Mifepristone and misoprostol versus placebo and misoprostol for resolution of miscarriage in women diagnosed with missed miscarriage: The MifeMiso RCT (2021)

Type of publication:Journal article

Author(s):Devall A.; Chu J.; Gallos I.; Coomarasamy A.; Beeson L.; Cheed V.; Sun Y.; Roberts T.; Ogwulu C.O.; Williams E.; Jones L.; La Fontaine Papadopoulos J.; Hardy P.; Bender-Atik R.; Brewin J.; Hinshaw K.; Ahmed A.; Choudhary M.; Naftalin J.; Nunes N.; Oliver A.; Izzat F.; Bhatia K.; Hassan I.; Jeve Y.; Hamilton J.; Deb S.; Bottomley C.; Ross J.; Watkins L.; *Underwood M.; Cheong Y.; Kumar C.; Gupta P.; Small R.; Pringle S.; Hodge F.; Shahid A.; Horne A.; Quenby S.

Citation:Health Technology Assessment; 2021; vol. 25 (no. 68), p. 1-114

Abstract:Background Miscarriage is the most common complication of pregnancy. As many as 15-25% of pregnancies end in a miscarriage, and the number of miscarriages in England is estimated to be approximately 125,000 per year. Management of miscarriage can be expectant (i.e. waiting for natural miscarriage), medical (i.e. with drugs) or surgical. About 25% of women opt for medical management; however, there is uncertainty about the optimal drug regimens for medical management. Before National Institute for Health and Care Excellence (NICE) guideline CG154 was published in 2012, it was common practice to use a combination of mifepristone (Mifegyne, Exelgyn, Paris, France) and misoprostol. The 2012 guideline, however, recommended that misoprostol alone should be given to women having medical management. This recommendation was based on very limited evidence, from one study of 115 women, which found no difference between a combination of mifepristone and misoprostol and misoprostol alone. Recognising the limited available evidence, NICE and the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) called for a trial. Objectives The primary objective was to test the hypothesis that treatment with mifepristone plus misoprostol is superior to treatment with misoprostol alone for the resolution of miscarriage within 7 days in women diagnosed by pelvic ultrasound scan with a missed miscarriage in the first 14 weeks of pregnancy. The key secondary objective aimed to test the hypothesis that the addition of mifepristone reduces the need for surgical intervention to resolve the miscarriage. Other secondary objectives aimed to evaluate if the addition of mifepristone reduces the need for further doses of misoprostol, to evaluate if the addition of mifepristone improves other clinical outcomes [including surgical intervention up to and including 7 days post randomisation and after 7 days post randomisation, duration of bleeding, infection, negative pregnancy test at 21 days post randomisation, time from randomisation to discharge from early pregnancy unit (EPU) care, side effects and complications], to evaluate if the addition of mifepristone improves patient satisfaction and acceptability of management and to assess the cost-effectiveness of the combination of mifepristone and misoprostol in the medical management of missed miscarriage. Methods Participants were randomised online in a 1: 1 ratio via a secure internet facility through an Integrated Trial Management System. Minimisation was implemented for maternal age (< 30 or >= 30 years), body mass index (< 35 or >= 35 kg/m2), previous parity (nulliparous or parous women), gestational age (< 70 or >= 70 days), amount of bleeding (Pictorial Blood loss Assessment Chart score; <= 2 or >= 3) and randomising centre. Clinical data were collected up to discharge from EPU care. Participants who agreed to participate in the qualitative study were interviewed by telephone or videoconference or face to face within approximately 6 weeks of their discharge date. The primary analysis was by intention to treat. A withintrial cost-effectiveness study and a nested qualitative study were also conducted as part of the trial. Results A total of 711 women, from 28 hospitals in the UK, received either mifepristone plus misoprostol (357 women) or placebo plus misoprostol (354 women). The follow-up rate for the primary outcome was 98% (696 of 711 women). The risk of failure to pass the gestational sac within 7 days was 17% (59 of 348 women) in the mifepristone plus misoprostol group, compared with 24% (82 out of 348 women) in the placebo plus misoprostol group [risk ratio (RR) 0.73, 95% confidence interval (CI) 0.54 to 0.98; p = 0.04]. Surgical intervention to resolve the miscarriage was needed in 17% (62 out of 355 women) in the mifepristone plus misoprostol group, compared with 25% (87 out of 353 women) in the placebo plus misoprostol group (RR 0.70, 95% CI 0.52 to 0.94; p = 0.02). There was no evidence of a difference in the incidence of adverse events between the two groups. A total of 42 women, 19 in the mifepristone plus misoprostol group and 23 in the placebo plus misoprostol group, took part in an interview.Women appeared to have a preference for active management of their miscarriage, to help bring a timely resolution to the physical process. Overall, when women experienced care that supported their psychological well-being throughout the care pathway, and information was delivered in a skilled and sensitive manner such that women felt informed and in control, they were more likely to express satisfaction with medical management. The within-trial cost-effectiveness analysis found that the use of mifepristone and misoprostol resulted in an absolute effect difference of 6.6% (95% CI 0.7% to 12.5%). The average cost per woman was lower in the mifepristone and misoprostol (MifeMiso) group than in the placebo and misoprostol group, with a cost saving of 182 (95% CI 26 to 338). Hence the use of mifepristone and misoprostol for the medical management of a missed miscarriage dominated the use of misoprostol alone. The modelbased analysis, that compared the trial intervention with other existing possible interventions for the management of miscarriage not analysed in the trial, showed that the MifeMiso intervention is dominant when compared with expectant management and the current medical management strategy. However, the intervention is a less effective, although less costly, strategy than surgical management. Conclusions Our trial showed that pre-treatment with mifepristone followed by misoprostol resulted in a higher rate of resolution of missed miscarriage than misoprostol treatment alone. Women were largely satisfied with medical management of missed miscarriage and would choose it again.

