Methotrexate vs expectant management for treatment of tubal ectopic pregnancy: An individual participant data meta-analysis.

INTRODUCTION: Ectopic pregnancy is an important health condition which affects up to 1 in 100 women. Women who present with mild symptoms and low serum human chorionic gonadotrophin (hCG) are often treated with methotrexate (MTX), but expectant management with close monitoring is a feasible alternative. Studies comparing the two treatments have not shown a statistically significant difference in uneventful resolution of ectopic pregnancy, but these studies were too small to define whether certain subgroups could benefit more from either treatment. MATERIAL AND METHODS: We performed a systematic review and individual participant data meta-analysis (IPD-MA) of randomized controlled trials comparing systemic MTX and expectant management in women with tubal ectopic pregnancy and low hCG (<2000 IU/L). A one-stage IPD-MA was performed to assess overall treatment effects of MTX and expectant management to generate a pooled intervention effect. Subgroup analyses and exploratory multivariable analyses were undertaken according to baseline serum hCG and progesterone levels. Primary outcome was treatment success, defined as resolution of clinical symptoms and decline in level of serum hCG to <20 IU/L, or a negative urine pregnancy test by the initial intervention strategy, without any additional treatment. Secondary outcomes were need for blood transfusion, surgical intervention, additional MTX side-effects and hCG resolution times. TRIAL REGISTRATION NUMBER: PROSPERO: CRD42021214093. RESULTS: 1547 studies reviewed and 821 remained after duplicates removed. Five studies screened for eligibility and three IPD requested. Two randomized controlled trials supplied IPD, leading to 153 participants for analysis. Treatment success rate was 65/82 (79.3%) after MTX and 48/70 (68.6%) after expectant management (IPD risk ratio [RR] 1.16, 95% confidence interval [CI] 0.95-1.40). Surgical intervention rates were not significantly different: 8/82 (9.8%) vs 13/70 (18.6%) (RR 0.65, 95% CI 0.23-1.14). Mean time to success was 19.7 days (95% CI 17.4-22.3) after MTX and 21.2 days (95% CI 17.8-25.2) after expectant management (P = 0.25). MTX specific side-effects were reported in 33 MTX compared to four in the expectant group. CONCLUSIONS: Our IPD-MA showed no statistically significant difference in treatment efficacy between MTX and expectant management in women with tubal ectopic pregnancy with low hCG. Initial expectant management could be the preferred strategy due to fewer side-effects.

The "lived" experience of menstruating women commencing anticoagulants.

Background: Although there is increased recognition that many menstruating women commenced on anticoagulants experience heavy menstrual bleeding, little research has been published describing what women go through and actually experience. Objectives: The aim of this study was to understand the "lived" experience of menstruating women commencing anticoagulants. Methods: We undertook a qualitative study using semistructured interviews. Women who had taken part in the parent PERIOD study and expressed an interest in an in-depth interview were recruited. Interviews were conducted online, and transcripts were generated through MS Teams. Data were analyzed using thematic analysis. Ethics committee approval: REC reference: 19/SW/0211. Results: A total of 15 participants were interviewed. The median age of the participants was 36 years (range, 20-49 years). The following 7 primary themes emerged from the interviews: (1) information received when commencing anticoagulation, (2) mood, (3) strategies used to manage heavy bleeding, (4) social/family life, (5) work life, (6) finances, and (7) multiple health issues-with saturation of themes achieved following 9 interviews. Women affected by heavy menstrual bleeding experienced a negative change in their work/social life and mood. Conclusion: Heavy menstrual bleeding experienced by women commencing anticoagulants has a significant impact on their lives. Recognized measures should be employed to support and minimize the problem for menstruating people.

How do anticoagulants impact menstrual bleeding and quality of life? - The PERIOD study.

