Ai-Wei Tang

Recent thoughts on management and prevention of recurrent early pregnancy loss

Purpose of review To provide an overview of the latest views and evidence available to clinicians managing couples with recurrent early pregnancy loss (RPL). Recent findings RPL is a heterogeneous condition associated with many pathologies, none of which is found in more than 50% of couples after routine investigations. The recommended treatment of low-dose aspirin and heparin in women with antiphospholipid syndrome has a weak evidence base. Recent randomized controlled trials (RCTs) of low-dose aspirin and heparin have failed to find an improvement in live birth rates, even in the presence of thrombophilia. Although parental karyotypic abnormalities are associated with RPL, conservative management of such couples may be optimal. Observational studies of hysteroscopic metroplasty have promising results, but evidence from RCTs is awaited. Progestogen therapy may improve pregnancy outcomes, but further RCTs are needed. Immunological factors are thought to be important in idiopathic RPL. Research is focused on natural killer cells and cytokines in influencing implantation as potential therapeutic treatments. Currently, RCTs have not substantiated a benefit for immunotherapy. Summary Management of RPL remains challenging, with many controversial issues regarding the underlying pathophysiology. Improvements in live birth rates in subsequent pregnancies have not been found in RCTs of treatment for most of the associated conditions. All women can be offered supportive care in subsequent pregnancies. Empirical treatment is widely used in idiopathic RPL. A better option may be to encourage women to participate in high-quality and methodologically sound studies to guide optimal management.

Prednisolone Trial: Study protocol for a randomised controlled trial of prednisolone for women with idiopathic recurrent miscarriage and raised levels of uterine natural killer (uNK) cells in the endometrium

BackgroundIdiopathic recurrent miscarriage is defined as 3 consecutive pregnancy losses with no contributing features found on investigations. At present there are no treatments of proven efficacy for idiopathic recurrent miscarriage. Uterine natural killer (uNK) cells, the most predominant leucocyte in the endometrium are adjacent to foetal trophoblast cells and thought to be involved in implantation. The exact mechanisms of how uNK cells affect implantation are not clear but are probably through the regulation of angiogenesis. Multiple studies have shown an association between high density of uterine natural killer cells and recurrent miscarriage. We have shown that prednisolone reduces the number of uNK cells in the endometrium. The question remains as to whether reducing the number of uNK cells improves pregnancy outcome.MethodsWe propose a randomised, double-blind, placebo controlled trial of prednisolone with a pilot phase to assess feasibility of recruitment, integrity of trial procedures, and to generate data to base future power calculations. The primary aim is to investigate whether prednisolone therapy during the first trimester of pregnancy is able to improve live birth rates in patients with idiopathic recurrent miscarriage and raised uNK cells in the endometrium. Secondary outcomes include conception rate, karyotype of miscarriage, miscarriages (first and second trimester), stillbirths, pregnancy complications, gestational age at delivery, congenital abnormality and side effects of steroids. The trial has 2 stages: i) screening of non-pregnant women and ii) randomisation of the pregnant cohort. All patients who fit the inclusion criteria (<40 years old, ≥3 consecutive miscarriages with no cause found and no contraindications to prednisolone therapy) will be asked to consent to an endometrial biopsy in the mid-luteal phase to assess their levels of uNK cells. Women with high levels of uNK cells (≥5%), will be randomised to either prednisolone or placebo when a pregnancy is confirmed. Follow-up includes 2 weekly ultrasound scans in the first trimester, an anomaly scan at 20 weeks gestation, growth scans at 28 and 34 weeks gestation and a postnatal follow-up at 6 weeks.Trial RegistrationCurrent Controlled Trials ISRCTN28090716

Pro forma for ultrasound reporting in suspected abnormally invasive placenta (AIP): an international consensus

