IVF and other ART in low- and middle-income countries: a systematic landscape analysis.

BACKGROUND: Infertility affects 48.5 million couples worldwide with a prevalence estimated at 3.5-16.7% in low- and middle-income countries (LMIC), and as high as 30-40% in Sub-Saharan Africa. ART services are not accessible to the majority of these infertile couples due to the high cost of treatments in addition to cultural, religious and legal barriers. Infertility and childlessness, particularly in LMIC, have devastating consequences, which has resulted in considerable interest in developing affordable IVF procedures. However, there is a paucity of evidence on the safety, efficiency and ability to replicate techniques under different field conditions, and how to integrate more affordable ART options into existing infrastructures. OBJECTIVE AND RATIONALE: This review was performed to investigate the current availability of IVF in LMIC and which other ART options are under development. This work will unfold the landscape of available and potential ART services in LMIC and is a key element in positioning infertility more broadly in the Global Public Health Agenda. SEARCH METHODS: A systematic literature search was performed of articles and gray literature on IVF and other ART options in LMIC published between January 2010 and January 2020. We selected studies on IVF and other ART treatments for infertile couples of reproductive age (18-44 years) from LMIC. The review was limited to articles published after 2010, based on the recent evolution in the field of ART practices in LMIC over the last decade. Citations from high-income countries, including data prior to 2010 and focusing on specialized ART procedures, were excluded. The literature search included PubMed, Popline, CINHAL, EMBASE and Global Index Medicus. No restrictions were applied with regard to study design or language. Two reviewers independently screened the titles and abstracts, and extracted data. A search for gray literature was performed using the 'Google' search engine and specific databases (worldcat.org, greylit.org). In addition, the reference lists of included studies were assessed. OUTCOMES: The search of the electronic databases yielded 3769 citations. After review of the titles and abstracts, 283 studies were included. The full texts were reviewed and a further 199 articles were excluded. The gray literature search yielded 586 citations, most of which were excluded after screening the title, and the remaining documents were excluded after full-text assessment due to duplicate entries, not from LMIC, not relevant or no access to the full document. Eighty-four citations were included as part of the review and separated into regions. The majority of the studies were observational and qualitative studies. In general, ART services are available and described in several LMIC, ranging from advanced techniques in China to basic introduction of IVF in some African countries. Efforts to provide affordable ART treatments are described in feasibility studies and efficacy studies; however, most citations were of low to very low quality. We found no studies from LMIC reporting the implementation of low-cost ART that is effective, accessible and affordable to most of those in need of the services. WIDER IMPLICATIONS: The World Health Organization is in a unique position to provide much needed guidance for infertility management in LMIC. This review provides insight into the landscape of ART in LMIC in various regions worldwide, which will guide efforts to improve the availability, quality, accessibility and acceptability of biomedical infertility care, including ART in these countries.

Is subclinical hypothyroidism associated with lower live birth rates in women who have experienced unexplained recurrent miscarriage?

Thyroid disorders have been associated with recurrent miscarriage. Little evidence is available on the influence of subclinical hypothyroidism on live birth rates. In this cohort study, women who had experienced miscarriage and subclinical hypothyroidism (defined as thyroid-stimulating hormone >97.5th percentile mU/l with a normal thyroxine level) were investigated; the control group included women who had experienced recurrent miscarriage and normal thyroid function. Multivariable logistic regression was used to investigate the association of subclinical hypothyroidism. Data were available for 848 women; 20 (2.4%) had subclinical hypothyroidism; 818 women (96%) had euthyroidism; and 10 (1.2%) had overt hypothyroidism. The live birth rate was 45% in women with subclinical hypothyroidism and 52% in euthyroid women (OR 0.69, 95% CI 0.28 to 1.71). The ongoing pregnancy rate was 65% versus 69% (OR 0.82, 95% CI 0.32 to 2.10) and the miscarriage rate was 35% versus 28% (OR 1.43, 95% CI 0.56 to 3.68), respectively. No differences were found when thyroid stimulating hormone 2.5 mU/l was used as cut-off level to define subclinical hypothyroidism. In women with unexplained miscarriage, no differences were found in live birth, ongoing pregnancy and miscarriage rates between women with subclinical hypothyroidism and euthyroid women.

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.

The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies.