Background: There is increasing recognition that menstruating women prescribed anticoagulants experience heavy menstrual bleeding. Objectives: The aim of this study is to report the extent of bleeding in menstruating women after commencing anticoagulants and the impact it has on their quality of life. Methods: Women aged 18 to 50, initiated on anticoagulant therapy, were approached to take part in the study. In parallel, a control group of women was also recruited. Women were asked to complete the menstrual bleeding questionnaire and a pictorial blood assessment chart (PBAC) during their next 2 menstrual cycles. Differences between the control and anticoagulated group were compared. Significance was considered at < .05. Ethics committee approval: REC reference: 19/SW/0211. Results: Fifty-seven women in the anticoagulation and 109 women in the control group returned their questionnaires. Women in the anticoagulated group reported an increase in the median length of their menstrual cycle from 5 to 6 days after commencing anticoagulation, compared to 5 days for women in the control group (P < .05). Anticoagulated women reported significantly higher PBAC scores as compared to the control group (P < .05), with two-thirds of women in the anticoagulation group reporting heavy menstrual bleeding. Women in the anticoagulation group reported worsening quality of life scores following the initiation of anticoagulation, compared with women in the control group (P < .05). Conclusion: Heavy menstrual bleeding occurred in two-thirds of women commencing anticoagulants, who completed a PBAC, which had negative impact on their quality of life. Clinicians commencing anticoagulation therapy should be mindful of this, and recognized measures should be taken to help minimize this problem for menstruating individuals.

The role of ultrasound imaging in the management of partial placental retention after third trimester livebirth.

OBJECTIVES: To evaluate the impact of different ultrasound signs in the management and the role of ultrasound guidance in the surgical evacuation of partial placental tissue retention. METHODS: This is an observational cohort study and retrospective case assessment of 82 patients with clinical symptoms of partial placental retention following a third trimester singleton livebirth between January 2013 and May 2019. The ultrasound signs were recorded using a standardized protocol and the outcome of the management strategy and the use of ultrasound guidance during any surgical procedure was evaluated. RESULTS: Out of the 64 patients who had a vaginal birth, 25 (39.1%) had a manual removal of the placenta at delivery. Fifteen patients were confirmed as not having retained placental tissue and did not require further treatment. Four patients were referred after failed surgical management and four after failed conservative management. All surgical procedures were vacuum aspiration and forceps removal under continuous ultrasound guidance. A significantly lower gestational age at delivery (p < .05), shorter interval between delivery and ultrasound diagnosis (p < .05) and lower number of patients presenting with heavy bleeding was found in the conservative compared to the surgical management subgroups (p < .05). The incidence of feeding vessels was significantly (p < .05) higher in the surgical than in the conservative management subgroups and associated with increased myometrial vascularity. Six patients developed intra-uterine adhesions. In four of these cases, ultrasound examination showed a hyperechoic mass surrounded by normal myometrial vascularity and no feeding vessel. CONCLUSIONS: Ultrasound imaging accurately differentiated between patient with and without partial placental retention after third trimester livebirth. Ultrasound-guided vacuum aspiration is safe and efficient in these cases.

Development of the utero-placental circulation in cesarean scar pregnancies: a case-control study.

