/total (%))

a. Nausea

I: 24/40 (60%)

C: 20/40 (50%)

b. Vomiting

I: 7/40 (17%)

C: 9/40 (22%)

c. Diarrhoea

I: 28/40 (70%)

C:11/40 (27%)

d. Fever

I: 23/40 (57%)

C: 19/40 (47%)

Pain

Severe pain

I: 30/40 (75%)

C: 30/40 (75%)

Measures of satisfaction (number of women/total (%))

a. Satisfied of excellent opinion about treatment

I: 30/38 (79%)

C: 31/39 (79%)

b. Would recommend treatment to others

I: 36/38 (94%)

C: 33/39 (85%)

Aim of the study

Outcomes

Complete miscarriage: The outcome of treatment was classified as complete miscarriage if surgical evacuation was not required up to the time of return to normal menstruation.

Need for further intervention

Duration of bleeding

Assessed on day 43

Adverse effects

Recorded during treatment. Fever was defined as a highest temperature of at least 38ºC.

Pain

Recorded during treatment.

Degree of pain was assessed using a questionnaire.

Satisfaction

Assessed by questionnaires on days 7 and 43. Unclear which results are reported, or whether they were combined.

Shah, 2010

Type of study: RCT

Setting and country:

Department of Obstetrics and Gynaecology at Civil Hospital, Karachi.

Pakistan

Funding and conflicts of interest:

Not reported

Inclusion criteria:

Ultrasound diagnosis of missed miscarriage < 20 weeks gestation

Exclusion criteria:

Incomplete miscarriage

Retained products of conception

Previous caesarean

section scars

N total at baseline: 50

Intervention: 25

Control: 25

Important prognostic factors²:

Age/years (mean (SD)) Sublingual: 26.2 (4.2) Vaginal: 26.4 (4.4) (p=0.870)

Parity (median (range)) Sublingual: 2 (0-5) Vaginal: 2 (0-5) (p=0.845)

Gestational age/weeks (mean (SD))

Sublingual: 10.1 (2.62) Vaginal: 10.6 (2.92) (p=0.480) (Note: 22/25 in the sublingual arm and 19/25 in the vaginal arm had a gestational age of less than or equal to 12 weeks, and hence constitute the main population of interest for this review question)

Uterine size/weeks (range) Sublingual: 8-16 Vaginal: 8-18 (p=0.952)

Groups comparable at baseline.

Describe intervention:

400 micrograms of sublingual misoprostol, every three hours up to a maximum of 5 doses (n=25)

(Note: those with a gestational age and uterine size of more than 12 weeks were given 200 micrograms of misoprostol instead, in both arms)

Describe control):

400 micrograms of vaginal misoprostol, every three hours up to a maximum of 5 doses (n=25)

Length of follow-up:

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size:

Complete miscarriage rate (number/total (%))

a. In those ≤ 12 weeks Sublingual: 11/22 (50) Vaginal: 10/19 (52.6) (p=0.557)

b. In those > 12 weeks Sublingual: 2/3 (66.7) Vaginal: 2/6 (33.3) (p=0.404)

 c. All women Sublingual: 13/25 (52.0) Vaginal: 12/25 (48.0) (p=0.571)

Need for further intervention

number/total (%)) Sublingual: 11/25 (44.0) Vaginal: 13/25 (52.0) (Note: 1 further woman in the sublingual group had an incomplete miscarriage - it is not reported whether she had a surgical evacuation)

Adverse effects of treatment (number/total (%))

a. Any side effects Sublingual: 18/25 (72.0) Vaginal: 5/25 (20.0) (p<0.001) b. Nausea Sublin3g12ual: 5/25 (20.0) Vaginal: 1/25 (4.0) (p=0.094)

c. Unpleasant taste Sublingual: 15/25 (60.0) Vaginal: 1/25 (4.0) (p<0.001)

 d. Shivering Sublingual: 6/25 (24.0) Vaginal: 4/25 (16.0)} (p=0.362)

Satisfaction (%)

Sublingual: 13/25 (52%)

Vaginal: 12/25 (48%) (NS) (Note: the authors report that this closely followed the success rate of the regimen)

Interval between misoprostol and expulsion/hours (mean (SD)) Sublingual: 13.07 (5.63) Vaginal: 13.29 (5.63) (NS)

Aim of the study

To compare the efficacy of sublingual and vaginal misoprostol in the medical management of missed miscarriage.