What is the recommended diagnostic work-up of female genital anomalies according to the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) system? The ESHRE/ESGE consensus for the diagnosis of female genital anomalies is presented. Accurate diagnosis of congenital anomalies still remains a clinical challenge due to the drawbacks of the previous classification systems and the non-systematic use of diagnostic methods with varying accuracy, with some of them quite inaccurate. Currently, a wide range of non-invasive diagnostic procedures are available, enriching the opportunity to accurately detect the anatomical status of the female genital tract, as well as a new objective and comprehensive classification system with well-described classes and sub-classes. The ESHRE/ESGE Congenital Uterine Anomalies (CONUTA) Working Group established an initiative with the goal of developing a consensus for the diagnosis of female genital anomalies. The CONUTA working group and imaging experts in the field have been appointed to run the project. The consensus is developed based on (1) evaluation of the currently available diagnostic methods and, more specifically, of their characteristics with the use of the experts panel consensus method and of their diagnostic accuracy performing a systematic review of evidence and (2) consensus for (a) the definition of where and how to measure uterine wall thickness and (b) the recommendations for the diagnostic work-up of female genital anomalies, based on the results of the previous evaluation procedure, with the use of the experts panel consensus method. Uterine wall thickness is defined as the distance between interostial line and external uterine profile at the midcoronal plane of the uterus; alternatively, if a coronal plane is not available, the mean anterior and posterior uterine wall thickness at the longitudinal plane could be used. Gynaecological examination and two-dimensional ultrasound (2D US) are recommended for the evaluation of asymptomatic women. Three-dimensional ultrasound (3D US) is recommended for the diagnosis of female genital anomalies in "symptomatic" patients belonging to high-risk groups for the presence of a female genital anomaly and in any asymptomatic woman suspected to have an anomaly from routine avaluation. Magnetic resonance imaging (MRI) and endoscopic evaluation are recommended for the sub-group of patients with suspected complex anomalies or in diagnostic dilemmas. Adolescents with symptoms suggestive for the presence of a female genital anomaly should be thoroughly evaluated with 2D US, 3D US, MRI and endoscopy. The various diagnostic methods should be used in a proper way and evaluated by experts to avoid mis-, over- and underdiagnosis. The role of a combined ultrasound examination and outpatient hysteroscopy should be prospectively evaluated. It is a challenge for further research, based on diagnosis, to objectively evaluate the clinical consequences related to various degrees of uterine deformity.

Transabdominal cerclage: preconceptual versus first trimester insertion.

OBJECTIVE: Transabdominal cerclage (TAC) is an effective intervention to prevent spontaneous mid-trimester loss and preterm delivery when a transvaginal cerclage has failed. A TAC may be inserted during the first trimester of pregnancy or preconceptually. The objective of this study was to determine whether or not preconceptual transabdominal cerclage (TAC) confers any benefit over first trimester TAC insertion in terms of associated surgical and pregnancy-related morbidity and subsequent pregnancy outcome. STUDY DESIGN: This was a retrospective and prospective cohort study of 161 consecutive women who underwent preconceptual (PC) TAC versus first trimester (T1) TAC over a 22-year period from January 1993 to January 2015 at a tertiary referral miscarriage clinic. Data was obtained from case note review retrospectively from 1993 to 2006 and prospectively between 2006 and 2015. Inclusion criteria comprised a history of at least one previous spontaneous mid-trimester loss coupled with at least one failed transvaginal cerclage and screening for antiphospholipid syndrome and bacterial vaginosis. Of 144 patients who conceived, 121 had complete pregnancy outcomes; 62 in the preconceptual group and 59 in the first trimester group. Both groups had similar previous pregnancy losses and previous transvaginal cerclage history. RESULTS: Successful pregnancies >24 weeks occurred in 97% of PC TACs compared to 93% in the T1 group. Furthermore, a successful pregnancy >34 weeks occurred in 90% (56/62) in the PC group compared to 74% (44/59) in the T1 group (OR 3.18; CI 1.14-8.8). Significantly fewer patients needed emergency caesarean section for preterm delivery in the PC group (7/62 (12%) versus 21/59 (36%); OR 4.34; CI 1.68-11.32). All 6 failures before 24 weeks gestation (T1=4, PC=2) were associated with antiphospholipid syndrome or bacterial vaginosis. In the T1 group 3/65 (5%) of patients suffered serious surgical complications and haemorrhage >500mls occurred in 32/65(50%) of cases whereas no surgical complications occurred in the PC group. CONCLUSIONS: Preconceptual TAC is more successful in preventing repeat spontaneous mid-trimester loss and preterm labour, and is associated with less surgical and pregnancy-related morbidity compared to first trimester TAC insertion.