Link to full-text [open access - no password required]

Altmetrics:

Healing pattern of the cervical stroma following cold coagulation treatment for cervical intraepithelial neoplasia: A case report (2022)

Type of publication:
Journal article

Author(s):
*Papoutsis D; *Williams J; *Underwood M; *Parry-Smith W

Citation:
Oncology letters; 2022 Mar; Vol. 23 (3), pp. 81

Abstract:
Cold coagulation of the cervix for cervical intraepithelial neoplasia (CIN), when compared with cervical excision, has previously demonstrated comparable cure rates and a reduction in the rate of spontaneous preterm birth. In the present report the healing pattern in the cervices of two women after cold coagulation is described. Both women underwent cold coagulation due to CIN3, which was found on pre-treatment cervical punch biopsies. They were followed up after cold coagulation and at 7 and 18 months, respectively, they underwent cervical excision. The histopathological slides from the excised specimen were reviewed, which represents the healed cervix after cold coagulation. A clear boundary of collagenisation was noted in the superficial stroma, which appeared to stop at the junction with the healthy muscular stroma. The collagenised superficial stroma depth, which represents the area that was thermally ablated and has now healed, measured 1.6 and 1.5 mm for the two women, respectively, which is less compared with that typically removed by cervical excision. Observations from these two cases indicate that cold coagulation does not appear to disrupt the deep tissue architecture of the cervix and could therefore explain the reduced levels of adverse obstetric morbidity in patients who underwent cold coagulation ablative treatment of the cervix, which has been previously reported.

Link to full-text [no password required]

Altmetrics:

Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial (2021)

Type of publication:
Randomised controlled trial

Author(s):
Devall A.; Chu J.; Beeson L.; Hardy P.; Cheed V.; Sun Y.; Roberts T.; Ogwulu C.O.; Williams E.; Jones L.; Papadopoulos J.F.; Bender-Atik R.; Brewin J.; Hinshaw K.; Choudhary M.; Ahmed A.; Naftalin J.; Nunes N.; Oliver A.; Izzat F.; Bhatia K.; Hassan I.; Jeve Y.; Hamilton J.; Deb S.; Bottomley C.; Ross J.; Watkins L.; *Underwood M.; Cheong Y.; Kumar C.; Gupta P.; Small R.; Pringle S.; Hodge F.; Shahid A.; Gallos I.; Horne A.; Quenby S.; Coomarasamy A.

