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.

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages.

BACKGROUND: Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain. METHODS: We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. RESULTS: A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, -4.0 to 9.0). There were no significant between-group differences in the rate of adverse events. CONCLUSIONS: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research; PROMISE Current Controlled Trials number, ISRCTN92644181.).

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.

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.

Ovum transmigration after salpingectomy for ectopic pregnancy.

STUDY QUESTION: What proportion of pregnancies are a result of ovum transmigration after salpingectomy for ectopic pregnancy? SUMMARY ANSWER: Approximately one-third of spontaneously conceived pregnancies are a result of pick-up of the ovum from the ovary contralateral to the remaining tube in women with a history of salpingectomy. WHAT IS KNOWN ALREADY: The corpus luteum has been found contralateral to tubal ectopic pregnancies in 32% of reported cases. The rate of contralateral ovum pick-up in intrauterine pregnancies is not known. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective cohort study of clinical and ultrasound records collected over a 12-year period 1999-2010. Ten per cent of cases identified were excluded from the final analysis due to incomplete data or bilateral corpora lutea. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Included were 842 pregnancies in 707 women with a history of unilateral salpingectomy for ectopic pregnancy and subsequent spontaneous pregnancy. The study was set in the Early Pregnancy Unit of a large UK inner city teaching hospital. The outcome measure was the side of the corpus luteum in relation to the side of the remaining tube. MAIN RESULTS AND THE ROLE OF CHANCE: The corpus luteum was located in the ovary contralateral to the remaining tube in 266/842 pregnancies (31.6%; 95% CI 28.5-34.8%). There was no significant difference in this proportion between intrauterine and ectopic pregnancies [246/769 (32.0%) versus 21/73 (28.8%), P = 0.60]. LIMITATIONS, REASONS FOR CAUTION: This was a retrospective study and so did not address the conception rate according to the laterality of ovulation. WIDER IMPLICATIONS OF THE FINDINGS: Our findings were very similar to the frequency of ectopic pregnancies found contralateral to the corpus luteum described in previous studies. Ovum pick-up from the cul-de-sac probably occurs reasonably frequently and is unlikely to have a causative role in the pathogenesis of ectopic pregnancy. It is not known how often this phenomenon occurs in women with intact Fallopian tubes. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained. The authors have no conflicts of interest to declare.

Yolk sac diameter in early pregnancy in maternal diabetes mellitus.

AIMS: To investigate the possible association between maternal diabetes mellitus and increased yolk sac diameter (YSD). METHODS: We searched the Early Pregnancy Unit database to identify singleton pregnancies with measurements of embryonic crown-rump length (CRL) and YSD at 6-10 weeks of gestation and subsequent delivery of phenotypically normal neonates. We compared the YSD in patients with pre-gestational and gestational diabetes with those who were unaffected by diabetes. RESULTS: A total of 3,686 cases were identified including 43 (1.2%) with type 1 diabetes, 31 (0.8%) with type 2 diabetes and 71 (1.9%) who subsequently developed gestational diabetes. The measured YSD in both the diabetic and non-diabetic groups were expressed as differences from the expected normal mean for CRL (Δ values). There were no significant differences in ΔYSD between the groups. The median (IQR) ΔYSD was 0.01 (-0.33 to 0.37) mm in the unaffected group, 0.01 (-0.35 to 0.51) mm in type 1 diabetes, -0.02 (-3.44 to 0.27) mm in type 2 diabetes and 0.01 (-0.28 to 0.35) mm in gestational diabetes. CONCLUSION: After exclusion of miscarriages and embryopathies, pre-gestational and gestational diabetes are not associated with altered YSD.

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.

Clinical use of a model to predict the viability of early intrauterine pregnancies when no embryo is visible on ultrasound.

BACKGROUND: When a small gestational sac with no visible embryo is seen at an early pregnancy ultrasound scan, the clinician cannot distinguish a viable from a non-viable pregnancy. A test for the prediction of early pregnancy viability at the initial visit was developed in 2003. Maternal age, gestational sac diameter (GSD) and serum progesterone levels were used in a logistic regression model to create an algorithm for estimation of the probability of a viable pregnancy. The objective of this study was to assess how well the test performed in routine clinical practice. METHODS: This is a retrospective observational study of women who had the test performed in our Early Pregnancy Unit over a 6-year period. Inclusion criteria were a spontaneous conception, gestational sac of <20 mm mean diameter, no visible embryo on transvaginal ultrasound scan and outcome data regarding the viability of the pregnancy. RESULTS: Of 5163 potentially eligible women, 472 had the test performed (9.1%) and 400 met the inclusion criteria for the study. Women who were older or with vaginal bleeding, a more advanced gestational age or a history of previous first trimester miscarriages were more likely to have the test performed. At follow-up, 199/400 (49.8%) women had a viable intrauterine pregnancy, and 201/400 (50.2%) had a non-viable pregnancy. The logistic regression model performed better than serum progesterone, ß-hCG, mean GSD or maternal age alone as single parameters to differentiate between viable and non-viable pregnancies, but the area under the curve was lower than in the 2003 study [0.85 (standard error 0.021) versus 0.97 (standard error 0.011)]. CONCLUSIONS: Although less effective than in the original study, the logistic regression model was able to predict pregnancy viability with reasonable accuracy when applied in clinical practice. The test appears to be under utilized and further prospective studies are needed to establish if the test is of clinical benefit, for example, in reducing patient anxiety.

Ultrasonographic prediction of early miscarriage.