Accurate antenatal diagnosis of an abnormally invasive placenta (AIP), allowing multidisciplinary management at the time of delivery, has been shown to improve maternal and fetal outcomes1–3. AIP can be predicted as early as in the first trimester, by identifying cases of suspected Cesarean scar pregnancy (CSP), as there is evidence that CSP in the first trimester and AIP in the second and third trimesters may represent different stages of a similar pathology4. Grayscale ultrasonography, with or without color Doppler and performed both transabdominally and transvaginally, has been used widely for antenatal screening and diagnosis of AIP. Many signs have been suggested, with reports varying as to their sensitivity and specificity5. Most of these ‘signs’ are poorly defined and, consequently, it is difficult to assess which are the most robust. To address this, the European Working Group on AIP (EW-AIP) have produced a consensus proposal to standardize the ultrasound descriptions used to define each sign, published in this issue of the Journal6. We assembled an international group of experts in the field with the specific aim of reaching an agreement regarding a standardized means of reporting ultrasound assessment of suspected AIP. If adopted by sonographers, clinicians and researchers worldwide, such a pro forma may facilitate better communication, and better evaluation of our diagnostic performance, in cases of suspected AIP. The group of international experts comprised an e-mail discussion group (n = 50) led by Jose Palacios Jaraquemada, members of the EW-AIP (n = 19) and members of the ISUOG (International Society of Ultrasound in Obstetrics and Gynecology) Clinical Standards Committee (n = 7). Each expert was asked to participate in a survey which involved completion of an online questionnaire to indicate what they believed should be included in the pro forma for reporting ultrasound assessment of suspected AIP. The online questionnaire, created using Survey Monkey, included risk factors known to be associated with AIP and all commonly reported ultrasound signs and definitions related to the diagnosis of AIP5–11. Ultrasound signs were divided into three subgroups according to modality: grayscale ultrasound, color Doppler and three-dimensional (3D) power Doppler. Each ultrasound sign in each subgroup had between one and six associated definitions reported in the published literature. To each selected demographic characteristic and ultrasound sign we assigned three options: (i) definitely include in report; (ii) include optionally in report and (iii) do not include in report. The definitions for each ultrasound sign were also assigned three options: (i) include; (ii) do not include and (iii) unsure. Participants were also asked whether clinical interpretation and relevance of the ultrasound findings should be included in the report. Options for preferred method of reporting clinical interpretation included: (i) give probability of clinically significant AIP, (ii) state whether manual removal of placenta should be attempted, and (iii) give free text description to provide guidance to the local team. There was the opportunity to provide free text comments for each section. A reminder to complete the questionnaire was sent out after 2 weeks, and we allowed 4 weeks for a response. All demographic characteristics and ultrasound signs for which >50% respondents selected ‘definitely include in report’ were incorporated into the standardized report, while those for which >50% respondents selected ‘do not include in report’ were excluded. For each ultrasound sign, the definitions for which >50% of respondents selected either ‘include’ or ‘unsure’ were kept for further evaluation. A second questionnaire was created for such items requiring further evaluation, in which respondents could specify first and second choice for definition of the ultrasound sign, and included additional suggestions from the free text comments, such as assessment for suspected parametrial involvement. For confirmation, we distributed a third and final round of the survey, with three domains, addressing: demographic and risk factors, ultrasound signs and clinical interpretation. At this round, consensus was sought from all participants that the ultrasound signs previously agreed on should be defined using the standardized descriptors proposed by the EW-AIP6. There were 42 respondents in the first round of the survey (response rate, 55%). For all of the demographic characteristics, placental location and grayscale ultrasound parameters, and for all but one color Doppler parameter, >50% of respondents chose ‘definitely include in report’. Only seven respondents thought that 3D power Doppler volumes should definitely be included and thus this criterion was excluded. All

Endometrial cell counts in recurrent miscarriage: a comparison of counting methods

Drury J A, Nik H, van Oppenraaij R H F, Tang A‐W, Turner M A & Quenby S 
(2011 Histopathology 59, 1156–1162 
Endometrial cell counts in recurrent miscarriage: a comparison of counting methods

Standardised pro forma for ultrasound reporting in suspected abnormally invasive placenta (AIP) – an international consensus