The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies.

STUDY QUESTION: What is the recommended diagnostic work-up of female genital anomalies according to the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) system? SUMMARY ANSWER: The ESHRE/ESGE consensus for the diagnosis of female genital anomalies is presented. WHAT IS KNOWN ALREADY: Accurate diagnosis of congenital anomalies still remains a clinical challenge because of the drawbacks of the previous classification systems and the non-systematic use of diagnostic methods with varying accuracy, some of them quite inaccurate. Currently, a wide range of non-invasive diagnostic procedures are available enriching the opportunity to accurately detect the anatomical status of the female genital tract, as well as a new objective and comprehensive classification system with well-described classes and sub-classes. STUDY DESIGN, SIZE, DURATION: The ESHRE/ESGE CONgenital UTerine Anomalies (CONUTA) Working Group established an initiative with the goal of developing a consensus for the diagnosis of female genital anomalies. The CONUTA working group and imaging experts in the field have been appointed to run the project. PARTICIPANTS/MATERIALS, SETTING, METHODS: The consensus is developed based on: (i) evaluation of the currently available diagnostic methods and, more specifically, of their characteristics with the use of the experts panel consensus method and of their diagnostic accuracy by performing a systematic review of evidence and (ii) consensus for the definition of where and how to measure uterine wall thickness and the recommendations for the diagnostic work-up of female genital anomalies, based on the results of the previous evaluation procedure, with the use of the experts panel consensus method. MAIN RESULTS AND THE ROLE OF CHANCE: Uterine wall thickness is defined as the distance between the interostial line and external uterine profile at the midcoronal plane of the uterus; alternatively, if a coronal plane is not available, the mean anterior and posterior uterine wall thickness at the longitudinal plane could be used. Gynecological examination and two-dimensional ultrasound (2D US) are recommended for the evaluation of asymptomatic women. Three-dimensional (3D) US is recommended for the diagnosis of female genital anomalies in 'symptomatic' patients belonging to high risk groups for the presence of a female genital anomaly and in any asymptomatic woman suspected to have an anomaly from routine evaluation. Magnetic resonance imaging (MRI) and endoscopic evaluation are recommended for the subgroup of patients with suspected complex anomalies or in diagnostic dilemmas. Adolescents with symptoms suggestive for the presence of a female genital anomaly should be thoroughly evaluated with 2D US, 3D US, MRI and endoscopically. LIMITATIONS, REASONS FOR CAUTION: The various diagnostic methods should always be used in the proper way and evaluated by experts to avoid mis-, over- and underdiagnosis. WIDER IMPLICATIONS OF THE FINDINGS: The role of a combined US examination and outpatient hysteroscopy should be prospectively evaluated. It is a challenge for further research, based on diagnosis, to objectively evaluate the clinical consequences related to various degrees of uterine deformity. STUDY FUNDING/COMPETING INTERESTS: None.

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.).

European view of subspecialty training on behalf of the European Society of Human Reproduction and Embryology (ESHRE).

Specialist training in reproductive medicine within Europe continues to evolve. Recent revisions, updates, and initiatives have helped to refine the core educational needs for the specialist trainee.

Mid-trimester pregnancy loss.

Mid-trimester pregnancy loss (MTL) occurs between 12 and 24 weeks' gestation. The true incidence of this pregnancy complication is unknown, because research into MTL in isolation is scarce, although the estimated incidence has been noted to be 2% to 3% of pregnancies. A comprehensive preconceptual screening protocol is recommended, because the cause for an MTL may be present in isolation or combined (dual pathology), and is often heterogeneous. Patients with a history of MTL are at an increased risk of future miscarriage and preterm delivery. This risk is increased further depending on the number of associative factors diagnosed.

Number and sequence of preceding miscarriages and maternal age for the prediction of antiphospholipid syndrome in women with recurrent miscarriage.

OBJECTIVE: To investigate the relationship between the number and sequence of preceding miscarriages and antiphospholipid syndrome (APS). DESIGN: Retrospective cohort study. SETTING: Recurrent miscarriage (RM) clinic. PATIENT(S): Women who attended the RM clinic from 1988 to 2006. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Number, type, and sequence of previous pregnancies were compared between women with APS and women with unexplained RM. RESULT(S): A total of 1,719 patients were included; 312 (18%) had APS, and 1,407 (82%) had unexplained RM. The mean maternal age (32.6 years) did not differ between women with and without APS. The median number of miscarriages was three in both groups. A total of 865 women (50%) had a history of at least one live birth, with no difference between the two groups. In both groups, 97% of the women had a history of consecutive miscarriages. CONCLUSION(S): The number of preceding miscarriage, type and sequence of previous pregnancies, and maternal age were not associated with APS in women with RM. There is no increased diagnostic yield for APS after three miscarriages rather than after two miscarriages and no increased diagnostic yield for APS after consecutive miscarriages rather than after nonconsecutive miscarriages. Therefore, APS testing should be considered for all women with two or more miscarriages.

