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 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.).

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 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.

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.

Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial.

BACKGROUND: Tubal ectopic pregnancy can be surgically treated by salpingectomy, in which the affected Fallopian tube is removed, or salpingotomy, in which the tube is preserved. Despite potentially increased risks of persistent trophoblast and repeat ectopic pregnancy, salpingotomy is often preferred over salpingectomy because the preservation of both tubes is assumed to offer favourable fertility prospects, although little evidence exists to support this assumption. We aimed to assess whether salpingotomy would improve rates of ongoing pregnancy by natural conception compared with salpingectomy. METHODS: In this open-label, multicentre, international, randomised controlled trial, women aged 18 years and older with a laparoscopically confirmed tubal pregnancy and a healthy contralateral tube were randomly assigned via a central internet-based randomisation program to receive salpingotomy or salpingectomy. The primary outcome was ongoing pregnancy by natural conception. Differences in cumulative ongoing pregnancy rates were expressed as a fecundity rate ratio with 95% CI, calculated by Cox proportional-hazards analysis with a time horizon of 36 months. Secondary outcomes were persistent trophoblast and repeat ectopic pregnancy (expressed as relative risks [RRs] with 95% CIs) and ongoing pregnancy after ovulation induction, intrauterine insemination, or IVF. The researchers who collected data for fertility outcomes were masked to the assigned intervention, but patients and the investigators who analysed the data were not. All endpoints were analysed by intention to treat. We also did a (non-prespecified) meta-analysis that included the findings from the present trial. This trial is registered, number ISRCTN37002267. FINDINGS: 446 women were randomly assigned between Sept 24, 2004, and Nov 29, 2011, with 215 allocated to salpingotomy and 231 to salpingectomy. Follow-up was discontinued on Feb 1, 2013. The cumulative ongoing pregnancy rate was 60·7% after salpingotomy and 56·2% after salpingectomy (fecundity rate ratio 1·06, 95% CI 0·81-1·38; log-rank p=0·678). Persistent trophoblast occurred more frequently in the salpingotomy group than in the salpingectomy group (14 [7%] vs 1 [<1%]; RR 15·0, 2·0-113·4). Repeat ectopic pregnancy occurred in 18 women (8%) in the salpingotomy group and 12 (5%) women in the salpingectomy group (RR 1·6, 0·8-3·3). The number of ongoing pregnancies after ovulation induction, intrauterine insemination, or IVF did not differ significantly between the groups. 43 (20%) women in the salpingotomy group were converted to salpingectomy during the initial surgery because of persistent tubal bleeding. Our meta-analysis, which included our own results and those of one other study, substantiated the results of the trial. INTERPRETATION: In women with a tubal pregnancy and a healthy contralateral tube, salpingotomy does not significantly improve fertility prospects compared with salpingectomy. FUNDING: Netherlands Organisation for Health Research and Development (ZonMW), Region Västra Götaland Health & Medical Care Committee.

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.

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 "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.

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.

Communities of practice - quality improvement or research in general practice.

BACKGROUND: A 'communities of practice' (CoP) approach has the potential to address quality improvement issues and facilitate research in general practice by engaging those most intimately involved in delivering services - the health professionals. OBJECTIVE: This article outlines the CoP approach and discusses some of the challenges involved in using this approach to raise standards in general practice and how these challenges might be addressed. DISCUSSION: General practitioner insight needs to be harnessed in order to develop solutions that are conceived in, and informed by, clinical practice. A CoP approach provides control to the practitioners over selection of the most relevant research question and outcome measure. However, the method is challenging as it requires a focus that is suitable, that motivates the participants, and effective management strategies and resources to support the CoP.

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.