Citation:

Health Technology Assessment, November 2021, 25(68) (pp 1-114)

Abstract:
TRIAL DESIGN: A randomised, parallel-group, double-blind, placebo-controlled multicentre study with health economic and nested qualitative studies to determine if mifepristone (Mifegyne, Exelgyn, Paris, France) plus misoprostol is superior to misoprostol alone for the resolution of missed miscarriage. METHOD(S): Women diagnosed with missed miscarriage in the first 14 weeks of pregnancy were randomly assigned (1:1 ratio) to receive 200mg of oral mifepristone or matched placebo, followed by 800mug of misoprostol 2 days later. A web-based randomisation system allocated the women to the two groups, with minimisation for age, body mass index, parity, gestational age, amount of bleeding and randomising centre. The primary outcome was failure to pass the gestational sac within 7 days after randomisation. The prespecified key secondary outcome was requirement for surgery to resolve the miscarriage. A within-trial cost-effectiveness study and a nested qualitative study were also conducted. Women who completed the trial protocol were purposively approached to take part in an interview to explore their satisfaction with and the acceptability of medical management of missed miscarriage. RESULT(S): A total of 711 women, from 28 hospitals in the UK, were randomised to receive either mifepristone plus misoprostol (357 women) or placebo plus misoprostol (354 women). The follow-up rate for the primary outcome was 98% (696 out of 711 women). The risk of failure to pass the gestational sac within 7 days was 17% (59 out of 348 women) in the mifepristone plus misoprostol group, compared with 24% (82 out of 348 women) in the placebo plus misoprostol group (risk ratio 0.73, 95% confidence interval 0.54 to 0.98; p=0.04). Surgical intervention to resolve the miscarriage was needed in 17% (62 out of 355 women) in the mifepristone plus misoprostol group, compared with 25% (87 out of 353 women) in the placebo plus misoprostol group (risk ratio 0.70, 95% confidence interval 0.52 to 0.94; p=0.02). There was no evidence of a difference in the incidence of adverse events between the two groups. A total of 42 women, 19 in the mifepristone plus misoprostol group and 23 in the placebo plus misoprostol group, took part in an interview. Women appeared to have a preference for active management of their miscarriage. Overall, when women experienced care that supported their psychological well-being throughout the care pathway, and information was delivered in a skilled and sensitive manner such that women felt informed and in control, they were more likely to express satisfaction with medical management. The use of mifepristone and misoprostol showed an absolute effect difference of 6.6% (95% confidence interval 0.7% to 12.5%). The average cost per woman was lower in the mifepristone plus misoprostol group, with a cost saving of 182 (95% confidence interval 26 to 338). Therefore, the use of mifepristone and misoprostol for the medical management of a missed miscarriage dominated the use of misoprostol alone. LIMITATIONS: The results from this trial are not generalisable to women diagnosed with incomplete miscarriage and the study does not allow for a comparison with expectant or surgical management of miscarriage. FUTURE WORK: Future work should use existing data to assess and rank the relative clinical effectiveness and safety profiles for all methods of management of miscarriage. CONCLUSION(S): Our trial showed that pre-treatment with mifepristone followed by misoprostol resulted in a higher rate of resolution of missed miscarriage than misoprostol treatment alone. Women were largely satisfied with medical management of missed miscarriage and would choose it again. The mifepristone and misoprostol intervention was shown to be cost-effective in comparison to misoprostol alone.

Link to full-text [Open access - no password required]

Altmetrics:

Myomectomy during cesarean section or non-caesarean myomectomy in reproductive surgery: This is the dilemma. (2021)

Type of publication:
Journal article

Author(s):
Tinelli A.; Nezhat C.H.; Likic-Ladjevic I.; Andjic M.; Tomasevic D.; *Papoutsis D.; Stefanovic R.; Sparic R.

