Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT (2020)

Type of publication:
Randomised controlled trial

Author(s):
Coomarasamy A.; Harb H.M.; Devall A.J.; Williams H.M.; Gallos I.D.; Ewer A.; Cheed V.; Roberts T.E.; Ogwulu C.B.; Middleton L.J.; Goranitis I.; Eapen A.; Daniels J.P.; Ahmed A.; Hinshaw K.; Bender-Atik R.; Bhatia K.; Bottomley C.; Kriedt K.; Jurkovic D.; Brewin J.; Choudhary M.; Crosfill F.; Deb S.; Duncan W.C.; Norman J.E.; Horne A.W.; Holland T.; Izzat F.; Johns J.; Ross J.; Lumsden M.-A.; Manda P.; Nunes N.; Overton C.E.; Quenby S.; Rao S.; Shahid A.; *Underwood M. ; Vaithilingham N.; Watkins L.; Wykes C.

Citation:
Health Technology Assessment (Winchester, England); Jun 2020; vol. 24 (no. 33); p. 1-70

Abstract:
BACKGROUND: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage. OBJECTIVE(S): (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding. DESIGN: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding. SETTING: A total of 48 hospitals in the UK. PARTICIPANTS: Women aged 16-39 years with early pregnancy bleeding. INTERVENTIONS: Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. MAIN OUTCOME MEASURES: The primary outcome was live birth at >=34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective. RESULT(S): A total of 4153 women from 48 hospitals in the UK received either progesterone (n=2079) or placebo (n=2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p=0.08). A significant subgroup effect (interaction test p=0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p=0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p=0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p=0.004). A significant post hoc subgroup effect (interaction test p=0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p=0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (7655 vs. 7572), with a mean cost difference of 83 (adjusted mean difference 76, 95% confidence interval -559 to 711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as 3305 per additional live birth at >=34 weeks of gestation. CONCLUSION(S): Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at >=34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets. TRIAL REGISTRATION: Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.

Link to full-text [no password required]

Altmetrics:

Reflective doctors and cool babies (2019)

Type of publication:
Conference abstract

Author(s):
*Charlesworth D.; Cunningham S.; Dudley L.; Bentley F.; Oguntimehin J.; Fairclough S.

Citation:
BJOG: An International Journal of Obstetrics and Gynaecology; Jun 2019; vol. 126 ; p. 45

Abstract:
Introduction In 2014, the RCOG launched the ‘Each Baby Counts’ initiative which included the aim of reducing the number of neonates who are left severely disabled by preventable incidents in labour. The initial report concluded that a different outcome may have been achieved in 76% of cases if different care had been received. Around the same time, reflective practice among doctors faced a significant challenge secondary to negative perceptions of its use in litigation, and resilience continued to be tested as work pressures, insufficient staff numbers, and public perceptions continued to increase. With the interplay between all these factors being crucial in achieving the state of experiential learning necessary to achieve the EBC goals, we look at a different method for reflective practice and quality improvement. Methods In 2015, we launched a series of measures inspired by EBC to reduce our rates of neonates requiring therapeutic hypothermia. One key component of our programme was a change in how our RCAs were undertaken. We changed RCA leads to include staff at all levels from across the multidisciplinary team, promoted a reflective journey and thematic analysis, changed our meetings to include staff recommended by the EBC report to achieve a more multidisciplinary and inclusive representation, promoted team learning, and fed back via casebased, reflective teaching. We then undertook a 48-month retrospective audit from 01/2015 to 12/2018 to see if we had improved care. Results In 2015, our therapeutic hypothermia annual incidence was 12, 11 in 2016, 7 in 2017, and 2 by 12/2018. Thematic analysis of our cases revealed a change in precipitating factors from preventable to unpredictable, and we subsequently increased the proportion of cases in which we concluded we could not improve the end outcome (though learning was identified in all). Staff empowerment increased, hierarchies flattened, and our ability to identify key targeted improvements increased to facilitate change and drive improvement. Conclusion We discovered that, if conducted well, with reflection as a key component, and the aim to promote a culture of learning and becoming, RCA can be used as a powerful teaching tool in training, and to promote improved patient care. As more staff engaged in our new RCA process, feedback indicated an increase in resilience and a more open culture of learning, unhindered by more traditional elements of reflective learning.

Link to full-text [NHS OpenAthens account required]

A national survey on the uterotonic use for the prevention of postpartum haemorrhage (2019)

Type of publication:
Conference abstract

Author(s):
*Stephanou M.; Gallos I.; Coomarasamy A.