Recurrent miscarriage and thrombophilia: an update.

PURPOSE OF REVIEW: Acquired and inherited thrombophilia is an important research avenue in the recurrent miscarriage field. The optimum treatment for patients with recurrent miscarriage and a confirmed thrombophilia remains a contentious issue. We aim to appraise and explore the latest research in the field of thrombophilia and recurrent miscarriage in this review. RECENT FINDINGS: Antiphospholipid syndrome (APS) is the only proven thrombophilia that is associated with adverse pregnancy outcomes. Research involving inherited thrombophilia and recurrent miscarriage is limited to small observational studies with small and heterogeneous populations. Aspirin and heparin therapy are frequently prescribed for APS, yet there is no robust evidence for the most efficacious regime. The combination of inherited hypercoagulability and environmental factors in association with recurrent miscarriage has recently been explored as an aid to identify high-risk individuals. SUMMARY: The cause of recurrent miscarriage is multifactorial and appropriate treatment continues to be a challenge. Laboratory tests need to be standardized and well designed multicentre research trials are essential to expand on the current knowledge base with the aim to produce strong evidence-based medicine.

Thrombophilia and early pregnancy loss.

Early pregnancy loss is the most common pregnancy complication. About 15% of pregnancies result in pregnancy loss and 1% of women experience recurrent miscarriage (more than three consecutive miscarriages). The influence of thrombophilia in pregnancy is a popular research topic in recurrent miscarriage. Both acquired and inherited thrombophilia are associated with a risk of pregnancy failure. Antiphospholipid syndrome is the only thrombophilia known to have a direct adverse effect on pregnancy. Historically, clinical research studying thrombophilia treatment in recurrent miscarriage has been of limited value owing to small participant numbers, poor study design and heterogeneity. The debate on the efficacy of aspirin and heparin has advanced with recently published randomised-controlled trials. Multi-centre collaboration is required to ascertain the effect of thrombophilia on early pregnancy loss and to establish an evidence-based treatment protocol.

Screening and treatment for heritable thrombophilia in pregnancy failure: inconsistencies among UK early pregnancy units.

The significance of heritable thrombophilia in pregnancy failure is controversial. We surveyed all UK Early Pregnancy Units and 70% responded. The majority test routinely for heritable thrombophilias; 80%, 76% and 88% undertook at least one screening test in late miscarriage, recurrent miscarriage and placental abruption, respectively. The range of thrombophilias sought is inconsistent: testing for proteins C and S deficiency and F5 R506Q (factor V Leiden) is most prevalent. Detection of heritable thrombophilia frequently leads to administration of antithrombotics in subsequent pregnancies. Thus, thrombophilia testing and use of antithrombotics are widespread in the UK despite controversies regarding the role of heritable thrombophilia in the pathogenesis of pregnancy complications, and the lack of robust evidence for the efficacy of antithrombotic therapy.

Genetic polymorphisms on the factor V gene in women with recurrent miscarriage and acquired APCR.

BACKGROUND: Recurrent miscarriage (RM) has been associated with the thrombophilia, activated protein C resistance (APCR). The factor V Leiden mutation located on the B domain of the factor V gene, causes 95% of APCR and since the B domain is pivotal to APCR, it seemed plausible that other mutations or polymorphisms affecting this active domain may instigate acquired APCR. The objective of this study was to determine whether other polymorphisms exist on the parts of the gene encoding the B domain of the factor V in women with acquired APCR and RM. METHODS: There were 51 women with RM and acquired APCR, 24 parous women (with no history of miscarriage and at least one normal full-term delivery) and 15 women with a history of idiopathic RM, who formed the study and two control groups, respectively. Six exons of the B domain of the factor V gene were intensely analysed using polymerase chain reactions, single-strand conformation polymorphism, genetic sequencing and restriction enzyme digestion analysis to identify single-nucleotide polymorphisms (SNPs). RESULTS: A significantly increased frequency of some SNPs on the factor V gene were observed in the women with acquired APCR and RM when compared with the control groups. CONCLUSIONS: The presence of some of these SNPs may predispose these women to acquired APCR and RM.

