Improving Miscarriage Prevention Research: a survey exploring the expectations of service users and stakeholders (IMPRESS) - a study protocol for a UK-based survey.

INTRODUCTION: Interventional clinical trials in recurrent miscarriage use varying expected effect sizes to inform their sample size calculations. Often these are not informed by what stakeholders consider a meaningful treatment effect. Adaptive trial designs may integrate stakeholder views on trial success and futility but the criteria to inform this is lacking. This study aims to understand relevant stakeholder views of what is considered a worthwhile treatment effect for miscarriage prevention interventions and what is acceptable stopping criteria in miscarriage clinical trials. METHODS AND ANALYSIS: The study is designed as a cross-sectional online anonymous survey. The survey presents different scenarios to respondents relating to varying target differences and probability thresholds and explores success and futility criteria for clinical trials. The survey was developed with personal and public involvement (PPI) through focus groups and a PPI partner. Eligible participants will be those with a personal history of miscarriage, including partners, and healthcare professionals who manage patients who experience a miscarriage. Convenience, snowball and purposive sampling techniques will be employed to invite eligible participants to complete the survey. The survey will be accepting responses for an initial 2-week pilot to check validity, prior to being open for a further 12 weeks. Descriptive analyses and linear regression analyses will synthesise the survey results. ETHICS AND DISSEMINATION: Ethical approval was obtained from the NHS Research Ethics Committee North West-Greater Manchester East (23/NW/0322) on 30 January 2024. Informed consent will be obtained prior to survey completion. No personal identifying information will be collected. The results will be published in a relevant scientific journal and communicated through our institutional website.

Lessons learned from bovine subclinical endometritis: A systematic review exploring its potential relevance to chronic endometritis in women.

Chronic endometritis (CE) in humans is asymptomatic inflammation of the endometrium, associated with poor reproductive outcomes. Similarly asymptomatic endometrial inflammation in cows, termed subclinical endometritis (SCE), is associated with adverse reproductive outcomes. While the pathophysiology and treatment options for CE in humans remains poorly defined, the financial implications of SCE in dairy cows mean it has been intensively researched. We performed a systematic review with an emergent theme thematic analysis of studies of SCE in cows, to determine potential areas of interest in human CE research. A literature search for studies of subclinical endometritis in cows published between 1990 and November 2021 was performed across Embase, Medline, Scopus and CINAHL. Studies of symptomatic or clinical endometritis were excluded. Thematic analysis across two broad themes were explored: diagnostic methods and pathophysiology of SCE. In total, 44 bovine studies were included. 12 studies reported on diagnostic methodology. The primary emergent theme was the use of cytology for the diagnosis of SCE. This method has a lower sensitivity than histopathology but is less invasive and more specific than alternative techniques of ultrasound, vaginoscopy, or metabolic markers. The subthemes related to pathophysiology were identified as type of endometritis, metabolic stress, artificial insemination, infective causes, and altered cellular pathways. Despite the lack of symptoms, cellular pathways of inflammation including NFkB, MAPK, and inflammasomes were found to be activated. The key themes related to the diagnosis and pathophysiology of SCE in cows identified in this systematic review highlight potential areas for future research into human CE.

COVID Recovery Laparoscopic Simulation Program for Gynecological Registrars-Trainee Perceptions of Regional Model.

STUDY OBJECTIVE: The acquisition of gynecological operating skills can be challenging for trainees given the conflicting demands of clinical work. Alternative models of surgical skill training such as laparoscopic simulation is, therefore, required. This study demonstrates the development of a regional gynecological surgery laparoscopic simulation program and trainee perceptions of such an approach. DESIGN: An intervention-based cohort study. SETTING: A regional model based in West Midlands training region. PATIENTS/PARTICIPANTS: Responses from 64 trainees in the training region who participated in this regional program were included. INTERVENTIONS: A 3-stream curriculum was developed to deliver key training outcomes as required by the Royal College of Obstetricians and Gynaecologists (RCOG) core curriculum as a component of a COVID Recovery Program. Courses were held in 7 teaching hospitals. Courses consisted of both theory and practical teaching. MEASUREMENTS: A structured feedback tool was used to collect trainee perceptions of the program. Trainee satisfaction was measured on the Likert scale of 1 to 3. A qualitative thematic analysis was conducted with rank-order analysis of coded free-text responses. MAIN RESULTS: Overall, the majority of trainees 92% (n = 58/64) were very satisfied with the course. Rank-order analysis demonstrated hands-on-practice to be the key perceived benefit of laparoscopic simulation among basic and intermediate trainees, while feedback on procedural skills was felt most useful among advanced trainees. CONCLUSION: A regional approach to laparoscopic simulation training is both achievable and acceptable. Trainee perceptions of usefulness are altered by seniority and experience. This should be accounted for in the development of laparoscopic simulation programs.