BACKGROUND: The aim of this retrospective study was to assess the value of maternal history and ultrasound scan findings at 6-10 weeks for predicting early miscarriage. METHODS: Embryonic crown-rump length (CRL), heart rate (HR), gestational sac diameter (GSD) and yolk sac diameter (YSD) were compared in two groups of women with singleton pregnancies attending an early pregnancy unit. In the first group the initial scan demonstrated a live embryo but in a subsequent visit the scan showed a dead embryo, complete or incomplete miscarriage. In the second group with a live embryo there was subsequent live birth of a normal neonate. RESULTS: There were 729 pregnancies with miscarriage and 4698 with normal outcome. Logistic regression analysis demonstrated that in the prediction of miscarriage the risk was higher in women of African racial origin [odds ratio (OR) 1.62], cigarette smokers (OR 1.91) and those with vaginal bleeding (OR 2.03) and increased with maternal age (OR 1.05) and YSD (OR 1.88) and was inversely related to CRL (OR 0.79), HR (OR 0.96) and GSD (OR 0.84). At false-positive rate of 30%, the detection rate of miscarriage in screening by vaginal bleeding was 45%, 53% by the addition of maternal history factors and 85.7% by the addition of ultrasound findings. CONCLUSIONS: In early pregnancy a prediction of miscarriage can be provided by a combination of maternal characteristics and ultrasound findings and the estimated risk can be used to rationalize follow-up. Our multivariate model requires prospective evaluation in a new sample population.

Prediction of outcome in dichorionic twin pregnancies at 6-10 weeks' gestation.

OBJECTIVE: The objective of the study was to predict the outcome of dichorionic (DC) twin pregnancies at 6-10 weeks' gestation from intertwin discordance in crown-rump length (CRL), heart rate (HR), and gestational sac diameter (GSD). STUDY DESIGN: Intertwin discordance in CRL, HR, and GSD, was compared in 3 groups of DC twin pregnancies with 2 live embryos at 6-10 weeks. In one group, there were 2 live births (n = 174), in another 1 live birth (n = 24), and in a third group there were no live births (n = 33). Regression analysis was used to determine the predictors of outcome. RESULTS: Significant contributors to the prediction of 1 intrauterine death were discordance in CRL and GSD. The only predictor of 2 deaths was discordance in CRL. Detection rates of screening for single or double death, at 10% false-positive rate, were 79.2% and 27.3%, respectively. CONCLUSION: In DC twins, intertwin discordance in CRL and GSD at 6-10 weeks can predict outcome.

Normal ranges of embryonic length, embryonic heart rate, gestational sac diameter and yolk sac diameter at 6-10 weeks.

OBJECTIVES: To construct normal ranges for embryonic crown-rump length (CRL), heart rate (HR), gestational sac diameter (GSD) and yolk sac diameter (YSD) at 6-10 weeks of gestation. METHODS: We examined 4,698 singleton pregnancies with ultrasound measurements of CRL, HR, GSD and YSD at 6-10 weeks and CRL at 11-13 weeks resulting in the live birth after 36 weeks of phenotypically normal neonates with birth weight above the 5th centile. Gestational age was derived from CRL at the 11- to 13-week scan using the formula of Robinson and Fleming. Regression analysis was used to establish normal ranges of CRL, fetal HR, GSD and YSD with gestation, and fetal HR, GSD and YSD with CRL. RESULTS: At 6-10 weeks there were significant quadratic associations between CRL, GSD, YSD and gestation and between HR, GSD, YSD and CRL, and a cubic association between HR and gestation. The estimated gestation from CRL was the same as that of Robinson and Fleming for a CRL of 10.2-36.5 mm, but the formula of Robinson and Fleming underestimated the gestation by 1 day for a CRL 7.4-10.2 mm and this increased to 9 days for a CRL of 1 mm. CONCLUSION: This study established normal ranges for early pregnancy biometry.

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.

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.

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.

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.

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.

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.

Sonographic markers of aneuploidies at 6-10 weeks of gestation.

OBJECTIVES: To determine if sonographic features of live embryos at 6-10 weeks' gestation are altered in aneuploidies. METHODS: Embryonic crown rump length (CRL), embryonic heart rate, gestational sac diameter (GSD) and yolk sac diameter (YSD) were measured by transvaginal sonography in 5603 live embryos from singleton pregnancies at 6-10 weeks' gestation. The measurements were expressed as differences from the expected normal mean for CRL (delta values) and median delta values in the aneuploid cases were compared to the euploid group. RESULTS: 5393 pregnancies resulted in the live birth of phenotypically normal neonates and these cases constituted the euploid group. In 55 cases there was subsequent prenatal diagnosis of aneuploidies (trisomy 21, n=28; trisomy 18, n=10; trisomy 13, n=10; triploidy, n=4; Turner syndrome, n=3). The median and interquartile range (IQR) of delta embryonic heart rate in trisomy 18 was -19.44 (-23.77 to -7.20)bpm and in trisomy 13 it was 11.12 (7.25 to 20.39)bpm, which were significantly lower and higher, respectively, than in euploid embryos (median -0.05, IQR -6.18 to 6.21bpm). The median delta YSD in trisomy 21 was higher than in euploid fetuses (median 0.56, IQR 0.23 to 0.79 and median -0.17, IQR -3.11 to 2.82 mm). There were no other significant differences in measurements between the groups. CONCLUSION: At 6-10 weeks' gestation there are sonographically detectable differences between euploid and trisomic embryos.