Citation:
Clinical and Experimental Obstetrics and Gynecology. December 2021, 48(6) (pp 1250-1258)

Abstract:
Nowadays it is quite common to encounter pregnants over 35 years with uterine fibroids (UFs), requiring cesarean section (CS). Large UFs may cause severe complications during delivery, as bleeding and hemorrhage, during vaginal or cesarean delivery. Frequently, the caesarean myomectomy (CM) is recommended, but generally obstetricians are reluctant to perform CM, since literature data do not agree on its surgical recommendation. CM is jet particularly controversial, due to increased risk of perioperative hemorrhage and cesarean hysterectomy, and UFs are often left in situ during cesarean section (CS). CM investigations are generally directed to myomectomy associated issues, whereas CS complications without CM are largely underreported. The risks of leaving UF for an interval myomectomy is underestimated and large UFs, left in uterus during CS, might cause significant early and late postoperative complications, even necessitating a relaparotomy and/or a subsequent hysterectomy. CM would be mandatory in some instances, whatever the UF diameter, to avoid further damage or complications. UFs management prior to CS should include a full counselling on pro and cons on the possible consequences of surgical decisioning. To illustrate what was discussed above, authors performed a narrative review with an expert opinion, reporting a case of a 31-year-old woman with a large UF who underwent a CS without myomectomy. Nine hours after CS, puerpera was submitted, for a massive postoperative hemorrhage and hemorrhagic shock, to an emergency relaparotomy with total hysterectomy without salpingo-oophorectomy

Link to full-text [Open access - no password required]

The effect of the measures taken during the coronavirus pandemic on specialty trainees in obstetrics and gynaecology in the United Kingdom: an online questionnaire survey in one region (2022)

Type of publication:
Journal article

Author(s):
Elghobashy M; Stout A; Hatti A; *Smotra G; El-Ghobashy A

Citation:
Journal of Obstetrics and Gynaecology : the journal of the Institute of Obstetrics and Gynaecology, 2022 Jan 12, pp. 1-6 [epub ahead of print]

Abstract:
The coronavirus pandemic (COVID-19) has had unprecedented effects on healthcare delivery. A 34-question online survey was sent to obstetrics and gynaecology trainees within the West Midlands to assess the impact of the pandemic on training, working practices and well-being. 101 responses were received from obstetrics and gynaecology trainees. Trainees reported a significant reduction in both elective and emergency surgeries as well as outpatient clinics. Over one third of respondents felt additional training time may be required following reduction of clinical opportunities. 44% of trainees felt their workload increased significantly. 55% of trainees felt the pandemic had a significant negative impact on their physical and mental well-being. Obstetrics and gynaecology trainees in the West Midlands have adapted to the challenges of the COVID-19 pandemic despite significant impact on their training, working practices and wellbeing. It is important to tailor training to improve trainees' education and combat lost training time during the pandemic. This should be considered for long-term shaping of the obstetrics and gynaecology training pathway.IMPACT STATEMENT What is already known on this subject? Little research is available about the impact of the COVID-19 pandemic on obstetrics and gynaecology trainees. This is the first study of its kind to assess the effect of the pandemic on obstetrics ang gynaecology trainees in the United Kingdom. What do the results of this study add? The results of this study have shown that obstetrics and gynaecology training has been heavily affected during the COVID-19 pandemic. There have been significant impacts on their training, working patterns and physical and mental wellbeing. What are the implications of these findings for clinical practice and/or further research? These findings can be used to mould the obstetrics and gynaecology training pathway based on the feedback given by the trainees during the pandemic. The survey questions can also be utilised as a framework for similar research projects across the United Kingdom Deaneries, among other specialties and around the world.

Intrauterine contraception (2021)

Type of publication:
Journal article

Author(s):
*Ritchie J.; Phelan N.; Briggs P.

Citation:
Obstetrician and Gynaecologist; Jul 2021; vol. 23 (no. 3); p. 187-195

Abstract:
Key content: An intrauterine device (IUD), also known as intrauterine contraceptive device (IUCD) or intrauterine contraception (IUC) offers reliable long-acting reversible contraception; however, some patients can be hesitant to choose this option because of misconceptions about side effects and perceived complications. A comprehensive knowledge of IUC is required to allow adequate counselling and to dispel myths. There are many different methods of IUC, including four different levonorgestrel-containing intrauterine systems (LNG-IUS) and multiple different copper intrauterine devices, with different insertion techniques. Considering contraception is important at several life stages, including post-delivery, post-termination of pregnancy and around the menopause; these will require different counselling. The use of IUC can have noncontraceptive benefits, including relief of heavy menstrual bleeding, management of menopause and premenstrual syndrome and reducing gynaecological cancer risk. Learning objectives: To learn the different types of IUC, including the different indications and possible complications. To understand the noncontraceptive benefits of IUC. To understand the challenges faced when a patient is hesitant to consider IUC