The endometrial microbiota and early pregnancy loss.

The human endometrium is a dynamic entity that plays a pivotal role in mediating the complex interplay between the mother and developing embryo. Endometrial disruption can lead to pregnancy loss, impacting both maternal physical and psychological health. Recent research suggests that the endometrial microbiota may play a role in this, although the exact mechanisms are still being explored, aided by recent technological advancements and our growing understanding of host immune responses. Suboptimal or dysbiotic vaginal microbiota, characterized by increased microbial diversity and reduced Lactobacillus dominance, has been associated with various adverse reproductive events, including miscarriage. However, the mechanisms linking the lower reproductive tract microbiota with pregnancy loss remain unclear. Recent observational studies implicate a potential microbial continuum between the vaginal and endometrial niche in patients with pregnancy loss; however, transcervical sampling of the low biomass endometrium is highly prone to cross-contamination, which is often not controlled for. In this review, we explore emerging evidence supporting the theory that a dysbiotic endometrial microbiota may modulate key inflammatory pathways required for successful embryo implantation and pregnancy development. We also highlight that a greater understanding of the endometrial microbiota, its relationship with the local endometrial microenvironment, and potential interventions remain a focus for future research.

Routine use of cell salvage during cesarean section: A practice evaluation.

INTRODUCTION: Intraoperative cell salvage is a well-documented alternative to donor blood transfusion given the scarcity of donor blood pools and the incumbent risk of allogenic blood transfusion. Its use in obstetrics has been limited by concern over fetal alloimmunization due to the risk of fetomaternal hemorrhage. However, there are a paucity of studies reporting on outcome. The aim of this study was to report on a four-year experience of routine use of intraoperative cell salvage and the impact on subsequent pregnancy outcomes. MATERIAL AND METHODS: This was a tertiary center retrospective service evaluation cohort study and included all women undergoing cesarean section between December 2014 and November 2018 in a tertiary obstetric unit, identifying women who had reinfusion of intraoperative cell salvage. Data regarding index pregnancy as well as subsequent pregnancies at the hospital were extracted from hospital electronic records. Subsequent pregnancy outcome and maternal antibody status in that pregnancy were collected up until November 2022. RESULTS: During the study period, 6656 cesarean sections were performed, with 436 (6.6%) receiving reinfusion of salvaged blood. The mean volume of reinfused blood was 396 mL. A total of 49 (0.7%) women received donor blood transfusion. Of those who received reinfusion of salvaged blood, 79 (18.1%) women had subsequent pregnancies over the eight-year follow-up period. There was one case (0.23%) of fetal cell alloimmunization demonstrated by the presence of anti-D antibodies on the subsequent pregnancy booking bloods. CONCLUSIONS: Routine intraoperative cell salvage may be used to reduce the need for blood transfusion during cesarean section. The risk of fetal cell alloimmunization in a future pregnancy following reinfusion of intraoperative cell salvage is one in 436. Given an apparent small risk of fetal cell alloimmunization, further work is required to establish the safety profile of intraoperative cell salvage in pregnancy.

Preconceptual administration of doxycycline in women with recurrent miscarriage and chronic endometritis: protocol for the Chronic Endometritis and Recurrent Miscarriage (CERM) trial, a multicentre, double-blind, placebo-controlled, adaptive randomised trial with an embedded translational substudy.

INTRODUCTION: Recurrent miscarriage is a common condition with a substantial associated morbidity. A hypothesised cause of recurrent miscarriage is chronic endometritis (CE). The aetiology of CE remains uncertain. An association between CE and recurrent miscarriage has been shown. This study will aim to determine if preconceptual administration of doxycycline, in women with recurrent miscarriages, and CE, reduces first trimester miscarriages, increasing live births. METHODS AND ANALYSIS: Chronic Endometritis and Recurrent Miscarriage is a multicentre, double-blind adaptive trial with an embedded translational substudy. Women with a history of two or more consecutive first trimester losses with evidence of CE on endometrial biopsy (defined as ≥5 CD138 positive cells per 10 mm2) will be randomised to oral doxycycline or placebo for 14 days. A subset will be recruited to a mechanistic substudy in which microbial swabs and preintervention/postintervention endometrial samples will be collected. Up to 3062 women recruited from 29 National Health Service (NHS) hospital sites across the UK are expected to be screened with up to 1500 women randomised in a 1:1 ratio. Women with a negative endometrial biopsy (defined as <5 CD138 positive cells per 10 mm2) will also be followed up to test validity of the tool. The primary outcome is live births plus pregnancies ≥24 + 0 weeks gestation at the end of the trial, in the first or subsequent pregnancy. Secondary clinical outcomes will also be assessed. Exploratory outcomes will assess the effect of doxycycline treatment on the endometrial microbiota, the differentiation capacity of the endometrium and the senescent profile of the endometrium with CE. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the NHS Research Ethics Committee Northwest-Haydock (19/NW/0462). Written informed consent will be gained from all participants. The results will be published in an open-access peer-reviewed journal and reported in the National Institute for Health and Care Research journals library. TRIAL REGISTRATION NUMBER: ISRCTN23947730.