BACKGROUND: Cesarean scar pregnancies carry a high risk of pregnancy complications including placenta previa with antepartum hemorrhage, placenta accreta spectrum, and uterine rupture. OBJECTIVE: To evaluate the development of utero-placental circulation in the first half of pregnancy in ongoing cesarean scar pregnancies and compare it with pregnancies implanted in the lower uterine segment above a previous cesarean delivery scar with no evidence of placenta accreta spectrum at delivery STUDY DESIGN: This was a retrospective case-control study conducted in 2 tertiary referral centers. The study group included 27 women who were diagnosed with a live cesarean scar pregnancy in the first trimester of pregnancy and who elected to conservative management. The control group included 27 women diagnosed with an anterior low-lying placenta or placenta previa at 19 to 22 weeks of gestation who had first and early second trimester ultrasound examinations. In both groups, the first ultrasound examination was carried out at 6 to 10 weeks to establish the pregnancy location, viability, and to confirm the gestational age. The utero-placental and intraplacental vasculatures were examined using color Doppler imaging and were described semiquantitatively using a score of 1 to 4. The remaining myometrial thickness was recorded in the study group, whereas the ultrasound features of a previous cesarean delivery scar including the presence of a niche were noted in the controls. Both the cesarean scar pregnancies and the controls had ultrasound examinations at 11 to 14 and 19 to 22 weeks of gestation. RESULTS: The mean color Doppler imaging vascularity score in the ultrasound examination at 6 to 10 weeks was significantly (P<.001) higher in the cesarean scar pregnancy group than in the controls. High vascularity scores of 3 and 4 were recorded in 20 of 27 (74%) cases of the cesarean scar pregnancy group. There was no vascularity score of 4, and only 3 of 27 (11%) controls had a vascularity score of 3. In 15 of the 27 (55.6%) cesarean scar pregnancies, the residual myometrial thickness was <2 mm. In the ultrasound examination at 11 to 14 weeks, there was no significant difference between the groups in the number of cases with an increased subplacental vascularity. However, 12 cesarean scar pregnancies (44%) presented with 1 or more placental lacunae whereas there was no case with lacunae in the controls. Of the 18 cesarean scar pregnancies that progressed into the third trimester, 10 of them were diagnosed with placenta previa accreta at birth, including 4 creta and 6 increta. In the 19 to 22 weeks ultrasound examination, 8 of the 10 placenta accreta spectrum patients presented with subplacental hypervascularity, out of which 6 showed placental lacunae. CONCLUSION: The vascular changes in the utero-placental and intervillous circulations in cesarean scar pregnancies are due to the loss of the normal uterine structure in the scar area and the development of placental tissue in proximity of large diameter arteries of the outer uterine wall. The intensity of these vascular changes, the development of placenta accreta spectrum, and the risk of uterine rupture are probably related to the residual myometrial thickness of the scar defect at the start of pregnancy. A better understanding of the pathophysiology of the utero-placental vascular changes associated with cesarean scar pregnancies should help in identifying those cases that may develop major complications. It will contribute to providing counseling for women about the risks associated with different management strategies.

Mifepristone and misoprostol versus placebo and misoprostol for resolution of miscarriage in women diagnosed with missed miscarriage: the MifeMiso RCT.

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. METHODS: Women diagnosed with missed miscarriage in the first 14 weeks of pregnancy were randomly assigned (1 : 1 ratio) to receive 200 mg of oral mifepristone or matched placebo, followed by 800 µg 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. RESULTS: 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. 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. The mifepristone and misoprostol intervention was shown to be cost-effective in comparison to misoprostol alone. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17405024. 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. 25, No. 68. See the NIHR Journals Library website for further project information.

Miscarriage is a common complication of pregnancy, affecting approximately one in four women. Sometimes, medical treatment (i.e. tablets) may be offered to start or speed up the miscarriage process in order for the womb to empty itself. A drug called misoprostol (a tablet that makes the womb contract) is currently recommended for this treatment. However, the addition of another drug called mifepristone [a tablet that reduces pregnancy hormones (Mifegyne^®, Exelgyn, Paris, France)] might help the miscarriage to resolve more quickly. Therefore, we carried out the MifeMiso trial to test if mifepristone plus misoprostol is more effective than misoprostol alone in resolving miscarriage within 7 days. Women were randomly allocated by a computer to receive either mifepristone or placebo, followed by misoprostol 2 days later. Neither the women nor their health-care professionals knew which treatment they received. Some women also talked to the researchers about their experiences of taking part in the study. In total, 711 women were randomised to receive either mifepristone plus misoprostol or placebo plus misoprostol. Overall, 83% of women who received mifepristone plus misoprostol had miscarriage resolution within 7 days, compared with 76% of the women who received a placebo plus misoprostol. Surgery was required less often in women who received mifepristone plus misoprostol: 17% of women who received it required surgery, compared with 25% of women who received the placebo. Treatment with mifepristone did not appear to have any negative effects. Treatment with mifepristone plus misoprostol was more cost-effective than misoprostol alone, with an average saving of £182 per woman. Having taken part in the study, most women would choose medical management again and would recommend it to someone they knew who was experiencing a miscarriage.

Diagnosis and outcome of hydatidiform moles in missed-miscarriage: a cohort-study, systematic review and meta-analysis.