Accurate antenatal diagnosis of an abnormally invasive placenta (AIP), allowing multidisciplinary management at the time of delivery, has been shown to improve maternal and fetal outcomes1–3. AIP can be predicted as early as in the first trimester, by identifying cases of suspected Cesarean scar pregnancy (CSP), as there is evidence that CSP in the first trimester and AIP in the second and third trimesters may represent different stages of a similar pathology4. Grayscale ultrasonography, with or without color Doppler and performed both transabdominally and transvaginally, has been used widely for antenatal screening and diagnosis of AIP. Many signs have been suggested, with reports varying as to their sensitivity and specificity5. Most of these ‘signs’ are poorly defined and, consequently, it is difficult to assess which are the most robust. To address this, the European Working Group on AIP (EW-AIP) have produced a consensus proposal to standardize the ultrasound descriptions used to define each sign, published in this issue of the Journal6. We assembled an international group of experts in the field with the specific aim of reaching an agreement regarding a standardized means of reporting ultrasound assessment of suspected AIP. If adopted by sonographers, clinicians and researchers worldwide, such a pro forma may facilitate better communication, and better evaluation of our diagnostic performance, in cases of suspected AIP. The group of international experts comprised an e-mail discussion group (n = 50) led by Jose Palacios Jaraquemada, members of the EW-AIP (n = 19) and members of the ISUOG (International Society of Ultrasound in Obstetrics and Gynecology) Clinical Standards Committee (n = 7). Each expert was asked to participate in a survey which involved completion of an online questionnaire to indicate what they believed should be included in the pro forma for reporting ultrasound assessment of suspected AIP. The online questionnaire, created using Survey Monkey, included risk factors known to be associated with AIP and all commonly reported ultrasound signs and definitions related to the diagnosis of AIP5–11. Ultrasound signs were divided into three subgroups according to modality: grayscale ultrasound, color Doppler and three-dimensional (3D) power Doppler. Each ultrasound sign in each subgroup had between one and six associated definitions reported in the published literature. To each selected demographic characteristic and ultrasound sign we assigned three options: (i) definitely include in report; (ii) include optionally in report and (iii) do not include in report. The definitions for each ultrasound sign were also assigned three options: (i) include; (ii) do not include and (iii) unsure. Participants were also asked whether clinical interpretation and relevance of the ultrasound findings should be included in the report. Options for preferred method of reporting clinical interpretation included: (i) give probability of clinically significant AIP, (ii) state whether manual removal of placenta should be attempted, and (iii) give free text description to provide guidance to the local team. There was the opportunity to provide free text comments for each section. A reminder to complete the questionnaire was sent out after 2 weeks, and we allowed 4 weeks for a response. All demographic characteristics and ultrasound signs for which >50% respondents selected ‘definitely include in report’ were incorporated into the standardized report, while those for which >50% respondents selected ‘do not include in report’ were excluded. For each ultrasound sign, the definitions for which >50% of respondents selected either ‘include’ or ‘unsure’ were kept for further evaluation. A second questionnaire was created for such items requiring further evaluation, in which respondents could specify first and second choice for definition of the ultrasound sign, and included additional suggestions from the free text comments, such as assessment for suspected parametrial involvement. For confirmation, we distributed a third and final round of the survey, with three domains, addressing: demographic and risk factors, ultrasound signs and clinical interpretation. At this round, consensus was sought from all participants that the ultrasound signs previously agreed on should be defined using the standardized descriptors proposed by the EW-AIP6. There were 42 respondents in the first round of the survey (response rate, 55%). For all of the demographic characteristics, placental location and grayscale ultrasound parameters, and for all but one color Doppler parameter, >50% of respondents chose ‘definitely include in report’. Only seven respondents thought that 3D power Doppler volumes should definitely be included and thus this criterion was excluded. All

A rapid, reliable method for uNK cell density estimation

Interest in uterine NK cell density as a diagnostic or screening tool in reproductive disorders is growing. However, current methods of analysis are time consuming. In this study, 997 images from 100 women were analysed both by the currently used method combining manual and computer aided counting, and by using colour splitting combined with area measurement as an estimate of positively stained cells. Good correlation was found between both methods (r(2)=0.92) centred around the line of equality, with no systematic differences observed in Bland Altman plots. The area measurement was significantly faster and thus is a useful screening method.