Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial.

STUDY QUESTION: In women with threatened miscarriage, does progesterone supplementation until the completion of the first trimester of pregnancy increase the probability of live birth? SUMMARY ANSWER: In women with threatened miscarriage, 400 mg vaginal progesterone nightly, from onset of bleeding until 12 weeks, did not increase live birth rates. WHAT IS KNOWN ALREADY: Limited evidence has indicated that vaginal micronized progesterone may make little or no difference to the live birth rate when compared with placebo in women with threatened miscarriage. Subgroup analysis of one recent randomized trial reported that in women with bleeding and at least one previous miscarriage, progesterone might be of benefit. STUDY DESIGN, SIZE, DURATION: We performed a randomized, double-blinded, placebo-controlled trial between February 2012 and April 2019. Eligible pregnant women under 10 weeks gestation, experiencing a threatened miscarriage as apparent from vaginal bleeding were randomized into two groups in a 1:1 ratio: the intervention group received 400 mg progesterone as vaginal pessaries, the control group received placebo vaginal pessaries, both until 12 weeks gestation. The primary endpoint was live birth. We planned to randomize 386 women (193 per group). The study was stopped at a planned interim analysis for futility after randomization of 278 women. PARTICIPANTS/MATERIALS, SETTING, METHODS: This trial was conducted at the Mater Mothers' Hospital, a tertiary centre for maternity care in South Brisbane, Queensland, Australia. We randomized 139 women to the intervention group and 139 women to the placebo group. Primary outcome data were available for 136 women in the intervention group and 133 women in the placebo group. MAIN RESULTS AND THE ROLE OF CHANCE: The live birth rates were 82.4% (112/136) and 84.2% (112/133) in the intervention group and placebo group, respectively (risk ratio (RR) 0.98, 95% CI 0.88 to 1.09; risk difference -0.02, 95% CI -0.11 to 0.07; P = 0.683). Among women with at least one previous miscarriage, live birth rates were 80.6% (54/67) and 84.4% (65/77) (RR 0.95, 95% CI 0.82-1.11; P = 0.550). No significant effect was seen from progesterone in women with two (RR 1.28, 95% CI 0.96-1.72; P = 0.096) or more (RR 0.79, 95% CI 0.53-1.19; P = 0.267) previous miscarriages. Preterm birth rates were 12.9% and 9.3%, respectively (RR 1.38; 95% CI 0.69 to 2.78; P = 0.361). Median birth weight was 3310 vs 3300 g (P = 0.992). There were also no other significant differences in obstetric and perinatal outcomes. LIMITATIONS, REASONS FOR CAUTION: Our study was single centre and did not reach the planned sample size because it was stopped prematurely at an interim analysis. WIDER IMPLICATIONS OF THE FINDINGS: We did not find evidence supporting the treatment effect of vaginal progesterone in women with threatened miscarriage. Progesterone in this setting should not be routinely used for threatened miscarriage. The treatment effect in women with threatened miscarriage after previous miscarriages warrants further research. STUDY FUNDING/COMPETING INTEREST(S): Mothers' and babies Golden Casket Clinical Fellowship (L.A.M.). Progesterone and placebo pessaries were provided by Perrigo Australia.B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work. TRIAL REGISTRATION NUMBER: ACTRN12611000405910. TRIAL REGISTRATION DATE: 19 April 2011. DATE OF FIRST PATIENT'S ENROLMENT: 06 February 2012.

Caesarean scar ectopic pregnancy: Experience from an Australian tertiary centre.

BACKGROUND: Despite the rising incidence of caesarean scar pregnancy (CSP), as yet there are no consensus or evidence-based guidelines for management. AIMS: To review diagnosis, treatment and management of all women with CSP over a 5 year period at Mater Mothers' Hospital, Brisbane, Australia. MATERIALS AND METHODS: Retrospective cohort study of CSP between 2013-2018. Data reviewed included demographics, presenting symptoms, gestational age, ultrasound findings, human chorionic gonadotrophin levels, treatment success, complications, and if available, subsequent pregnancy outcomes. RESULTS: Twenty-eight women were treated for CSP during the study period. Initial diagnosis was delayed in ten (36%). Overall success rates of initial treatment were 22/28 (79%). Of the six cases of failed treatment, five had been treated with systemic methotrexate alone. All women requiring further intervention had fetal pole present, and 50% had fetal cardiac activity. Failure rate of systemic methotrexate alone was 5/11 (45%). Eleven women deemed appropriate for conservative management did not require further treatment or experience complications. Nine women had data available for subsequent pregnancies, of whom two developed placenta accreta. CONCLUSION: This study provides data that may assist in guideline development and decision-making for management of CSP. Conservative management in carefully selected women appeared to be safe. Nearly half of women treated with systemic methotrexate alone required another treatment modality, suggesting a role for intralesional treatment, particularly in the presence of fetal pole ± fetal cardiac activity. More than one in five women with documented subsequent pregnancies were diagnosed with placenta accreta.

Utility of ßhCG monitoring in the follow-up of medical management of miscarriage.