Link to full-text [NHS OpenAthens account required]

A rare case of anti-NMDA receptor encephalitis associated with an ovarian teratoma (2021)

Type of publication:
Conference abstract

Author(s):
*Korrapati S.; *Sahu B.; *Parry-Smith W.

Citation:
BJOG: An International Journal of Obstetrics and Gynaecology; May 2021; vol. 128 ; p. 135

Abstract:
Introduction Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an auto-immune and paraneoplastic encephalitis with an incidence of 1.5 per million population per year. About 80% are women and nearly half of them have an ovarian teratoma. It is associated with antibodies against NR1 or NR2 subunits of NMDA receptor in cerebrospinal fluid (CSF) and serum. Given the rarity of occurrence, it remains an unrecognised entity among gynaecologists. Hence, we report a case of anti-NMDAR encephalitis associated with ovarian teratoma. Case report A 34-year-old woman attended under physicians with confusion, memory loss and agitation. She had a history of bilateral ovarian teratomas removed in 2018. Patient's vitals and neurological examination were normal. She was unable to perform motor tasks. Routine laboratory examinations and CT head were normal except for mild leucocytosis (WCC 13.3). She was empirically treated for infectious encephalitis. CSF examination showed normal glucose and protein, negative for viral PCR, gram staining but positive for NMDA receptor antibodies, prompting us to explore for an underlying tumour. CT abdomen/pelvis showed 9mm focus of fat suspicious of residual/recurrent teratoma in right adnexa. PET CT showed no metabolically active pathology. She was commenced on first line immunotherapy, IV Methylprednisolone followed by IV immunoglobulins and then plasma exchange. Following gynaecology MDT decision, she underwent laparoscopic right oophorectomy. Histopathology revealed a right ovarian teratoma. Postprocedure her neurological symptoms including confusion & memory retention improved considerably. Conclusion Anti-NMDAR encephalitis is rare but potentially debilitating condition. It is important to remove any associated ovarian teratoma promptly to improve outcome.

Link to full-text [no password required]

A case of antepartum haemorrhage at 18 weeks gestation leading to DIC (2021)

Type of publication:
Journal article

Author(s):
*Barker V.; *Biswas N.; Brett-Miller C.

Citation:
BJOG: An International Journal of Obstetrics and Gynaecology; Jun 2021; vol. 128 ; p. 77

Abstract:
Objective A rare case of vaginal bleeding before 20 weeks' gestation with a 1.2 L blood loss leading to
Disseminated Intravascular Coagulation. Follow up of the case at 25 weeks gestation revealed an ongoing pregnancy with resolution of clotting function. Case report A 33 year old patient who had previously had six normal vaginal deliveries attended labour ward at 18 + 6 weeks gestation with pain, a sensation of pressure and a small amount of brown PV loss. She previously had a small bleed at 15 weeks' gestation when a subchorionic bleed was demonstrated on scan. Thirty minutes after arrival she started to bleed very heavily and within forty minutes had lost more than 1 litre of fresh blood. On examination she had a closed cervix with active ongoing bleeding. A bedside ultrasound scan revealed a viable pregnancy. Tranexamic acid 1 g was given intravenously. Clotting function on admission was markedly deranged; INR 2.4, prothrombin time 23.5, activated partial thromboplastin time 56, fibrinogen < 0.3 and D-Dimer 2157. Disseminated intravascular coagulation was diagnosed. Following discussion with the haematology consultant, she received two units of cryoprecipitate. The bleeding subsequently settled with total loss of 1.2 litres. She had further blood tests which showed normalisation of clotting function within 24 h. Departmental ultrasound scan showed no evidence of bleeding on scan but placenta was noted to extend to the cervix. Follow up at 25 weeks showed an ongoing pregnancy with no further bleeding. Discussion Disseminated Intravascular Coagulation is a rare complication of pregnancy and can be associated with a number of obstetric disorders including placental abruption and praevia, amniotic fluid embolism, intrauterine fetal demise, HELLP syndrome, preeclampsia/eclampsia, septic abortion, intrauterine infection, PPH and acute fatty liver of pregnancy. It can occur at any time in pregnancy but most commonly occurs in the 3rd trimester. DIC can be diagnosed using the International Society on Thrombosis and Haemostasis DIC Diagnostic Criteria. The classic picture is a prolonged prothrombin time and activated partial thromboplastin time, low platelets, low fibrinogen and elevated D-dimer test. Management involves addressing the obstetric cause and supportive therapy. Conclusion DIC occurs secondary to a trigger which stimulates the release of procoagulant substances resulting in activation of the clotting pathway. The hypercoagulable state in pregnancy increases the vulnerability of pregnant women. This is a rare case of rapid onset DIC in the second trimester with an ongoing pregnancy.