OBJECTIVE: To evaluate the ultrasound diagnostic rates of complete hydatidiform moles (CHM) and partial hydatidiform moles (PHM) in women presenting with a missed miscarriage, the clinical complications at diagnosis and the risk of gestational trophoblastic neoplasia (GTN) after surgical evacuation and to compare our findings with those of the published literature by completing a systematic review and meta-analysis STUDY DESIGN: Retrospective review of the data of 295 women diagnosed with a histologically confirmed hydatidiform moles (HM) over a 15-year period, including 128 CHM and 167 PHM. All women were referred to a regional specialist centre for follow-up and further management. An electronic search of PubMed, Google Scholar and MEDLINE was performed for studies published between September 1973 and September 2017 reporting on the early ultrasound diagnosis of hydatidiform mole. Only cohort studies which provided ultrasound data confirmed by histopathology were included. RESULTS: In the cohort study, ultrasound imaging diagnosed a significantly (p < 0.001) higher number of CHM (95/128 (74.2%) than PHM (68/167 (40.7%). Ovarian theca lutea cysts were observed in three CHM and one PHM. There were no cases of pre-eclampsia or thyrotoxicosis at the time of diagnosis. Maternal serum ß-human chorionic gonadotrophin levels were abnormally low (< 0.5 MoM) in 5/51 (10%) CHM and 23/43 (53%) PHM and abnormally high (> 2.0 MoM) in 20/51 (39%) CHM and 2/43 (5%) PHM. Seventeen (12.3%) CHM and two (1.4%) PHM developed a GTN requiring treatment. In the literature the proportion of histologically diagnosed HM, suspected on ultrasound in early pregnancy, ranged between 34.2 and 90.2% for HM, 57.8 and 95% for CHM and 17.6 and 51.6% for PHM. The meta-analysis indicated substantial heterogeneity in the overall ultrasound diagnosis of HM and in the differential diagnosis between CHM and PHM. CONCLUSION(S): As around a third of CHM and two thirds of PHM are not diagnosed on ultrasound in cases of missed miscarriage, histopathological examination of all products of conception in case of early pregnancy failure is essential to detect molar changes. This is particularly important for the management of women with CHM who have a higher risk of developing a GTN.

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

BACKGROUND: The anti-progesterone drug mifepristone and the prostaglandin misoprostol can be used to treat missed miscarriage. However, it is unclear whether a combination of mifepristone and misoprostol is more effective than administering misoprostol alone. We investigated whether treatment with mifepristone plus misoprostol would result in a higher rate of completion of missed miscarriage compared with misoprostol alone. METHODS: MifeMiso was a multicentre, double-blind, placebo-controlled, randomised trial in 28 UK hospitals. Women were eligible for enrolment if they were aged 16 years and older, diagnosed with a missed miscarriage by pelvic ultrasound scan in the first 14 weeks of pregnancy, chose to have medical management of miscarriage, and were willing and able to give informed consent. Participants were randomly assigned (1:1) to a single dose of oral mifepristone 200 mg or an oral placebo tablet, both followed by a single dose of vaginal, oral, or sublingual misoprostol 800 µg 2 days later. Randomisation was managed via a secure web-based randomisation program, with minimisation to balance study group assignments according to maternal age (<30 years vs ≥30 years), body-mass index (<35 kg/m2vs ≥35 kg/m2), previous parity (nulliparous women vs parous women), gestational age (<70 days vs ≥70 days), amount of bleeding (Pictorial Blood Assessment Chart score; ≤2 vs ≥3), and randomising centre. Participants, clinicians, pharmacists, trial nurses, and midwives were masked to study group assignment throughout the trial. The primary outcome was failure to spontaneously pass the gestational sac within 7 days after random assignment. Primary analyses were done according to intention-to-treat principles. The trial is registered with the ISRCTN registry, ISRCTN17405024. FINDINGS: Between Oct 3, 2017, and July 22, 2019, 2595 women were identified as being eligible for the MifeMiso trial. 711 women were randomly assigned to receive either mifepristone and misoprostol (357 women) or placebo and misoprostol (354 women). 696 (98%) of 711 women had available data for the primary outcome. 59 (17%) of 348 women in the mifepristone plus misoprostol group did not pass the gestational sac spontaneously within 7 days versus 82 (24%) of 348 women in the placebo plus misoprostol group (risk ratio [RR] 0·73, 95% CI 0·54-0·99; p=0·043). 62 (17%) of 355 women in the mifepristone plus misoprostol group required surgical intervention to complete the miscarriage versus 87 (25%) of 353 women in the placebo plus misoprostol group (0·71, 0·53-0·95; p=0·021). We found no difference in incidence of adverse events between the study groups. INTERPRETATION: Treatment with mifepristone plus misoprostol was more effective than misoprostol alone in the management of missed miscarriage. Women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Ultrasound diagnosis of complete and partial hydatidiform moles in early pregnancy failure: An inter-observer study.