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

by verbally asking patients whether they were satisfied, dissatisfied or neutral with regards to their treatment regimen.

El Sokkary, 2016

Type of study:

RCT

Setting and country:

Single center, Egypt

Funding and conflicts of interest:

No conflict of interest.

Funding not mentioned.

Inclusion criteria:

missed abortion:

– Gestational sac with mean sac diameter of [25 mm,

without fetal pole (blighted ovum).

– The presence of fetal pole [7 mm, with no cardiac

pulsations.

– Gestational sac mean diameter \18 mm, with no

interval growth being observed on rescanning 10 days

later.

– The absence of embryo with heartbeat at least 2 weeks

after an ultrasound scan that showed a gestational sac

without a yolk sac.

– The absence of embryo with heartbeat at least 11 days

after an ultrasound scan that showed a gestational sac

with a yolk sac

Exclusion criteria:

-

N total at baseline:

Intervention: 80

Control: 80

Groups comparable at baseline.

Describe intervention:

100 mcg of misoprostol (1/2 tablet) was administrated to group 1 cases sublingually

and were repeated every 4 h for four doses.

Describe control:

(vaginal group); 100mcg of misoprostol (1/2

tablet) was administrated to group 2 vaginally in the posterior fornix, and this was repeated every 4 h for four

doses 1

Length of follow-up:

1 day

Loss-to-follow-up:

Not mentioned

Incomplete outcome data:

Not mentioned

Outcome measures and effect size:

Treatment success (number/total (%))

I: 56/80 (70%)

C: 41/80 (51%)

Need for further intervention (number of women/total (%))

I: 24/80 (30%)

C: 39/80 (49%)

Adverse events of treatment

a. Nausea

I: 44/80 (55%)

C: 32/80 (40%)

b. Severe Pain

I: 20/80 (25%)

C: 16/80 (20%)

c. Hyperpyrexia

I: 12/80 (15%)

C: 4/80 (5%)

Aim of the study

To compare between

sublingual administration of misoprostol and vaginal

administration in the management of missed abortion.

Outcome

Complete abortion

The absence of remnant of conception or endometrial interface thickness less than

15 mm is mandatory to diagnose complete abortion (24h from the beginning of first dose)

Dehbasi, 2016

Type of study:

RCT

Setting and country:

Single center, Iran

Funding and conflicts of interest:

None

Funding not mentioned

Inclusion criteria:

- fetal IUFD or missed abortion in sonography reports.

Exclusion criteria:

-Patients with external and internal opening of the cervix is open to both symptoms of abortion is spontaneous

N total at baseline:

Intervention: 27

Control:25

Important prognostic factors²:

age ± SD:

I:31.56 ± 5.85

C: 29.48 ± 6.21

Previous spontaneous abortion:

N (%)

I: 17 (34%)

C: 18 (36%)% M

Groups comparable at baseline.

Describe intervention:

Sublingual

Misoprostol (400 μg)

The initial dose repeated every 4 hours t0 termination of pregnancy or maximum dose of 2000 microgram

Describe control):

Vaginal Misoprostol (400 μg)

The initial dose repeated every 4 hours t0 termination of pregnancy or maximum dose of 2000 microgram

Length of follow-up:

6 weeks

Loss-to-follow-up:

Not mentioned

Incomplete outcome data:

Not mentioned

Outcome measures and effect size:

Treatment success (number/total (%))

I: 0/27 (0%)

C: 9/25 (36%)

Adverse events of treatment

Adverse events total

I: 13/27 (48%)

C:5/25 (20%)

b. Nausea and vomiting

I: 6/27 (22.2%)

C: 0/25 (0%)

c. Diarrhoea

I: 6/27 (22.2%)

C: 5/25 (20%)

d. Abdominal Pain

I: 1/27 (3.7%)

C: 0/25 (0%)

Aim of the study

Outcomes

Complete abortion

Complete abortion was defined as complete expulsion of the pregnancy products or endometrial diameter less than 10 mm and absence of residue in sonographic report, otherwise it was considered as incomplete abortion

The main criterion for effective medical abortion was considered occurring abortion within 24 hours after induction.