Link to full-text [no password required]

Appendicitis with concurrent COVID-19 infection in a patient during the third trimester of pregnancy (2021)

Type of publication:
Journal article

Author(s):
*Sanders-Davis L.J.; *Ritchie J.

Citation:
BMJ Case Reports; Jun 2021; vol. 14 (no. 6)

Abstract:
This article presents an unusual case of appendicitis in pregnancy complicated by the novel coronavirus (SARS-CoV-2). The novel coronavirus has affected the way medicine is practised across most parts of the world with over 160 000 000 global cases to date. Tackling management of these cases is more complex when other pathological processes are ongoing. Appendicitis is a common occurrence in pregnancy, with most obstetric centres seeing about one or two cases a year. Though maternal morbidity and mortality are relatively unimpacted by this event, fetal loss and preterm labour are common sequelae. This case involves a 35-year-old woman presenting in her third trimester with abdominal pain and who went on to be diagnosed with concurrent appendicitis and SARS-CoV-2 infection. Although spinal anaesthesia would be most appropriate as it avoids aerosol generation, general anaesthetic techniques were indicated due to thrombocytopenia in this case. She underwent a successful appendicectomy, although preterm delivery was indicated as a result of maternal and fetal concerns.

Link to full-text [no password required]

Urinary symptoms in pregnant women in their third trimester-a cross-sectional study (2021)

Type of publication:
Journal article

Author(s):
Soundararajan K.; *Panikkar M.; Annappa M.

Citation:
International Urogynecology Journal; Jul 2021; vol. 32 (no. 7); p. 1867-1873

Abstract:
Introduction and hypothesis: Urinary symptoms are common in pregnancy. Our study aims to understand the extent of these symptoms in a cohort of pregnant women in the third trimester and their impact on quality of life (QOL) from the women's perspective. Method(s): A single-centre cross-sectional study of self-reported urinary symptoms of pregnant women in the third trimester conducted from August 2018 at the Diana Princess of Wales Hospital, Northern Lincolnshire, and Goole NHS Foundation Trust, Grimsby, UK. We used an international validated questionnaire (ICIQ-FLUTS questionnaire) (Brookes et al. Am J Obstet Gynecol. 191(1):73-82, 2004). Result(s): A total of 302 women were included in this study. Nocturia was the most common symptom, reported by 97%, affecting QOL in 80%. Urgency of micturition was the second most common, present in 83%, adversely affecting QOL in 75%. Our study showed a startling finding of bladder pain in 47% (95% CI 41.1%, 52.3%) of these women. There was a high prevalence of nocturnal enuresis in 9.9% (95% CI 7.05%, 13.8%). Straining during micturition is not a well-known symptom in pregnancy, however reported by 18.2% (95% CI 14.2%, 23.0%). Conclusion(s): The high prevalences of bladder pain, nocturnal enuresis and straining in the third trimester of pregnancy are novel findings. Our study also confirms that the prevalence of all voiding, filling and incontinence symptoms in pregnancy is significantly higher than in the non-pregnant population, having a negative impact on QOL, and yet is not discussed as part of routine antenatal care.

Altmetrics: