1.
Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT
Coomarasamy A, Harb HM, Devall AJ, Cheed V, Roberts TE, Goranitis I, Ogwulu CB, Williams HM, Gallos ID, Eapen A, et al
Health Technol Assess. 2020;24(33):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. OBJECTIVES (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 400 mg 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. RESULTS 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 (pound7655 vs. pound7572), with a mean cost difference of pound83 (adjusted mean difference pound76, 95% confidence interval - pound559 to pound711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as pound3305 per additional live birth at ≥ 34 weeks of gestation. CONCLUSIONS 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. Miscarriage is a common complication of pregnancy that affects one in five pregnancies. Several small studies have suggested that progesterone, a hormone essential for maintaining a pregnancy, may reduce the risk of miscarriage in women presenting with early pregnancy bleeding. This research was undertaken to test whether or not progesterone given to pregnant women with early pregnancy bleeding would increase the number of live births when compared with placebo (dummy treatment). The women participating in the study had an equal chance of receiving progesterone or placebo, as determined by a computer; one group received progesterone (400 mg twice daily as vaginal pessaries) and the other group received placebo with an identical appearance. Treatment began when women presented with vaginal bleeding, were < 12 weeks of gestation and were found to have at least a pregnancy sac on an ultrasound scan. Treatment was stopped at 16 weeks of gestation, or earlier if the pregnancy ended before 16 weeks. Neither the participants nor their health-care professionals knew which treatment was being received. In total, 23,775 women were screened and 4153 women were randomised to receive either progesterone or placebo pessaries. Altogether, 2972 participants had a live birth after at least 34 weeks of gestation. Overall, the live birth rate in the progesterone group was 75% (1513 out of 2025 participants), compared with 72% (1459 out of 2013 participants) in the placebo group. Although the live birth rate was 3% higher in the progesterone group than in the placebo group, there was statistical uncertainty about this finding. However, it was observed that women with a history of one or more previous miscarriages and vaginal bleeding in their current pregnancy may benefit from progesterone. For women with no previous miscarriages, our analysis showed that the live birth rate was 74% (824 out of 1111 participants) in the progesterone group compared with 75% (840 out of 1127 participants) in the placebo group. For women with one or more previous miscarriages, the live birth rate was 75% (689 out of 914 participants) in the progesterone group compared with 70% (619 out of 886 participants) in the placebo group. The potential benefit appeared to be most strong for women with three or more previous miscarriages, who had a live birth rate of 72% (98 out of 137 participants) in the progesterone group compared with 57% (85 out of 148 participants) in the placebo group. Treatment with progesterone did not appear to have any negative effects. eng
2.
A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy
Coomarasamy A, Devall AJ, Cheed V, Harb H, Middleton LJ, Gallos ID, Williams H, Eapen AK, Roberts T, Ogwulu CC, et al
The New England journal of medicine. 2019;380(19):1815-1824
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.).
3.
Blood loss after intraarticular and intravenous tranexamic acid in total knee arthroplasty
Ahmed S, Ahmed A, Ahmad S, Javed S, Aziz A
Jpma. The Journal of the Pakistan Medical Association. 2018;68((10)):1434-1437.
Abstract
OBJECTIVE To compare postoperative blood loss after intravenous and intraarticular tranexamic acid injection in patients of bilateral total knee arthroplasty. METHODS This comparative randomised study was conducted at Ghurki Trust Teaching Hospital, Lahore, between July 2015 and January 2016, and comprised all patients admitted for bilateral total knee replacement. Patients were randomly divided into two equal groups. Group-A received intraarticular while Group-B received intravenous injection of 1.5 gmtranexamic acid. All data was analysed using SPSS 17. RESULTS The total 140 patients were divided into two equal groups of 70(50%) each. In Group-A there were 32(45.7%) males and 38(54.3%) females, while in Group-B, there were 28(40%) males and 42(60%) females. The mean ages were 64.39+/-9.07 years in Group-A and 63.30+/-9.51 years in Group B. Blood loss in Group-A was significantly lower than Group-B (p=0.01).. CONCLUSIONS Intraarticular administration of tranexamic acid was more effective than intravenous administration in terms of reducing blood loss.
4.
Chronic anemia and fatigue in elderly patients: results of the first randomized double-blind placebo-controlled cross-over study with epoetin alfa
Agnihotri P, Ahuja M, Telfer MC, Ahmed A, Kozma CM, Cella D, Butt Z
Blood. 2005;106((11):):991-2.. Abstract No. 3553.
5.
Effect of aprotinin on plasma fibronectin levels during cardiopulmonary bypass
al Khudhairi DM, Nadeem F, Zuleika AM, Hussain A, Ahmed A, el Sharkawy M
Annals of Thoracic Surgery. 1997;63((1):):64-7.
Abstract
BACKGROUND Acute depletion of plasma fibronectin levels has been reported during and after cardiopulmonary bypass; degradation of fibronectin by proteolytic enzymes has been suggested as one of the causes. This study was designed to assess the possible preservation of fibronectin levels by aprotinin during cardiopulmonary bypass. METHODS Plasma fibronectin levels were evaluated in 19 patients undergoing either elective coronary artery bypass grafting or a valvular heart operation. The study was conducted prospectively in a controlled, randomized, double-blinded manner. Nine test patients (group A) received intraoperative, intravenous administration of aprotinin; 10 control patients (group B) received equivalent volume of normal saline solution. Fibronectin levels were measured immediately after induction of anesthesia (as the baseline for the study) and at the following times: after 5 minutes on bypass, after 30 minutes on bypass, immediately before the start of rewarming, and after being off bypass for 5 minutes, but before protamine administration. RESULTS Both groups' basic characteristics were very similar. Group A patients were found to have significantly greater fibronectin levels than group B during and immediately after cardiopulmonary bypass (p < 0.002). CONCLUSIONS Administration of aprotinin intraoperatively appears to result in better preservation of fibronectin levels during cardiopulmonary bypass. Although the mechanism of action of aprotinin as a proteolytic inhibitor remains unclear, it has been suggested that it exerts an inhibiting effect on proteolytic enzymes by forming an aprotinin-proteinase complex. The clinical implications of the greater level of fibronectin achieved by the intraoperative use of aprotinin during cardiopulmonary bypass need further evaluation.