Journal Club: MIST trial Management of miscarriage: expectant, medical, or surgical? Results of randomized controlled trial (miscarriage treatment (MIST) trial) BMJ: 2006 May 27; 332(7552): 1235–1240. Tuesday, 6/23/15 Marina Morie, R1 Dr. Tipu Khan

Case: 38 year old healthy G2P1 at 12w and 2/7d gestation by LMP c/w 1 st trimester US presents to AFMC one day after routine prenatal US for 1 st trimester genetic screening showed intrauterine fetal pole with no fetal heart activity, measuring 7w and 2/7d. She is saddened and tearful and tells you that she has had some spotting and uterine cramping. She is unable to tell you if she has had passage of tissue as she has been too distraught to examine what she has passed.

Background and Aim Background Approx. 1 in 9 pregnancies end in spontaneous 1 st trimester miscarriages Many trials have looked at various management options, but tend to be small and compare expectant vs. surgical or medical vs. surgical management Randomized controlled trials to assess management options has recruiting problems given that this is generally an emotional time for patients and up to 8 in 9 women have a definite treatment option, so decline randomization Aim To look at which management option (expectant vs. medical vs. surgical) is best for managing miscarriage and how to counsel patients on their options

Literature Search Key terms used Spontaneous abortion, miscarriage, missed abortion, intrauterine fetal demise Resources Uptodate, Pubmed Findings This particular study was chosen as it is the only large randomized control study comparing medical, surgical, and expectant management

PICO-D Population Women with a pregnancy < 13 weeks gestation diagnosed as incomplete miscarriage or early fetal/embryonic demise Intervention All women were given an information sheet, 30 tabs of co-dydramol, and an emergency telephone number. Expectant management, medical management, or surgical management Comparison The traditional intervention of surgical curettage Outcome Primary: documented gynecological infection within 14 days of trial entry Secondary: treatment with antibiotics for presumed gynecologic infection within 14 days and within 8 weeks, duration of clinical symptoms, complications, efficacy, and return to normal activities Design Randomized controlled trial

Management of miscarriage: expectant, medical, or surgical? Results of randomised controlled trial (miscarriage treatment (MIST) trial) J Tinder, P Brocklehurst, R Porter, M Red, S Vyas, L Smith BMJ: 2006 May 27; 332(7552):

Hypothesis The paper’s hypothesis: a clinically important difference would exist in documented gynecological infection within 14 days of expectant or medical management compared with surgical management of 1 st trimester miscarriage

Design Randomized controlled trial Multicenter with 7 participating hospitals with an early pregnancy clinic. Recruited from 5/1997 – 12/2001. Goal was to recruit a total of 1422 women, 1200 women were recruited and randomized Based on a previous study, the expected incidence of the primary outcome in the standard care group (surgical) was 10%. To detect the treatment effect at the 5% level, 474 women needed to be recruited to each group Advantages: randomized and controlled, large sample size (at least compared to previous studies) Disadvantages: inability to blind patient or provider

Design Inclusion criteria Women with pregnancy < 13 weeks gestation diagnosed with incomplete miscarriage or early fetal/embryonic demise Early embryonic demise: intact gestation sac >20 mm mean diameter with no internal structures Early fetal demise: feus >6 mm CRL with no heart activity on TVUS Incomplete miscarriage: areas of mixed uterine echogenicity within the uterine cavity with or without a disordered gestation sac Exclusion criteria Severe hemorrhage or pain Fever >37.5 degrees C Severe asthma Hemolytic disease or blood dyscrasias Current anticoagulation or systemic corticosteroid treatment Twin or higher order pregnancy Smoker >35 years of age Inability to understand written English

Design How were variables defined and measured? Primary outcome: Gynecological infection within 14 days 2 or more of the following: Purulent vaginal discharge, fever >38C, uterine tenderness on abdominal exam, WBC >15 Secondary outcomes Treatment with antibiotics for presumed gynecologic infection within 14 days and 8 weeks Duration of clinical symptoms (pain, additional analgesia, vaginal bleeding, days off work, days before returning to daily activities) Complications (decrease in Hb at days, blood transfusion, unplanned consultation or admissions within 14 days and 8 weeks) Efficacy: no unplanned surgical curettage within 8 weeks Psychological outcomes (depression & anxiety at 8 weeks) Return to normal activity