An intrapartum cervical buttonhole tear: A case report and review of rare tear pathogenesis.

Genital tract trauma and obstetric anal sphincter injuries are known complications of normal vaginal and assisted vaginal delivery. Cervical tears are an uncommon complication that can lead to significant postpartum haemorrhage and may have implications for future pregnancies. Careful evaluation of the genital tract, including the cervix, along with adequate resuscitation are essential to reduce maternal morbidity and mortality. This is a case report of a 36-year-old primigravida woman at 41 + 6 weeks of gestation with delay in the second stage requiring Neville Barnes forceps delivery. She then went on to have a major postpartum haemorrhage, initially thought to be a result of uterine atony. However, inadequate response to uterotonics led to identification of a cervical buttonhole tear with an intact external os. She required repair under general anaesthesia. A rigid sigmoidoscope was utilised to ensure cervical canal patency during the repair. Previous reports have described annular cervical tears, thought to occur from the extension of a cervical buttonhole tear, but to the best of our knowledge the latter has not previously been reported. The case demonstrates the importance of awareness of such tears and proposes a novel technique for repair with the use of a rigid sigmoidoscope.

Fertility preservation, its effectiveness and its impact on disease status in pre-menopausal women with breast cancer: A systematic review and meta-analysis.

INTRODUCTION: Preservation of reproductive function is a key concern for many premenopausal women with breast cancer, given the known gonadotoxic effects of treatments. The present systematic review aimed to investigate the effectiveness and safety of fertility preservation strategies in pre-menopausal women with breast cancer. METHODS: Primary research assessing fertility preservation strategies of any type was identified. Markers of preservation of fertility including return of menstrual function, clinical pregnancy rates and live birth rates were selected as main outcome measures. An additional analysis of safety data was also performed. RESULTS: Fertility preservation interventions were overall associated with higher fertility outcomes: with a pooled odds ratio 4.14 (95% CI 3.59-4.77) for any kind of fertility preservation intervention. This was seen both for return of menstruation and for clinical pregnancy rate, but not for live birth rates. Fertility preservation was associated with a reduced rate of disease recurrence (OR 0.63 (95% CI 0.49-0.81)), while there was no significant difference in disease free survival (OR 0.88 (95% CI 0.74-1.05)) or in overall survival (OR 0.9 (95% CI 0.74-1.10)) between the fertility preservation group and those who had not undergone fertility preservation. CONCLUSION: Fertility preservation is both effective in preserving reproductive function, and safe with regard to disease recurrence, disease free survival and overall survival in premenopausal women with breast cancer.

EndoTime: non-categorical timing estimates for luteal endometrium.