Citation:
BJOG: An International Journal of Obstetrics and Gynaecology; Jun 2019; vol. 126 ; p. 148-149

Abstract:
Objective: To map the current national practice of the first line uterotonic drug given for the prevention of
postpartum haemorrhage (PPH) at both vaginal and caesarean section deliveries. Design A prospective national survey was carried out by contacting maternity units by means of telephone contact. Survey questions were set out to evaluate the uterotonic drug of choice in accordance with local hospital policy which was then compared with national guidance.
Methods: Maternity units across England were identified using the NHS Maternity Statistics 2016-2017 data available from NHS Digital. 136 NHS trusts were identified and 143 maternity units were contacted. Responses were collected by means of telephone communication with each of the maternity units. Maternity governance leads were the first point of contact followed by labour ward coordinators and senior labour ward doctors. The Health Research Authority Ethics toolkit was applied and determined that Research and Ethics council approval was not required.
Results: All 143 maternity units identified were contacted to answer the survey. 118 (82.5%) responses were obtained for the uterotonic of choice used for the prevention of postpartum haemorrhage at vaginal birth, of which 75 (63.5%) maternity units administered oxytocin with ergometrine combination as the first-line uterotonic. 116 (81%) responses were collected for the uterotonic of choice at caesarean section, where 95 (81.9%) administered intravenous oxytocin as first line.
Conclusion: The National Institute of Clinical Excellence (NICE) and World Health Organization (WHO)
guidelines recommend oxytocin as the first-line uterotonic of choice for the prevention of postpartum
haemorrhage. This survey has shown that current UK practice conflicts with both international and national guidance, favouring oxytocin with ergometrine over oxytocin alone at vaginal birth. Postpartum haemorrhage is a significant cause of morbidity and mortality; it is recommended that further attention be paid towards the first line uterotonic agent used for the prevention of a PPH in line with the most current up to date evidence.

Link to full-text [NHS OpenAthens account required]

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy (2019)

Type of publication:
Randomised controlled trial

Author(s):
A. Coomarasamy, A.J. Devall, V. Cheed, H. Harb, L.J. Middleton, I.D. Gallos, H. Williams, A.K. Eapen, T. Roberts, C.C. Ogwulu, I. Goranitis, J.P. Daniels, A. Ahmed, R. Bender‑Atik, K. Bhatia, C. Bottomley, J. Brewin, M. Choudhary, F. Crosfill, S. Deb, W.C. Duncan, A. Ewer, K. Hinshaw, T. Holland, F. Izzat, J. Johns, K. Kriedt, M.-A. Lumsden, P. Manda, J.E. Norman, N. Nunes, C.E. Overton, S. Quenby, S. Rao, J. Ross, A. Shahid, *M. Underwood , N. Vaithilingam, L. Watkins, C. Wykes, A. Horne, and D. Jurkovic

Citation:
New England Journal of Medicine 2019;380:p.1815-24.

Abstract:
BACKGROUND
Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy.
METHODS
We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data.
RESULTS
A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P=0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P=0.08). The incidence of adverse events did not differ significantly between the groups.
CONCLUSIONS
Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.)

Altmetrics

Early and late pregnancy outcomes in women treated with cold-coagulation versus LLETZ cervical treatment for cervical intraepithelial neoplasia; a retrospective cohort study (2018)

Type of publication:
Journal article

Author(s):
*Papoutsis, Dimitrios; *Underwood, Martyn ; *Parry-Smith, William; *Panikkar, Jane

Citation:
Archives of Gynecology and Obstetrics; Apr 2018; Vol.297(4):1015-1025

Abstract:
PURPOSE To compare the pregnancy outcomes between women who were treated with cold-coagulation versus large loop excision of the transformation zone (LLETZ) for cervical intraepithelial neoplasia. METHODS This was a retrospective cohort study of women who had a single cervical treatment between 2010 and 2011. We identified those women who had a singleton pregnancy subsequent to their cervical treatment until September 2017. Women with previous cervical treatment, previous miscarriage or preterm delivery were excluded. RESULTSWe identified 86 women with a pregnancy after LLETZ treatment and 75 women after cold coagulation. Those who had LLETZ when compared to cold coagulation miscarried more often in the first trimester (33.7 vs 17.3%; p = 0.01) than in the second trimester. In women with LLETZ this effect of increased early miscarriage was shown to be prolonged and to persist up to 17 months after excision. Women with LLETZ when compared to cold coagulation had higher spontaneous preterm birth rates (8.9 vs 6.7%) even though the difference was non significant, with the earliest spontaneous preterm birth occurring at 32 weeks and 34 weeks, respectively. CONCLUSION We found that women who received LLETZ treatment when compared to cold coagulation had higher spontaneous preterm birth rates in their subsequent pregnancy and miscarried more frequently in the first trimester, and demonstrated an increased early miscarriage risk that persisted for more than a year after excisional treatment.