OBJECTIVE: To evaluate the percentage change in total ßeta-unit human chorionic gonadotropin (ßhCG) levels (%ΔßhCG) in the prediction of treatment outcomes following intravaginal misoprostol for missed miscarriage before 13 weeks. METHODS: A secondary analysis of a randomised controlled study of medical management of miscarriage was performed. Total ßhCG levels were collected before misoprostol (baseline) and after a planned seven day interval (follow-up), when a transvaginal ultrasound (TVUS) reported a gestational sac as present or not. If no sac at TVUS, surgery was indicated on clinical criteria. %ΔßhCG ((baseline ßhCG - follow-up ßhCG)/baseline ßhCG × 100) was evaluated in the prediction of a sac at TVUS and surgery on clinical criteria. RESULTS: %ΔßhCG was calculated for cases with ßhCG levels within two days of misoprostol and TVUS; calculation interval determined case number. The median %ΔßhCG for 24 cases with a persistent sac (6-9 day interval) was significantly lower than for 145 with no sac (58.75% (interquartile range (IQR): 37.59-76.69; maximum 86.54) vs 97.65% (IQR: 95.44-98.43); P < 0.0001). The median %ΔßhCG for eight cases needing surgery on clinical criteria (5-9 day interval) was significantly lower than for 140 cases with no sac not needing surgery (79.68% (IQR: 64.63-91.15; maximum 94.06) vs 97.68% (IQR: 95.61-98.50); P < 0.0001). The area under the receiver-operator curve was 0.975 for prediction of a persistent sac and 0.944 for prediction of surgery on clinical criteria, respectively. %ΔßhCG > 87% predicted no sac at TVUS. %ΔßhCG > 94.5% predicted no surgery on clinical criteria. CONCLUSION: %ΔßhCG calculation over one week reliably predicted treatment outcomes after medical management of missed miscarriage.

The medical management of missed miscarriage: outcomes from a prospective, single-centre, Australian cohort.

OBJECTIVE: To report the prospective outcomes of medical management of missed miscarriage before 13 weeks' gestation from an Australian cohort. DESIGN: Descriptive study of a cohort selected out of a randomised controlled trial. SETTING: Outpatient management at a maternity hospital between 1 May 2007 and 28 July 2010. PARTICIPANTS: 264 women requesting medical management of missed miscarriage. MAIN OUTCOME MEASURES: Number of doses of misoprostol required, unscheduled visits for care, findings at ultrasound follow-up, requirement for surgical management, number of cases of gestational trophoblastic disease (GTD), and self-reported patient experience. RESULTS: 107 women (40.5%) received a repeat dose of misoprostol, and 79 women (29.9%) made unscheduled visits for care. Among the 241 women with Day 7 ultrasound follow-up, a gestational sac was found in 32 women (13.3%), indicating failure of medical management. Complete miscarriage was induced without the need for surgery in 206 women (78.0%). Surgery was performed as an emergency in 13 women (4.9%). Twelve women (4.5%) had surgery for ongoing bleeding after medical management, and four of these did not have chorionic villi on histopathological examination. Five women (1.9%) had GTD, which was managed incidentally under the protocol. Among those who returned patient questionnaires, 73.0% participants (116/159) indicated that they would recommend medical management of miscarriage to other women, while 18.2% (29/159) indicated that they would undergo surgery next time. CONCLUSION: The medical management of missed miscarriage on an outpatient basis is safe and effective. TRIAL REGISTRATION: ACTRN12612000150842.

Can we use a lower intravaginal dose of misoprostol in the medical management of miscarriage? A randomised controlled study.

BACKGROUND: The optimal dose of misoprostol to be used in the medical management of miscarriage before 13 weeks has not been resolved. AIM: To evaluate the effectiveness and side effect profile of two different dosages of misoprostol. METHODS: A randomised controlled, equivalence study comparing 400 vs 800 µg misoprostol per vaginum (PV) on an outpatient basis. The allocated dose was repeated the next day if clinically the products of conception had not been passed. Complete miscarriage was evaluated using two methods: ultrasound criteria on Day 7 and the need for surgical management (clinical criteria). Equivalence was demonstrated if the 95% confidence interval [CI] of the observed risk difference between the two doses for complete miscarriage lay between -15.0 and 15.0%. Differences in side effects and patient satisfaction were evaluated using patient-completed questionnaires. RESULTS: One hundred and fifty-eight women were allocated to receive 400 µg and 152 women to 800 µg misoprostol for the management of missed (91.3%) or incomplete (8.7%) miscarriage. The rate of induced complete miscarriage was equivalent using both ultrasound criteria (observed risk difference (ORD) -4.6%, 95% CI -12.8 to 3.7%; P = 0.313) and clinical criteria (ORD -5.6%, 95% CI -14.8 to 3.6%; P = 0.273). Following the 400 µg dose, the reported rate of fever/rigors was lower (ORD -15.6%, 95% CI -28.1 to -3.0%; P = 0.015), and more women reported their decision to undergo medical management as a good decision (ORD 15.2%, 95% CI 2.8 to 27.7%; P = 0.018). CONCLUSION: Four hundred-microgram misoprostol PV can be recommended for the medical management of miscarriage on an outpatient basis.