STUDY QUESTION: Can the accuracy of timing of luteal phase endometrial biopsies based on urinary ovulation testing be improved by measuring the expression of a small number of genes and a continuous, non-categorical modelling approach? SUMMARY ANSWER: Measuring the expression levels of six genes (IL2RB, IGFBP1, CXCL14, DPP4, GPX3 and SLC15A2) is sufficient to obtain substantially more accurate timing estimates and to assess the reliability of timing estimates for each sample. WHAT IS KNOWN ALREADY: Commercially available endometrial timing approaches based on gene expression require large gene sets and use a categorical approach that classifies samples as pre-receptive, receptive or post-receptive. STUDY DESIGN, SIZE, DURATION: Gene expression was measured by RTq-PCR in different sample sets, comprising a total of 664 endometrial biopsies obtained 4-12 days after a self-reported positive home ovulation test. A further 36 endometrial samples were profiled by RTq-PCR as well as RNA-sequencing. PARTICIPANTS/MATERIALS, SETTING, METHODS: A computational procedure, named 'EndoTime', was established that models the temporal profile of each gene and estimates the timing of each sample. Iterating these steps, temporal profiles are gradually refined as sample timings are being updated, and confidence in timing estimates is increased. After convergence, the method reports updated timing estimates for each sample while preserving the overall distribution of time points. MAIN RESULTS AND THE ROLE OF CHANCE: The Wilcoxon rank-sum test was used to confirm that ordering samples by EndoTime estimates yields sharper temporal expression profiles for held-out genes (not used when determining sample timings) than ordering the same expression values by patient-reported times (GPX3: P < 0.005; CXCL14: P < 2.7e-6; DPP4: P < 3.7e-13). Pearson correlation between EndoTime estimates for the same sample set but based on RTq-PCR or RNA-sequencing data showed a high degree of congruency between the two (P = 8.6e-10, R2 = 0.687). Estimated timings did not differ significantly between control subjects and patients with recurrent pregnancy loss or recurrent implantation failure (P > 0.05). LARGE SCALE DATA: The RTq-PCR data files are available via the GitHub repository for the EndoTime software at https://github.com/AE-Mitchell/EndoTime, as is the code used for pre-processing of RTq-PCR data. The RNA-sequencing data are available on GEO (accession GSE180485). LIMITATIONS, REASONS FOR CAUTION: Timing estimates are informed by glandular gene expression and will only represent the temporal state of other endometrial cell types if in synchrony with the epithelium. Methods that estimate the day of ovulation are still required as these data are essential inputs in our method. Our approach, in its current iteration, performs batch correction such that larger sample batches impart greater accuracy to timing estimations. In theory, our method requires endometrial samples obtained at different days in the luteal phase. In practice, however, this is not a concern as timings based on urinary ovulation testing are associated with a sufficient level of noise to ensure that a variety of time points will be sampled. WIDER IMPLICATIONS OF THE FINDINGS: Our method is the first to assay the temporal state of luteal-phase endometrial samples on a continuous domain. It is freely available with fully shared data and open-source software. EndoTime enables accurate temporal profiling of any gene in luteal endometrial samples for a wide range of research applications and, potentially, clinical use. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by a Wellcome Trust Investigator Award (Grant/Award Number: 212233/Z/18/Z) and the Tommy's National Miscarriage Research Centre. None of the authors have any competing interests. J.L. was funded by the Biotechnology and Biological Sciences Research Council (UK) through the Midlands Integrative Biology Training Partnership (MIBTP, BB/M01116X/1).

Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids.

Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterized endometrial assembloids, consisting of gland-like organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by eliminating the emergence of senescent decidual cells. In co-culture experiments, accelerated decidualization resulted in entrapment of collapsed human blastocysts in a robust, static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Our findings suggest that decidual senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.

At the beginning of a human pregnancy, the embryo implants into the uterus lining, known as the endometrium. At this point, the endometrium transforms into a new tissue that helps the placenta to form. Problems in this transformation process are linked to pregnancy disorders, many of which can lead to implantation failure (the embryo fails to invade the endometrium altogether) or recurrent miscarriages (the embryo implants successfully, but the interface between the placenta and the endometrium subsequently breaks down). Studying the implantation of human embryos directly is difficult due to ethical and technical barriers, and animals do not perfectly mimic the human process, making it challenging to determine the causes of pregnancy disorders. However, it is likely that a form of cellular arrest called senescence, in which cells stop dividing but remain metabolically active, plays a role. Indeed, excessive senescence in the cells that make up the endometrium is associated with recurrent miscarriage, while a lack of senescence is associated with implantation failure. To study this process, Rawlings et al. developed a new laboratory model of the human endometrium by assembling two of the main cell types found in the tissue into a three-dimensional structure. When treated with hormones, these 'assembloids' successfully mimic the activity of genes in the cells of the endometrium during implantation. Rawlings et al. then exposed the assembloids to the drug dasatinib, which targets and eliminates senescent cells. This experiment showed that assembloids become very robust and static when devoid of senescent cells. Rawlings et al. then studied the interaction between embryos and assembloids using time-lapse imaging. In the absence of dasatinib treatment, cells in the assembloid migrated towards the embryo as it expanded, a process required for implantation. However, when senescent cells were eliminated using dasatinib, this movement of cells towards the embryo stopped, and the embryo failed to expand, in a situation that mimicks implantation failure. The assembloid model of the endometrium may help scientists to study endometrial defects in the lab and test potential treatments. Further work will include other endometrial cell types in the assembloids, and could help increase the reliability of the model. However, any drug treatments identified using this model will need further research into their safety and effectiveness before they can be offered to patients.