We evaluated the accuracy of the ultrasound signs suggestive of complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM) in a cohort of women with histologically confirmed hydatidiform mole (HM) who presented with early pregnancy failure, including 103 CHM and 95 PHM for which ultrasound images were available. The accuracy of the differential diagnosis was significantly (p < 0.001) greater during secondary examination of ultrasound images compared with the original primary ultrasound examination. The interobserver agreement analysis indicated only a fair to moderate agreement between the two examinations (kappa value 0.41; 95% CI 0.29-0.53). Most HM present as early pregnancy failure and identification of early ultrasound signs can improve the differential diagnosis between CHM and PHM.

Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT.

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 (£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. 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.

The Prevalence of Thyroid Dysfunction and Autoimmunity in Women With History of Miscarriage or Subfertility.

OBJECTIVE: To describe the prevalence of and factors associated with different thyroid dysfunction phenotypes in women who are asymptomatic preconception. DESIGN: Observational cohort study. SETTING: A total of 49 hospitals across the United Kingdom between 2011 and 2016. PARTICIPANTS: Women aged 16 to 41years with history of miscarriage or subfertility trying for a pregnancy. METHODS: Prevalences and 95% confidence intervals (CIs) were estimated using the binomial exact method. Multivariate logistic regression analyses were conducted to identify risk factors for thyroid disease. INTERVENTION: None. MAIN OUTCOME MEASURE: Rates of thyroid dysfunction. RESULTS: Thyroid function and thyroid peroxidase antibody (TPOAb) data were available for 19213 and 19237 women, respectively. The prevalence of abnormal thyroid function was 4.8% (95% CI, 4.5-5.1); euthyroidism was defined as levels of thyroid-stimulating hormone (TSH) of 0.44 to 4.50 mIU/L and free thyroxine (fT4) of 10 to 21 pmol/L. Overt hypothyroidism (TSH > 4.50 mIU/L, fT4 < 10 pmol/L) was present in 0.2% of women (95% CI, 0.1-0.3) and overt hyperthyroidism (TSH < 0.44 mIU/L, fT4 > 21 pmol/L) was present in 0.3% (95% CI, 0.2-0.3). The prevalence of subclinical hypothyroidism (SCH) using an upper TSH concentration of 4.50 mIU/L was 2.4% (95% CI, 2.1-2.6). Lowering the upper TSH to 2.50 mIU/L resulted in higher rates of SCH, 19.9% (95% CI, 19.3-20.5). Multiple regression analyses showed increased odds of SCH (TSH > 4.50 mIU/L) with body mass index (BMI) ≥ 35.0 kg/m2 (adjusted odds ratio [aOR] 1.71; 95% CI, 1.13-2.57; P = 0.01) and Asian ethnicity (aOR 1.76; 95% CI, 1.31-2.37; P < 0.001), and increased odds of SCH (TSH ≥ 2.50 mIU/L) with subfertility (aOR 1.16; 95% CI, 1.04-1.29; P = 0.008). TPOAb positivity was prevalent in 9.5% of women (95% CI, 9.1-9.9). CONCLUSIONS: The prevalence of undiagnosed overt thyroid disease is low. SCH and TPOAb are common, particularly in women with higher BMI or of Asian ethnicity. A TSH cutoff of 2.50 mIU/L to define SCH results in a significant proportion of women potentially requiring levothyroxine treatment.

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy.

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.).

Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception.

BACKGROUND: Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes. METHODS: We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 µg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation. RESULTS: The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, -0.4 percentage points; 95% CI, -6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14). CONCLUSIONS: The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.).

Ultrasound diagnosis of molar pregnancy.