Design

Intervention Expectant management: home with no further intervention Medical management: Incomplete miscarriage: hospital admit, misoprostol 800 mcg PV x 1 Early fetal/embryonic demise: pretreated with mifepristone 200 mg PO x 1, hospital admit, then misoprostol 800 mcg PV x 1 Surgical evacuation for RPOC offered if expulsion of RPOC did not start within 8h of misoprostol insertion Surgical management: hospital admit, suction curettage under general anesthesia. No ppx antibiotics used. All women received an information sheet, 30 co-dydramol (dihydrocodeine- paracetamol) tabs, and an emergency phone # All women got CBC, f/u appointment in 10 – 14 days after trial entry for a TVUS, CBC, consult with study RN, and exam by OB/GYN if s/sx of infection were present. If RPOC present on US or if other clinic s/sx present, suction curettage was offered

Results Gynecological infection No significant difference between the three groups (surgical group 3%, medical group 3%, expectant group 2%) Incidence of antibiotic use for presumed gynecological infection within the first 14 days (but not at 8 weeks) was significantly higher in the expectant group compared to the surgical group (risk difference 4%, 95% CI 1 – 8%). Medical group was similar to the surgical group.

Results Unplanned hospital consultation and admissions No significant difference in hospital consultation between the three groups at 14 days and at 8 weeks Unplanned hospital admissions was significantly higher in the expectant group compared to the surgical group (risk difference 41%, 95% CI 36 – 47%) and in the medical group compared to the surgical group (risk difference 10%, 95% CI 6 – 15%)

Results Unplanned surgical intervention (curettage) 142 women (36%) in the medical group had curettage 90 (23%) for failure of medical management 52 (13%) had unplanned curettage (excess bleeding, pain, patient request, RPOC on scan, other) 11 (3%) had an emergency procedure prior to planned admission 177 women (44%) in the expectant group had unplanned curettage 22 women (5%) in the surgical group had unplanned curettage Type of miscarriage was a factor in the success of management Early fetal demise 20 (6%) in the surgical group, 116 (38%) in the medical group, and 154 (50%) in the expectant group had unplanned curettage Incomplete miscarriage 2 (2%) in the surgical group, 26 (29%) in the medical group, and 23 (25%) in the expectant group had unplanned curettage

Results Clinical symptoms, complications, and side effects Cessation of bleeding was significant earlier in the surgical group compared to the medical group (p=0.0004) and to the expectant group (p<0.0001) Hb/Hct did not differ between the groups at 10 – 14 days 7 (2%) in the expectant group and 4 (1%) in the medical group received blood transfusions compared to 0 in the surgical group No significant difference in nausea, vomiting, or pain, though the expectant group received “extra analgesia” as an outpatient No significant difference in the incidence of surgical complications, rates ranged from 1-2%.

Results Psychological and activities outcomes No difference in median time to return to usual daily activities (2 days), sick leave (8-9 days), activities of daily living (UK SF-36), or anxiety and depression scores Anxiety and depression questionnaire done 6-8 weeks after miscarriage

Results

Follow-up study: Incidence of pregnancy after expectant, medical, or surgical management of spontaneous first trimester miscarriage: long term follow-up of miscarriage treatment (MIST) randomised controlled trial. AUSmith, LF, Ewings PD, Quinlan CSO. BMJ.2009;339:b3827. Comparison of fertility rates between the three management groups 762 of the 1199 recruited to the MIST trial (68% response rate) self reported pregnancy/live birth rates The live birth rate 5 years following the index miscarriage did not differ significantly between the three management groups Expectant management: 177/224 (79%) Medical management: 181/230 (79%) Surgical management: 192/235 (82%) Long-term fertility and subsequent pregnancy rates do not appear to be affected by the method of management for prior 1 st trimester miscarriage

Critique “Failure” of medical management was assessed only 8 hours following medication administration Cannot generalize to women with other comorbidities or to patients in areas without access to 24h medical care There is no clearly recommended regimen for the medical management option – inpatient or outpatient Lack of reproducibility - no large comparison studies looking at all three management options, largely due to the difficulty in recruiting participants

Critical Appraisal Tool d

Back to the case… The patient was offered expectant, medical, and surgical management options. The patient opted for medical management. Medical regimen: cytotec 800 mcg PV x 1, then 6 hrs later, cytotec 600 mcg PV x 1 She returned 1 week later for follow up. She had experienced heavy bleeding and cramping soon after cytotec therapy. By the time of the follow up clinic visit, her bleeding had slowed to minimal spotting. Bedside US at the time of the clinic visit showed an evacuated uterine cavity.

Summary The rates of the primary outcome, gynecological infections, do not differ between management groups, and the rates of infection were low even without prophylactic antibiotics or infection screening Long-term fertility and subsequent pregnancy rates do not appear to be affected by the method of management for prior 1 st trimester miscarriage In the absence of comorbidities and if access to medical care permits, women should be counseled on their options for management of 1 st trimester pregnancy loss and allowed to choose the method they feel most comfortable with