Different types of recurrent miscarriage are associated with varying patterns of adhesion molecule expression in endometrium.

This study investigated the hypothesis that different types of recurrent miscarriage history are associated with different markers of endometrial receptivity. A secondary objective was to compare the distribution in endometrial epithelium of a group of cell surface components with roles in cell adhesion. Of 54 women who had an implantation window endometrial biopsy, 17 had idiopathic recurrent fetal loss, 17 had idiopathic recurrent loss of empty gestation sacs, 10 had recurrent implantation failure and 10 had two or more normal pregnancies. Immunohistochemistry and HSCORE was used with frozen sections for integrins (alpha1beta1, alpha4beta1, alpha(v)beta3), and MUC1 (BC2) and paraffin sections for osteopontin and MUC1 (BC3). Epithelial beta1 integrins were located primarily in the basolateral membrane compartment. Consistently greater expression of alpha4beta1, alpha1beta1 and alpha(v)beta3 was seen in the luminal epithelium and greater expression of alpha4beta1 and alpha1beta1 in the glandular epithelium of women with recurrent fetal loss when compared with those with recurrent loss of empty gestation sacs. There were no significant differences in the expression of osteopontin or MUC1 between groups. Different endometrial integrin distribution was found in women suffering different types of recurrent pregnancy loss. It is postulated that impairment of the implantation barrier contributes to recurrent fetal loss.

Uterine natural killer cells, implantation failure and recurrent miscarriage.

Uterine natural killer (uNK) cells are the most abundant leukocytes in preimplantation endometrium and early pregnancy decidua. Maternal uNK cells are adjacent to, and have the ability to interact directly with, fetal trophoblasts. uNK cells can secrete an array of cytokines that are important in angiogenesis and thus placental development and the establishment of pregnancy. Increased numbers of uNK cells have been associated with reproductive failure. The number of preimplantation uNK cells has been reduced with prednisolone. However, despite these exciting advances in understanding of the uNK cells, considerably more work needs to be done to establish a specific role for uNK cells and to use uNK cells as a test of malfunctioning endometrium and the basis for future treatment for reproductive failure.

Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage.

Recurrent miscarriage (RM; > or =3 consecutive early pregnancy losses) affects around 1% of fertile couples. Parental chromosomal anomalies, maternal thrombophilic disorders and structural uterine anomalies have been directly associated with recurrent miscarriage; however, in the vast majority of cases the pathophysiology remains unknown. We have updated the ESHRE Special Interest Group for Early Pregnancy (SIGEP) protocol for the investigation and medical management of RM. Based on the data of recently published large randomized controlled trials (RCTs) and meta-analyses, we recommend that basic investigations of a couple presenting with recurrent miscarriage should include obstetric and family history, age, BMI and exposure to toxins, full blood count, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), parental karyotype, pelvic ultrasound and/or hysterosalpingogram. Other investigations should be limited to particular cases and/or used within research programmes. Tender loving care and health advice are the only interventions that do not require more RCTs. All other proposed therapies, which require more investigations, are of no proven benefit or are associated with more harm than good.

Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage.

OBJECTIVE: To test the hypothesis that high numbers of uterine natural killer (uNK) cells in the endometrium of women with recurrent miscarriage (RM) could be reduced with prednisolone. DESIGN: A before and after study. SETTING: A tertiary referral teaching hospital. PATIENT(S): Eighty-five women with idiopathic RM recruited from all over the UK and 18 women attending for sterilization (controls). INTERVENTION(S): An endometrial sample was taken on day 21 +/- 2 of the menstrual cycle. Immunohistochemistry was used to identify uNK (CD56+, CD16-, CD3-). Twenty-nine women with RM and >5% uNK agreed to take 20 mg oral prednisolone daily from day 1 to 21 of their menstrual cycle, when a second biopsy was obtained and analyzed. MAIN OUTCOME MEASURE(S): The percentage of stromal cells that were uNK. The normal range was defined using control samples as <5%. RESULT(S): Women with RM had significantly more uNK than the controls (P=.008). Prednisolone treatment significantly reduced the number of CD56 cells in the endometrium, from a median of 14% (before) to 9% (after) (P=.0004). CONCLUSION(S): We have demonstrated that high numbers of uNK in preimplantation endometrium of women with recurrent miscarriage can be reduced with administration of prednisolone.