Immunological Testing in Assisted Reproductive Technology.

Fetal implantation requires carefully orchestrated involvement of the maternal immune system. Aberrant function within implantation has been suggested as a cause of implantation failure. The emergence of immunological theories of miscarriage has led to immunological testing as an adjuvant treatment in assisted reproductive technology; however, it remains controversial, with mixed evidence both for immunological cause and the benefits of immunological testing. Literature on common methods of immunological testing within assisted reproductive technology is reviewed including those of peripheral and uterine natural killer cells, chronic endometritis, and T-helper cells cytokine ratio. There is little consensus in the evidence on immunological testing in the context of recurrent implantation failure. The field is limited by a lack of uniformity in approach to testing and heterogeneity of the pathophysiological cause. Nevertheless, the maternal immune system is heavily involved in implantation and the new era of personalized medicine ensures that a more defined approach to immunological testing will be achieved.

Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss.

Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5-18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3-11·4%), two miscarriages is 1·9% (1·8-2·1%), and three or more miscarriages is 0·7% (0·5-0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.

Characterization of highly proliferative decidual precursor cells during the window of implantation in human endometrium.

Pregnancy depends on the wholesale transformation of the endometrium, a process driven by differentiation of endometrial stromal cells (EnSC) into specialist decidual cells. Upon embryo implantation, decidual cells impart the tissue plasticity needed to accommodate a rapidly growing conceptus and invading placenta, although the underlying mechanisms are unclear. Here we characterize a discrete population of highly proliferative mesenchymal cells (hPMC) in midluteal human endometrium, coinciding with the window of embryo implantation. Single-cell transcriptomics demonstrated that hPMC express genes involved in chemotaxis and vascular transmigration. Although distinct from resident EnSC, hPMC also express genes encoding pivotal decidual transcription factors and markers, most prominently prolactin. We further show that hPMC are enriched around spiral arterioles, scattered throughout the stroma, and occasionally present in glandular and luminal epithelium. The abundance of hPMC correlated with the in vitro colony-forming unit activity of midluteal endometrium and, conversely, clonogenic cells in culture express a gene signature partially conserved in hPMC. Cross-referencing of single-cell RNA-sequencing data sets indicated that hPMC differentiate into a recently discovered decidual subpopulation in early pregnancy. Finally, we demonstrate that recurrent pregnancy loss is associated with hPMC depletion. Collectively, our findings characterize midluteal hPMC as novel decidual precursors that are likely derived from circulating bone marrow-derived mesenchymal stem/stromal cells and integral to decidual plasticity in pregnancy.

The challenges of trials in reproductive medicine: can a Bayesian approach help?

Reproductive medicine is imbued with debates over the results of key trials. This has resulted in heterogeneity in clinical practice and a disconnect between researchers and the patient group they aim to treat. The criticisms of trials originate from the nature of reproductive health conditions and limitations imposed in designing trials to assess effect in a patient group with heterogenous pathologies leading to the same condition. This leads to challenges in balancing the difficulties of recruiting an enriched patient cohort versus the dilutionary effect and need for subgroup analysis from wider recruitment. These challenges manifest as a failure to achieve traditional statistical significance. One potential solution to overcoming these inherent challenges is that of a Bayesian statistical approach. Using examples from the literature we demonstrate the benefits of a Bayesian approach. Taking published data and using a flat prior (no background information used), a Bayesian re-analysis of the PRISM and EAGeR trials is presented. This demonstrated a 94.7% chance of progesterone and a 95.3% probability of aspirin preventing miscarriage, in contrast to the original trial conclusions. These highlight the role a Bayesian approach can play in overcoming the challenges of trials within reproductive health.

Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window.

During the implantation window, the endometrium becomes poised to transition to a pregnant state, a process driven by differentiation of stromal cells into decidual cells (DC). Perturbations in this process, termed decidualization, leads to breakdown of the feto-maternal interface and miscarriage, but the underlying mechanisms are poorly understood. Here, we reconstructed the decidual pathway at single-cell level in vitro and demonstrate that stromal cells first mount an acute stress response before emerging as DC or senescent DC (snDC). In the absence of immune cell-mediated clearance of snDC, secondary senescence transforms DC into progesterone-resistant cells that abundantly express extracellular matrix remodelling factors. Additional single-cell analysis of midluteal endometrium identified DIO2 and SCARA5 as marker genes of a diverging decidual response in vivo. Finally, we report a conspicuous link between a pro-senescent decidual response in peri-implantation endometrium and recurrent pregnancy loss, suggesting that pre-pregnancy screening and intervention may reduce the burden of miscarriage.