Altmetrics

Does gestational weight gain of more than 12 kg in women increase the risk of a cesarean section delivery, gestational diabetes and pregnancy induced hypertension? A retrospective case series (2017)

Type of publication:
Journal article

Author(s):
Antonakou A.; *Papoutsis D.; Kechagia A.

Citation:
Clinical and Experimental Obstetrics and Gynecology; 2017; vol. 44 (no. 4); p. 540-544

Abstract:
Purpose: The purpose of this study was to investigate whether the gestational weight gain of more than 12 kg represented a risk factor for an increased rate of cesarean section (CS) delivery, gestational diabetes, and pregnancy-induced hypertension (PIH). Materials and Methods: This was a retrospective case series study performed in a Greek National Health Service hospital and included women having given birth to singleton pregnancies between 2004-2009. Cases with multiple pregnancies, stillbirths, and congenital fetal abnormalities were excluded. Results: 600 eligible women were included in the study. Gestational weight increase correlated positively and was higher in women with a CS delivery, gestational diabetes, and PIH. The prepregnancy body mass index was identified as a predictor of gestational diabetes. The weight gain of less than 12 kg during pregnancy provided a protective effect against CS delivery by reducing the likelihood of this by 85%. Conclusion: The present authors have shown that the increased body weight gain during pregnancy of more than 12 kg is associated with increased rates of CS delivery, gestational diabetes, and hypertensive disorders in pregnancy.

An unusual cause of fetomaternal distress at term: uterine vessel rupture in pregnancy (2015)

Type of publication:
Journal article

Author(s):
Calcott G.A., Gaber M., Freedman J., Patni S.

Citation:
BMJ Case Reports, August 2015, vol./is. 2015

Abstract:
This report describes a case of spontaneous bleeding from uterine vessels presenting as hyperstimulation and fetomaternal distress at term. A 40-week primigravid woman underwent an emergency caesarean section for fetal distress, which unexpectedly revealed a spontaneous haemoperitoneum. Clinical assessment and investigations postoperatively gave a diagnosis of a rightsided uterine artery aneurysm that, it was believed, had ruptured, causing the haemoperitoneum. This was successfully treated postnatally using interventional radiological techniques leading to expeditious maternal recovery and discharge home.

Link to full-text: http://casereports.bmj.com/content/2015/bcr-2014-209004.full.pdf

Thrombolysis for stroke in pregnancy at 39 weeks gestation with a subsequent normal delivery (2015)

Type of publication:
Journal article

Author(s):
*Ritchie J., *Lokman M., *Panikkar J.

Citation:
BMJ Case Reports, August 2015, vol./is. 2015

Abstract:
Stroke during pregnancy is fortunately a rare event, however, it can have severe consequences, with 9.5% of all maternal deaths being related to stroke. The most common presentation is an ischaemic stroke. There has been much debate as to the correct treatment for such cases’ and whether thrombolysis can be used safely in pregnancy. Our case describes a 28-year-old woman with a previous normal vaginal delivery presenting in her third trimester with a sudden onset of dense left hemiparesis. She was successfully treated with alteplase, an intravenous recombinant tissue-type plasminogen activator, and made a full recovery after normal delivery of a healthy infant. This case report highlights one of the first documented successful outcomes from thrombolysis for this condition in the UK and may help inform future management of these women.

Link to full-text: http://casereports.bmj.com/content/2015/bcr-2015-209563.full.pdf

Postpartum posterior reversible encephalopathy syndrome (PRES) in a twin pregnancy complicated by preeclampsia-eclampsia: Case report (2014)

Type of publication:
Journal article

Author(s):
*Papoutsis D., *El-Attabi N., *Sizer A.

Citation:
Clinical and Experimental Obstetrics and Gynecology, 2014, vol./is. 41/3(351-353), 0390-6663 (2014)

Abstract:
This is the second case in literature of posterior reversible encephalopathy syndrome (PRES) in a twin pregnancy complicated by preeclampsia-eclampsia. A 27-year-old primigravida with dichorionic diamniotic twin pregnancy was admitted at 36 weeks of gestation for induction of labour due to preeclampsia. On the second day postpartum, the patient developed severe hypertension, visual symptoms, confusion, headache, and eclamptic fits. Head computed tomography (CT) showed hypodense basal ganglia lesions. The patient was treated in the intensive treatment unit with hydralazine and labetalol infusions and anticonvulsants. Five days later, there was complete clinical improvement and follow-up magnetic resonance imaging (MRI) was normal. The patient was discharged 11 days post-delivery. Diagnosis of PRES is based on the presence of clinical features of acute neurologic compromise, abnormal neuroimaging findings, and complete reversibility of findings after prompt treatment. Early recognition and proper treatment result in complete reversibility of this condition.