Seervi, 2014

Type of study: RCT

Setting and country: Department of Obst. & Gynae, S.M.S. Medical College & Hospital, Jaipur, Rajasthan, India

Funding and conflicts of interest: none

Inclusion criteria:

Women patients with

an ultrasound diagnosis of early pregnancy failure, singleton

pregnancy, less than 12 weeks gestation, who had not experienced

uterine cramping, no active bleeding (os closed on per

vaginal examination) and were in a normal frame of mind to

give consent and willing for a surgical evacuation in case of

failure with medication or active bleeding, were included in

the study. embryo with CRL greater than 7mmwith no cardiac activity or irregular gestational sac with

mean sac diameter greater than 16 mm or a gestational sac

more than 25 mm with no visible fetal pole.5

Exclusion criteria:

N total at baseline:

Intervention: 56

Control:54

Important prognostic factors²:

age ± SD:

I:23.79 ±5.2

C:24.57±5.1

Primigravida

I: 21 (37.5%)

C: 19 (35.18%)

Gestational age

7.946 ±1.3

7.905±1.2

Anembryonic sac

I: 13 (20.91%

C: 10 (18.52%)

79.09% of the women patients

had fetal pole absent or irregular gestational sac in the ultrasonographic findings. The other finding was a blighted ovum

seen 20.91%.

Groups comparable at baseline

Describe intervention:

sublingual-

tablet misoprostol 600 mcg every 6 hourly for 3 doses.

The dose was decreased to lessen the side effects.

Describe control):

vaginal e tablet misoprostol 800 mcg every 6 hourly up to 3 doses.

Length of follow-up:

Loss-to-follow-up:

Intervention:

N 4/56 (3.36%)

Reasons (surgical evacuation for other causes (4), excessive haemorrhage (2)), sever allergic reaction (1), time regimen not followed (1)

Control:

N 5/56 (4.20%)

Reasons (absconded (1) surgical evacuation for other causes (4), excessive haemorrhage (4))

Incomplete outcome data:

Not reported

Outcome measures and effect size:

Treatment success (number/total (%))

I:52/56 (92.9%)

C:48/54 (89%)

Satisfaction

Highly satisfied:

I: 28/56 (50%)

C: 27/54 (50%)

Just satisfied

I: 20/56 (35.71%)

C: 18/54 (33.33%)

Unsatisfied

I; 8/56 (14.29%

C: 9/54 (16.67%)

Adverse events of treatment

Excessive haemorrhage

I: 2/56 (1.68%

C: 4/54 (3.36)

b. Vomiting

I: 6/56 (10.71%)

C: 2/54 (3.7%)

C. Diarrhoea

I: 5/56 (8.93 %)

C: 4/54 (7.41%)5

d. Abdominal pain (requiring analgesics):

I: 18/56 (32.14%)

C: 15/54 (27.78%)

e. Fever/ chills

I: 6/56 (10.71%)

C: 2/54 (3.7%)

F. Headache

I: 3/56 (5.36%)

C: 1/54 (1.85%)

Allergy

I: 3/56 (5.36%)

C: 2/54 (3.70%)

Induction abortion interval

I: 18.241

C: 18.125

Aim of the study

To compare the efficacy and the side effects of different regimes

of misoprostol in causing the complete expulsion of products

of conception in early pregnancy failure.

Outcomes

Evaluation was done 6 h after 3rd dose of misoprostol, i.e.

at 24 h. If the uterus was not felt empty on per vaginal examination

and ultrasonography showed products of conception, then dilatation and evacuation was done and was considered a true drug failure.

Akanksha, 2016;

Type of study: RCT

Setting and country: Department of Obstetrics & Gynecology, Kasturba Hospital, New Delhi, India

Funding: No funding sources

conflicts of interest: None

Inclusion criteria:

Missed miscarriage is

characterized by closed cervix and minimal or no

bleeding per vaginum. On ultrasound it is defined as an

intrauterine gestational sac with a mean sac diameter of

25 mm or more with no visible embryonic pole, an

embryonic pole of more than 7 mm with no cardiac

activity or persistent absence of cardiac activity on a

second scan at least 7 to 10 days later

Exclusion criteria:

Women with

suspected ectopic pregnancy, excessive bleeding per

vaginum, incomplete miscarriage, hemodynamically

unstable, history of asthma, previous cesarean or allergy

to prostaglandins were excluded from this study

N total at baseline: 50

Intervention: 25

Control:25

Important prognostic factors²:

age ± SD:

I: 24.92 ±3.17

C: 24.48 ±3.41

Primigravida

I: 12/25 (48%)

C: 10/25 (40%)

Gestational age

9.42 ±2.05

9.55±2.43

Groups comparable at baseline.

Describe intervention:

400microg of misoprostol sublingually every four hours for a maximum of 5 doses

Describe control):

400 microgram of misoprostol vaginally every

four hours for a maximum of 5 doses

Length of follow-up:

Loss-to-follow-up:

I: 0/25

C: 0/25

Incomplete outcome data:

I: 0/25

C: 0/25

Outcome measures and effect size:

Treatment success (number/total (%))

I:17/25 (68%)

C:15/25 (60%)

Reintervention (surgical)

I: 8/25 (32%)

C: 10/25 (40%)

Satisfaction:

Comfortable

I: 22/25 (88%)

C: 13/25 (52%)

Discomfort:

I:2/25 (12%)

C: 12/25 (48%)

Adverse events

Excessive bleeding, requiring blood transfusion

I: 1/25 (4%)

C: 1/25 (4%)

a. Vomiting

I: 10/25 (40%)

C: 12 / 25 (48%)

Nausea

I: 18/25 (72%)

C: 20/25 (80%)

Diarrhoea

I: 8/25 (32%)

C: 03/25 (12%)

Shivering

I: 12/25 (24%)

C: 5/25 (4%)

Fever

I: 10/25 (40%)

C: 4/16 (16%)

Unpleasant taste

I: 15/25 (60%)

C: 1/25 (4%)

Induction abortion interval

I: 11.67 ± 6.90

C: 18.33 ±5.60

Mean doses:

I:L 3.29 ±1.02

C: 4.2 ± 0.85

Aim of the study

to compare the efficacy, outcome and side effects of sublingual and vaginal

misoprostol for the medical management of missed

miscarriage.

Succes: complete expulsion of the products

of conception without surgical intervention.

Failure was defined as cases with incomplete or

no dilatation within 12 hours of last dose of misoprostol.

Surgical evacuation was considered for those who failed

to abort after receiving 5 doses of misoprostol and those who had incomplete miscarriage.

Sonsanoh, 2014

Type of study:

RCT

Setting and country:

Hospital, Thailand

Funding : not reported.

and conflicts of interest: none

Inclusion criteria:

as 1) an intrauterine gestational sac with a mean diameter of 25 mm or greater and no visible embryonic pole; 2) an embryonic pole of 5-14 mm with no cardiac activity; and 3) abnormal growth or persistent absence of fetal cardiac activity on a second scan 7-10 days later(16). In addition, all participants should be over 18 years old. Parental consent was required if the participant’s age was less than 18 years old.

Exclusion criteria: Women with suspected ectopic pregnancy, heavy vaginal bleeding, and maternal history of asthma or cardiac disease, open internal cervical on speculum examination, history allergy to prostaglandins, vital sign unstable and an inability to confirm pregnancy failure or intrauterine gestational sac location were excluded from this study.

N total at baseline:

Intervention: 60

Control: 60

Important prognostic factors²:

For example

age ± SD:

I:29.5 ±6.2

C: 29.4 ± 7.3

Type (embryonic death / anembryonic pregnancy

I: 24 (40%) / 36 (60%)

C: 29 (48.3% / 31 (51.6%)

Groups comparable at baseline?

No, different in, BMI. Weight gain and primigravida

Describe intervention (treatment/procedure/test):

In Group 1 (n = 60), they were given 4 tablets of 200 μg misoprostol with 2-3 drops of normal saline placed in the posterior vaginal fornix by digital insertion. The women remained in the semiprone position for 30 min.

Every 6 hours, maximum of 3 dosis

Describe control (treatment/procedure/test):

In Group 2 (n = 60), 4 tablets of 200 μg misoprostol were sublingually given.

Every 6 hours, maximum of 3 dosis

Length of follow-up:

2 wk

Loss-to-follow-up:

None

Incomplete outcome data:

none

Outcome measures and effect size (include 95%CI and p-value if available):

Treatment success (number/total (%))

I: 41/60 (68.3%)

C: 36/60 (60%), p=0.44

Reintervention (surgical)

I: 16/60 (26.7%)

C: 24/60 (40%)

Adverse events (bleeding

, perforations)

Heavy bleeding:

12/60 (20%)

3/60 (5%)

Side effects: general

Side effects: vomiting

-

Side effects: nausea

6/60 (10%)

7/60 (11.7%)

Side effects: diarrhea

I: 4/60 (6.7%)

C: 3/60 (5.0%)

Side effects: pain

I: 27/60 (45%)

C: 19/60 (31.7%)

Satisfaction: (The assessment of satisfaction ranged from dissatisfied, satisfied and very satisfied.)

Women from both groups were equally satisfied with the treatments that they have received; none of the participants was dissatisfied.

Aim:

 To compare the complete abortion rate, the induction-abortion time and the side effects of 800 μg misoprostol via vaginal and sublingual routes.

Comparison 3. Oral vs. Sublingual

Ayudhaya, 2006

Type of study:

RCT

Setting and country:

Department of Obstetrics and Gynaecology at Ramathibodi Hospital,

Bangkok,

Thailand

Funding and conflicts of interest: not reported

Inclusion criteria:

Diagnosis of early pregnancy failure, defined as one of the following: - Intrauterine gestational sac with mean sac diameter of >2 cm without a fetal pole (blighted ovum) - Presence of a fetal pole without cardiac pulsations - Gestational sac diameter <2cm with no interval growth or a persistent absence of fetal cardiac pulsation on re-scanning after 7-10 days

Gestational age of 7-12 weeks

Exclusion criteria:

Abnormal vaginal bleeding

Severe abdominal pain

N total at baseline:

N=138

(however 2 participants were later excluded)

Intervention:

Control:

Important prognostic factors²:

Age/years (mean (SD)) Oral: 32.0 (5.8) Sublingual: 33.4 (6.2) (NS)

Gestational age/weeks (mean (SD)) Oral: 10.7 (1.5) Sublingual: 11.0 (1.4) (NS)

Nulliparous (number/total (%)) Oral: 31/68 (45.6) Sublingual: 27/70 (38.6) (NS)

Groups comparable at baseline

Describe intervention:

400 micrograms of misoprostol orally every 4 hours, up to a maximum of 6 doses (n=68)

Women in the sublingual group had two tablets placed under the tongue by a nurse. They were not allowed to eat for 20 minutes, to allow complete dissolution. A nurse was also responsible for oral administration to the patients. Patients were allowed 30 ml of water to drink, then misoprostol was given the same way every 4 hours until products of

conception were detected.

Describe control):

400 micrograms of misoprostol sublingually every 4 hours, up to a maximum of 6 doses (n=70)

Length of follow-up:

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Outcome measures and effect size:

Clinical outcome of treatment (number/total (%))

a.Complete miscarriage Oral: 17/66 (25.8) Sublingual: 15/70 (21.4)

(NS)

b.Incomplete miscarriage Oral: 23/66 (34.8) Sublingual: 27/70 (38.6) (NS)

b.Medical failure

Oral: 26/66 (39.4) Sublingual: 28/70 (40.0) (NS)

Adverse effects of treatment (number of women/total (%)) a. Nausea/vomiting Oral: 3/66 (4.5) Sublingual: 2/70 (2.9)

b. Diarrhoea Oral: 7/66 (10.6) Sublingual: 6/70 (8.6)

c. Fever Oral: 2/66 (3.0) Sublingual: 15/70 (21.4)

d. Chills Oral: 0/66 (0)

Sublingual: 4/70 (5.7)

(Note: these % have been calculated by the technical team and differ slightly from those reported in the paper, because the authors calculated % using 68 women in the oral arm, despite reporting excluding them, and excluding them for other outcomes. The authors also report that no serious complications occurred in either group.)

Measures of pain: abdominal pain (number of women/total (%)) Oral: 40/66 (60.6) Sublingual: 47/70 (67.1)

Aim of the study

To compare repeated doses of sublingual with oral misoprostol in the medical management of early

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

Complete miscarriage was defined as no active bleeding, closed cervical os and endometrial thickness < 1 cm.

Induction to expulsion interval/hours (mean (SD)) Oral: 10.7 (6.6) Sublingual: 8.7 (5.4)

Total dosage received/micrograms (mean (SD)) Oral: 1706 (90.1) Sublingual:

Kushwah, 2009

Type of study: RCT

Setting and country:

prenatal clinic of the Department of Obstetrics and Gynaecology of Sucheta Kriplani Hospital, Delhi, India

Funding and conflicts of interest:

Not reported

Inclusion criteria:

Gestational sac of 25 mm or larger with no embryo present (anembryonic gestation) Presence of a fetal pole without cardiac pulsations (missed miscarriage)

All participants had early pregnancy failure confirmed by ultrasound between the 7th and 14th week of gestation.

Exclusion criteria:

Vaginal bleeding Any evidence of infection History of allergy to misoprostol Major medical problems

N total at baseline: 100

Intervention: 50

Control:50

Important prognostic factors²:

Age/years (mean (SD)) Sublingual: 26.6 (4.4) Oral: 24.6 (3.8)

Parity (mean (SD)) Sublingual: 2.1 (0.9) Oral: 2.1 (0.9)

Gestation/days (mean (SD)) Sublingual: 57.7 (7.8) Oral: 59.9 (9.0) (Note: only 1 woman, from the oral arm, had gestation of over 80 days)

Type of pregnancy (number/total (%)) Sublingual: - Anembryonic: 23/50 (46)

- Missed miscarriage: 27/50 (54) Oral: - Anembryonic: 34/50 (68) - Missed miscarriage: 16/50 (32)

Groups comparable at baseline.

Describe intervention:

200mg of oral mifepristone + 600 micrograms sublingual misoprostol (n=50)

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.

Describe control):

200mg of oral mifepristone + 600 micrograms of oral misoprostol (n=50)

Length of follow-up:

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Outcome measures and effect size:

Successful uterine evacuation (number of women/total

(%)) Sublingual: 46/50 (92) Oral: 42/50 (84)

Adverse effects of treatment (number of women/total (%))

a. Nausea Sublingual: 17/50 (34) Oral: 26/50 (52) (Note: 1 woman from each arm required medication)

b. Vomiting Sublingual: 11/50 (22) Oral: 22/50 (44) (Note: 3 women from the oral arm required medication)

c. Diarrhoea Sublingual: 24/50 (48) Oral: 28/50 (56) (Note: 5 women in each arm had more than 4 episodes and required medication)

d. Fever: any

Sublingual: 10/50 (20) Oral: 26/50 (52)

e. Fever: ≥37.8ºC Sublingual: 0 Oral: 4/50 (8)

Measures of pain (number/total (%))

a. Incidence of pain requiring no analgesia Sublingual: 14/50 (28) Oral: 26/50 (52)

b. Incidence of pain requiring analgesia Sublingual: 9/50 (18) Oral: 18/50 (36)

c. Incidence of pain: total Sublingual: 23/50 (46) Oral: 44/50 (88)

Reported satisfaction (number/total (%)) Sublingual: 46/50 (92%)

Oral: 36/50 (72%)

Aim of the study

To compare the efficacy of misoprostol administered sublingually or orally for uterine evacuation after

early pregnancy failure.

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

Induction to evacuation interval/hours (mean (SD)) Sublingual: 46 (4.5) Oral: 9.4 (5.6) (Note: this only includes women for whom evacuation was successful) It is not reported how many women required the supplemental doses of misoprostol.

Evacuation was considered 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

evacuation under paracervical block.

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Creinin, 1997

computer-generated random number table

Unlikely

Neither the clinician nor the patient was blinded to the treatment group

Neither the clinician nor the patient was blinded to the treatment group

Neither the clinician nor the patient was blinded to the treatment group

Unlikely

Unlikely

Likely

Ngoc, 2004

computer-generated code in blocks of 10.

sequentially

numbered randomized envelope

Neither the investigator nor the woman was blinded to the treatment assignment

Neither the investigator nor the woman was blinded to the treatment assignment

Neither the investigator nor the woman was blinded to the treatment assignment

Unlikely

Unlikely

Likely ( 2 women wrongly diagnosed)

Rita, 2006

permuted block method

Not reported

Not reported

Not reported

Not reported

Unclear how and when "severe pain" and adverse effects were judged.

Not reported

Unlikely

Marwah, 2016

computer generated sequentially numbered envelopes

Not reported

Not reported

Not reported

Not reported

Unlikely

Unlikely

Unlikely

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

El Sokkary, 2016

Not reported

Unlikely

Not reported

Not reported

Not reported

Unlikely

Unlikely

Unlikely

Dehbasi, 2016

block randomization was performed according to the

time of admission

Unlikely

Not blinded

Single blind allocation and intervention

were conducted by a nurse working in the midwifery unit.

Single blind allocation and intervention

were conducted by a nurse working in the midwifery unit.

Unlikely

Not described

Likely, 2 excluded that did not repond or had severe abdominal pain

Tanha, 2010

computer-generated code

Not reported

Neither the clinician or the patient were blinded to treatment allocation.

Neither the clinician or the patient were blinded to treatment allocation.

Those assessing treatment outcome were not blinded to treatment allocation.

Unlikely

Unlikely

5 of the participants were later diagnosed as having a partial or complete mole (however, this represents only 2.3% of the study population)

Tang, 2003

computer-generated

random numbers

Not reported

Blinding is not reported - this would be impossible for the participants, however could have been achieved for those assessing outcomes.

Blinding is not reported - this would be impossible for the participants, however could have been achieved for those assessing outcomes.

Blinding is not reported - this would be impossible for the participants, however could have been achieved for those assessing outcomes.

Likely (satisfaction)

Unlikely

Unlikely

Shah, 2010

consecutive sealed envelopes.

Not reported

Blinding was not done. Blinding the participants would have been difficult (although not impossible), however they could have blinded the physicians judging treatment success and need for further intervention.

Blinding was not done. Blinding the participants would have been difficult (although not impossible), however they could have blinded the physicians judging treatment success and need for further intervention.

Blinding was not done. Blinding the participants would have been difficult (although not impossible), however they could have blinded the physicians judging treatment success and need for further intervention.

Unlikely

Unlikely

Unlikely

Seervi, 2014

coin tossing method

Not reported

Not reported

Not reported

Not reported

Outcome measures not reported in methods

Unlikely

Unlikely

Akanksha, 2016

lottery method

(random sampling).

Not reported

Not reported

Not reported

Not reported

Unlikely

Unlikely

Unlikely

Sonsanoh, 2014

We used and assigned blocks of four randomizations to two groups of participants.

Cards labeled with the assigned route were placed in sealed, opaque envelopes which were filled and labeled in accordance with the list of randomizations. The allocation was concealed by the use of sealed number of treatments.

Not reported

Not reported

Not reported

Unlikely

Note: satisfaction was defined in methods in a 3 point rating scale but is only descriptive in results

Unlikely

Unlikely

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Kushwah, 2009

computer generated random numbers.

Not reported

Not reported

Not reported

Not reported

The point at which adverse effects, pain and satisfaction were assessed is not reported.

Unlikely

Unlikely

Ayudhaya, 2006

computer generated random numbers

Not reported

Blinding is not reported. It would have been difficult to blind the participants (although not impossible); however those assessing the outcome of the

treatment could have been blinded to allocation.

Blinding is not reported. It would have been difficult to blind the participants (although not impossible); however those assessing the outcome of the

treatment could have been blinded to allocation.

Blinding is not reported. It would have been difficult to blind the participants (although not impossible); however those assessing the outcome of the

treatment could have been blinded to allocation.

Unlikely

Unlikely

Unlikely