INTRODUCTION: The primary aims of this study were to establish what proportion of ultrasonically suspected molar pregnancies were proven on histological examination and what proportion of histologically diagnosed molar pregnancies were identified by ultrasound pre-operatively. The secondary aim was to review the features of these scans to help identify criteria that may improve ultrasound diagnosis. METHODS: This was a retrospective observational study conducted in the Early Pregnancy Unit at King's College Hospital London over an 11-year period. Cases of ultrasonically suspected molar pregnancy or other gestational trophoblastic disease were identified and compared with the final histopathological diagnosis. In addition, cases which were diagnosed on histopathology that were not suspected on ultrasound were also examined. In discrepant cases, the images were reviewed unblinded by two senior sonographers. Statistical analysis for likelihood ratio and post-test probabilities was performed. RESULTS: One hundred eighty-two women had gestational trophoblastic disease suspected on ultrasound examination (1:360, 0.3%); 106/182 (58.2%, 95% CI 51.0 to 65.2%) had histologically confirmed gestational trophoblastic disease. The likelihood ratio for gestational trophoblastic disease after a positive ultrasound was 607.27, with a post-test probability of 0.628.The sensitivity of ultrasound for gestational trophoblastic disease was 70.7% (95% CI 62.9% to 77.4%) with an estimated specificity of 99.88% (95% CI 99.85% to 99.91%); 102/143 (71.3%, 95% CI 63.4 to 78.1%) molar pregnancies were suspected on pre-op ultrasound; 60/68 (88.2%, 95% CI 78.2 to 94.2%) of complete moles were suspected on pre-op ultrasound, compared with 42/75 (56.0%, 95% CI 44.7 to 66.7%) of partial moles. On retrospective review of the pre-op ultrasound images, there were cases that could have been suspected prior to surgery. CONCLUSION: Detecting molar pregnancy by ultrasound remains a diagnostic challenge, particularly for partial moles. These data suggest that there has been an increase in both the predictive value and the sensitivity of ultrasound over time, with a high LR and post-test probability; however, the diagnostic criteria remain ill-defined and could be improved.

New insights in the pathophysiology of complete hydatidiform mole.

OBJECTIVE: The majority of complete hydatidiform moles (CHM) are detected on ultrasound examination by the end of the first trimester when they present as multiple sonolucent cysts. To better understand the pathophysiology of this unique placental pathology and improve its prenatal diagnosis and management we have reviewed the ultrasound features of CHM before the appearance of cystic changes. STUDY DESIGN: We searched our database to identify all women diagnosed with a complete hydatidiform mole confirmed by histopathology who had an ultrasound examination before 9 weeks' gestation. We reviewed their ultrasound reports and all the corresponding images. RESULTS: The study group included 39 women with a positive pregnancy test and vaginal bleeding, 36 of whom had at least two ultrasound examinations before 9 weeks' gestation. At the first scan (mean gestation age 7 + 1 weeks; SD 1.1), 29 out 39 (74.4%) of CHM presented as a heterogeneous hyperechogenic mass with or without gestational sac and the remaining ten (25.6%) cases as a regular 4-week gestational sac. Cystic molar changes became apparent from the end of the second month of gestation. CONCLUSION: The development of a CHM follows a well-defined pattern starting with a macroscopically normal gestation sac at 4 weeks, which transforms into a polypoid mass between 5 and 7 weeks of gestation. The hydropic changes of the villous tissue is progressive and rarely visible in utero on ultrasound before 8 weeks of gestation. These findings should allow an earlier diagnosis and assist in the management counselling of women with CHM.

Negative histology with surgically treated tubal ectopic pregnancies - A retrospective cohort study.

OBJECTIVE: To determine the outcome of histological examinations of surgical specimens obtained from treatment of tubal ectopic pregnancy and to correlate with clinical findings, pre-operative ultrasound scans and the type of surgery. STUDY DESIGN: A retrospective cohort study of 941 women diagnosed with a tubal ectopic pregnancy in the Early Pregnancy Unit and having surgical treatment at King's College Hospital, London. Clinical and ultrasound data had been entered contemporaneously on our electronic early pregnancy database and hospital clinical records over an 11year period from 2004 to 2014. Demographic data, clinical history, ultrasound scan parameters, type of surgical management and histological diagnosis were recorded. The primary outcome measure was the presence or absence of chorionic villi in the surgical specimen. Data were analysed using Mann Whitney U test for non-parametric data, relative risk for categorical data and binomial logistic regression. RESULTS: A surgical specimen was obtained in 925 cases. Of these, 881/925 (95.2%) were positive for the presence of chorionic villi on histological examination. Patients with negative histology had a lower median gestational age, smaller ectopic pregnancies and lower serum human chorionic gonadotrophin levels. The relative risk of negative histology was significantly higher with a solid ectopic pregnancy on ultrasound (RR1.91, 95% CI 1.07-3.4) and with conservative surgery (RR 3.68, 95% CI 1.25-10.77). The relative risk was significantly lower with the presence of embryonic cardiac activity (RR 0.12, 95% CI 0.02-0.85). Only the serum hCG level was a significant predictor of negative histology on logistic regression analysis (p=0.048). In 39/44 women with negative histology, the human chorionic gonadotrophin level declined after surgery with no further intervention. Five of the 44 required a second surgical procedure as the ectopic pregnancy had been missed at the initial surgery and did not resolve. CONCLUSION: There is lack of histological confirmation of sonographically diagnosed and surgically confirmed ectopic pregnancies in approximately 5% of cases, making this a relatively common finding following surgical treatment of tubal ectopic pregnancy. Clinicians should be aware of this when counselling women with tubal ectopic pregnancies about to undergo surgery, include this risk in the consent process and plan post-surgical follow up with this in mind.

Are early pregnancy complications more common in women with hyperemesis gravidarum?

Ultrasound evaluation is usually requested for women presenting with hyperemesis gravidarum (HG) in early pregnancy. This is to check viability as well as to diagnose multiple pregnancies and exclude gestational trophoblastic disease (GTD). The aim of this retrospective case control study was to evaluate the early pregnancy outcomes in women with HG and to compare them with an asymptomatic control group. 790 women referred with HG between 2002 and 2014 were matched for gestational age and maternal age with an asymptomatic patient attending for a reassurance or dating scan. A higher proportion of women with HG had ongoing pregnancies compared with controls and conversely, embryonic demise was less frequent in the HG group. The risk of twin pregnancy was doubled in the HG group compared to controls. There was no evidence of an increase in the prevalence of GTD. There appears to be a limited role for ultrasound in women who present with HG alone.

Is There a Role for Hyperglycosylated hCG in the Diagnosis of Ectopic Pregnancy in Women with a Pregnancy of Unknown Location?

OBJECTIVE: To examine the potential use of hyperglycosylated human gonadotropin (hCG-H) in identifying ectopic pregnancies in pregnancies of unknown location (PULs) on ultrasound scan. STUDY DESIGN: This was a prospective observational study. An additional blood sample was taken from women whose initial transvaginal ultrasound scan showed none of the following: intact intrauterine pregnancy, retained placental tissue, or ectopic pregnancy. Parallel sandwich ELISAs were performed using sheep monoclonal antibodies to the 12F6 epitope for detection of total hCG and to the 4D8 epitope for hCG-H detection, and an automated immunoassay technique was used for progesterone and serum ß-hCG measurements. Patients were managed accord-ing to our standard clinical protocol. RESULTS: hCG-H was significantly higher in ectopic pregnancies (85.6 ng/mL) than in viable intrauterine pregnancies (26.8 ng/mL) and spontaneously resolving pregnancies (23.2 ng/mL). The ability to distinguish ectopic pregnancies from nonectopic pregnancies, expressed as area under the curve, was 0.816 for hCG-H and 0.824 for total hCG. CONCLUSION: Women with an underlying ectopic pregnancy tended to have higher hCGs, whichever assay was used. However, the current study does not support a role for a single measurement of hCG-H in the diagnosis of ectopic pregnancy within the PUL population.

PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation.

BACKGROUND AND OBJECTIVES: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted. DESIGN AND SETTING: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites). PARTICIPANTS AND INTERVENTIONS: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks). MAIN OUTCOME MEASURES: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use. METHODS: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth. RESULTS: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341. CONCLUSIONS: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM. LIMITATIONS: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle. FUTURE WORK: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44. 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. 20, No. 41. See the NIHR Journals Library website for further project information.